Publishing type：Research paper (scientific journal)  

Objective: Asymptomatic craniocervical junction arteriovenous fistulas (CCJ AVFs) are rare and, thus, a consensus has not yet been reached regarding the indication of surgical interventions. This retrospective multicenter cohort study investigated the risks associated with surgery for asymptomatic CCJ AVFs and discussed the indication of surgical interventions. Methods: Using data from 111 consecutive patients with CCJ AVFs registered with the Neurospinal Society of Japan between 2009 and 2019, we analyzed the treatment, complications, and outcomes of 18 patients with asymptomatic CCJ AVF. Results: The median age of the patient cohort was 68 years (37–80 years), and there were 11 males and 7 females. Diagnoses were 14 patients with dural AVF, one perimedullary AVF, one radicular AVF, one epidural AVF, and one bilateral dural and epidural AVF. Initial treatment included direct surgery in 12 patients, endovascular treatment in four, and conservative treatment in two. Among 16 patients, three complications (18.7%) occurred: spinal cord infarction associated with the surgical procedure, cerebral infarction associated with intraoperative angiography, and mortal medullary hemorrhage after endovascular treatment followed by open surgery. Complete occlusion was achieved in all 12 patients in the direct surgery group and in one out of four in the endovascular treatment group. Conclusions: Given the risk of serious complications associated with asymptomatic CCJ AVF and the fact that no case of asymptomatic CCJ AVF became symptomatic in this study, prophylactic surgery for asymptomatic CCJ AVF should be carefully considered.

DOI： 10.1016/j.wneu.2023.04.068

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Authorship：Last author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1186/s13287-023-03362-z

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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A 35-year-old female presented with headache, photophobia and developed sudden loss of vision after having undergone right-side ophthalmectomy and radiochemotherapy for retinoblastoma in infancy. A neoplastic lesion was found in the left middle cranial fossa and was surgically removed. The diagnosis was radiation-induced osteosarcoma with RB1 gene alteration. Although she received chemotherapy for the residual tumor, it progressed 17 months later. Maximal surgical resection with craniofacial reconstruction was required. We utilized two three-dimensional models for surgical planning. She was discharged without neurological deficits other than loss of light perception subsequent to left ophthalmectomy. In cases where retinoblastoma is treated with radiotherapy, long-term follow-up is necessary to monitor for radiation-induced tumor development.

DOI： 10.18926/AMO/64367

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BACKGROUND: Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. METHODS: Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 μl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups. RESULTS: SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05). CONCLUSIONS: This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

DOI： 10.1186/s13287-023-03236-4

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DOI： 10.31662/jmaj.2023-0006

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BACKGROUND: Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent- or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined. OBJECTIVE: To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats. METHODS: Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats underwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA administration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively. RESULTS: Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects. CONCLUSION: Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.

DOI： 10.1016/j.brs.2023.03.003

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Diffusely infiltrative midline gliomas are known to have a poor prognosis. The standard treatment for typical diffuse midline glioma in the pons is local radiotherapy as surgical resection is inappropriate. This case reports a brainstem glioma in which stereotactic biopsy and foramen magnum decompression were concomitantly performed to confirm the diagnosis and improve symptoms. A 23-year-old woman was referred to our department with a chief complaint of headache for six months. Magnetic resonance imaging (MRI) showed diffuse T2 hyperintense swelling of the brainstem with the pons as the main locus. Enlargement of the lateral ventricles was observed because of cerebrospinal fluid obstruction out of the posterior fossa. This was atypical for a diffuse midline glioma in terms of the longstanding slow progression of symptoms and patient age. Stereotactic biopsy was performed for diagnosis, and foramen magnum decompression (FMD) was concomitantly performed to treat the obstructive hydrocephalus. The histological diagnosis was astrocytoma, IDH-mutant. Post-surgery, the patient's symptoms were relieved, and she was discharged on the fifth day after surgery. The hydrocephalus was resolved, and the patient returned to normal life without any symptoms. The tumor size follow-up with MRI demonstrated no marked change for 12 months. Even though diffuse midline glioma is considered to have a poor prognosis, clinicians should contemplate if it is atypical. In atypical cases like the one described herein, surgical treatment may contribute to pathological diagnosis and symptom improvement.

DOI： 10.2176/jns-nmc.2022-0159

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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AIMS: SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. METHODS: We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. RESULTS: In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. CONCLUSION: SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

DOI： 10.1111/cns.13947

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We report a rare case of idiopathic spinal cord herniation (ISCH) with a history of cerebrospinal fluid (CSF) leakage. ISCH is a protrusion of the spinal cord through a dural defect. Thin constructive interference in steady-state (CISS) images clearly demonstrated the herniated cord in the present case. The myelopathy worsened and the patient underwent surgery for reduction of herniated spinal cord; the dural defect was filled by placing collagen matrix graft (DuraGen®) between the inner and outer dural layers. The patient's symptoms have improved without relapse for 8 months since surgery. This method may be a good surgical option for cases of spinal cord herniation.

DOI： 10.18926/AMO/64124

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OBJECTIVE: To assess the current management of primary spinal cord tumors (PSCTs) and determine whether and to what extent there are differences in surgical strategies for PSCTs. METHODS: The Neurospinal Society of Japan conducted a survey between April 1 and 30, 2021. Certified spine surgeons were requested for information on the frequency of surgeries in 2020 and the surgical strategies adopted for each PSCTs. The following tumor histologies were focused: schwannoma, meningioma, and cauda equina tumor as extramedullary tumors; and ependymoma, hemangioblastoma, astrocytoma, and cavernoma as intramedullary tumors. The participants were divided according to their response as follows: experts, who had experienced ≥ 100 surgeries for PSCTs, and nonexperts. RESULTS: Among 308 participants (63%), 35 (11%) were experts. The total number of PSCTs in 2020 was 802 of which 564 tumors were extramedullary and 223 were intramedullary. Schwannoma accounted for 53% of the extramedullary tumors, and ependymoma accounted for 39% of the intramedullary tumors. Surgical strategies significantly differed among both the experts and nonexperts groups. Some discrepancies in the adopted surgical strategies were observed between groups. Some of the nonexperts, and none of the experts, ruled out surgery for schwannomas (Eden type 4), astrocytomas, or cavernomas. Five nonexperts (2.2%), and none of the experts, resected the entire dura for meningiomas. CONCLUSION: A nationwide survey revealed that a sufficient consensus did not exist regarding surgical strategies for PSCTs. A disease-specific registry for PSCTs is necessary in academic societies.

DOI： 10.14245/ns.2244686.343

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Intensive care unit (ICU) survivors after traumatic brain injury (TBI) frequently have serious disabilities with subsequent difficulty in reintegration into society. We aimed to investigate outcomes for ICU survivors after moderate to severe TBI (msTBI) and to identify predictive factors of return home (RH) and return to work (RTW). This single-center retrospective cohort study was conducted on all trauma patients admitted to the emergency ICU of our hospital between 2013 and 2017. Of these patients, adult (age ≥ 18 years) msTBI patients with head Abbreviated Injury Scale ≥ 3 were extracted. We performed univariate/multivariate logistic regression analyses to explore the predictive factors of RH and RTW. Among a total of 146 ICU survivors after msTBI, 107 were included (median follow-up period: 26 months). The RH and RTW rates were 78% and 35%, respectively. Multivariate analyses revealed that the predictive factors of RH were age < 65 years (P < 0.001), HR < 76 bpm (P = 0.015), platelet count ≥ 19× 104/μL (P = 0.0037), D-dimer < 26 μg/mL (P = 0.034), and Glasgow Coma Scale (GCS) score > 8 (P = 0.0015). Similarly, the predictive factors of RTW were age < 65 years (P < 0.001) and GCS score > 8 (P = 0.0039). This study revealed that "age" and "GCS score on admission" affected RH and RTW for ICU survivors after msTBI.

DOI： 10.2176/jns-nmc.2022-0149

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BACKGROUND AND PURPOSE: The lateral spinal artery (LSA) perfuses the dorsolateral part of the spinal cord at the craniocervical junction (CCJ). We analyzed the angioarchitecture of the normal LSA and CCJ arteriovenous fistula (AVF). METHODS: The first study included 26 patients with a cerebral aneurysm of the posterior circulation. Using slab maximum intensity projection (MIP) images from three-dimensional rotational angiography (3D-RA) and contrast-enhanced cone-beam CT (CE-CBCT), we analyzed the origin of the LSA, its anastomosis with the posterior inferior cerebellar artery (PICA), the point where it reaches the spinal cord, and the visualized range. In the second study, we analyzed the angioarchitecture and treatment results of 7 CCJAVF lesions treated in our department between 2016 and 2021. RESULTS: We visualized the normal LSA for all patients. In 23 patients with an intradural origin PICA, all LSAs originated from the C1 or C2 radicular artery, and 8 patients had an anastomosis with the PICA. In three patients with a C1 level origin PICA, all LSAs originated from the PICA. All LSAs reached the dorsolateral part of the spinal cord. The mean visualized range of the LSA was 27.4 mm. The LSA was involved in five of seven CCJAVF lesions (71%). There was one lesion with a spinal infarction after LSA embolization. Other lesions were treated by direct interruption of the AVF, and the ASA and LSA were preserved. CONCLUSION: This is the first report that visualized the LSA's normal anatomy using slab MIP images from 3D-RA and CE-CBCT. Knowledge of LSA anatomy is critical to avoid complications during the treatment of CCJAVF.

DOI： 10.1007/s00062-022-01218-2

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PURPOSE: Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, a subset of PA patients shows unfavorable outcomes. In this study, we retrospectively reviewed PA patients and performed further molecular analysis, such as DNA methylation profiling, to identify prognostic factors. METHODS: We analyzed 29 histologically-confirmed PA patients from a single center from 2002 to 2021 and conducted integrated molecular analyses among elderly PA patients since age was an independent prognostic factor for poor outcomes. RESULTS: The median age at diagnosis was 14 years (range 3-82 years) and 4 patients (14%) were elderly (patients ≥ 60 years old). Age over 60 was associated with poor progression-free survival and overall survival. We performed DNA methylation analysis on 2 of the 4 elderly patients. Both cases were histologically diagnosed as PA, but DNA methylation profiling revealed one as high-grade astrocytoma with piloid features (all methylation class scores were below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score was over 0.5 in both v11b4 and v12.5), using the German Cancer Research Center methylation profiling classifiers and t-SNE analysis. CONCLUSIONS: Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, further molecular analysis and DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.

DOI： 10.1007/s11060-022-04131-3

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.11477/mf.1436204670

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Functional neurosurgery for epilepsy, movement disorders, and spasticity includes some device-based surgeries such as deep brain stimulation, subdural electrode placement, vagus nerve stimulation, and baclofen pump implantation. These surgeries have a higher risk of surgical site infection(SSI)than other general neurological surgeries. Furthermore, because device removal after infection can significantly impair patients'activities of daily living and quality of life, SSI in functional neurosurgery is a worrisome surgical complication. In this study, we conducted a mini-review of the risk of infection in each device-based surgery and described associated surgical procedures and preparations performed at our institution, with a focus on infection prevention.

DOI： 10.11477/mf.1436204662

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Cortical tubers are one of the typical intracranial manifestations of tuberous sclerosis complex (TSC). Multiple cortical tubers are easy to diagnose as TSC; however, a solitary cortical tuber without any other cutaneous or visceral organ manifestations can be confused with other conditions, particularly focal cortical dysplasia. We report a surgical case of refractory epilepsy caused by a solitary cortical tuber mimicking focal cortical dysplasia type II, and describe the radiological, electrophysiological, and histopathological findings of our case.

DOI： 10.18926/AMO/63742

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(公社)日本リハビリテーション医学会  

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A 3-year-old boy had difficulty sitting up and walking for several months. Magnetic resonance imaging (MRI) revealed an intradural tumor at the L3-4 level. The tumor was successfully resected by unilateral hemilaminectomy and diagnosed as dermoid cyst. The patient had an uneventful postoperative course without pain, and MRI found no recurrence after surgery. A small bone defect remained that might be favorably reconstructed with autologous and artificial bone. Hemilaminectomy allowed us to resect the cauda equina dermoid cyst with minimal invasiveness. Pediatric patients require follow-up as they are more likely to experience spinal deformity or instability after surgery.

DOI： 10.18926/AMO/63426

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Language：Japanese   Publisher：(一社)日本定位・機能神経外科学会  

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Early-onset isolated (DYT1) dystonia is one of the most common forms of primary dystonia in childhood, and deep brain stimulation of the globus pallidus internus (GPi-DBS) is a highly effective treatment for it. However, the effectiveness of GPi-DBS in monozygotic twins with DYT1 dystonia has never been reported globally. Here, we report the cases of monozygotic twins with DYT1 dystonia who were treated using GPi-DBS, and we include a literature review. The younger brother showed an abnormal gait, with external rotation of the right lower leg at 6 years old. The symptoms gradually became so severe that he had difficulty walking on his own at 9 years of age. Treatment with levodopa-carbidopa partially resolved his symptoms, but most of the symptoms remained. Meanwhile, the older brother developed dystonia in both upper limbs at 8 years of age, with gradual symptom progression. At 13 years of age, they were diagnosed with DYT1 dystonia. Bilateral GPi-DBS was performed in both patients at 16 years of age. Their symptoms remarkably improved after surgery. The Burke-Fahn-Marsden dystonia rating scale (BFMDRS) movement score was reduced from 52 to 2 points for the younger brother and from 35 to 1 point for the older brother. Even if monozygotic twins have the same genes, the onset and severity of symptoms might vary in accordance with differences in epigenomic profiles. However, GPi-DBS treatment was very effective for the two cases; thus, we should consider the surgical interventions for each patient.

DOI： 10.2176/jns-nmc.2022-0084

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In the management of patients with craniosynostosis, it is important to understand growth curve of the normal cranium. Although three-dimensional (3D) computed tomography (CT) images taken in thin slices are easily available nowadays, data on the growth curves of intracranial volume (ICV), cranial length, cranial width, and cranial height in the normal cranium are mainly based on older studies using radiography, and there are insufficient reports using CT images especially taken in thin slices. The purpose of this study was to establish growth curves in the normal cranium of Japanese children using thin-slice images. Cranial images of 106 subjects (57 males, 49 females; aged 0-83 months) without significant cranial abnormalities were retrospectively analyzed. Using thin-slice CT images, the ICV and two-dimensional parameters such as cranial length, cranial width, and cranial height were measured by iPlan, followed by generating growth curves and calculating cephalic index (CI). ICV calculated from thin-slice CT images was compared with that obtained by substituting two-dimensional parameters into Mackinnon formula. The ICV growth curves for males and females were similar in shape. As with the ICV, the two-dimensional parameters increased most rapidly in the first year after birth. There was no significant difference in CI between the sexes or among any age groups. ICV calculated from thin-slice 3D CT images was 60% of that obtained from Mackinnon formula. These data will enable us to compare these specific measurements in craniosynostosis patients directly with those of normal children, which will hopefully help in managing these patients.

DOI： 10.2176/nmc.oa.2021-0208

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Accurate diagnosis is important for lumbar degenerative diseases. Patients' history, neurological examination, and diagnostic imaging are the three pillars for accurate diagnosis. While collecting medical history, 5W1H of the symptoms should be considered. Muscle strength, pain and numbness, and deep tendon reflex are the basic parameters in the neurological examination. A combination of the results of each tool is needed to facilitate precise diagnosis. This should be followed by diagnostic imaging to confirm the diagnosis. We feel relieved when neurological examination and diagnostic imaging reveals congruent results. The symptoms of lumbar degenerative diseases are the results of[static factors: the stenosis of the canal/intervertebral foramen]×[dynamic factor: the instability]. The T2-weighted MRI images effectively reveal canal/intervertebral foramen stenosis. Short-T1 inversion recovery(STIR)of MRI reveals early fractures and inflammation of the spine. CT findings help to imagine the process of drilling and screw insertion. A whole spine X-ray is good to reveal spinal alignment. Roentogenkymography with anteflexion/retroflexion reveals the instability of the lumbar spine. Myelography is effective in knowing the cerebrospinal fluid flow in a standing position. Therefore, accurate diagnosis and careful treatment are needed to obtain the appropriate outcome for a prolonged period after spinal surgery.

DOI： 10.11477/mf.1436204510

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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OBJECTIVE: There have been no accurate surveillance data regarding the incidence rate of spinal arteriovenous shunts (SAVSs). Here, the authors investigate the epidemiology and clinical characteristics of SAVSs. METHODS: The authors conducted multicenter hospital-based surveillance as an inventory survey at 8 core hospitals in Okayama Prefecture between April 1, 2009, and March 31, 2019. Consecutive patients who lived in Okayama and were diagnosed with SAVSs on angiographic studies were enrolled. The clinical characteristics and the incidence rates of each form of SAVS and the differences between SAVSs at different spinal levels were analyzed. RESULTS: The authors identified a total of 45 patients with SAVSs, including 2 cases of spinal arteriovenous malformation, 5 cases of perimedullary arteriovenous fistula (AVF), 31 cases of spinal dural AVF (SDAVF), and 7 cases of spinal epidural AVF (SEAVF). The crude incidence rate was 0.234 per 100,000 person-years for all SAVSs including those at the craniocervical junction (CCJ) level. The incidence rate of SDAVF and SEAVF combined increased with advancing age in men only. In a comparative analysis between upper and lower spinal SDAVF/SEAVF, hemorrhage occurred in 7/14 cases (50%) at the CCJ/cervical level and in 0/24 cases (0%) at the thoracolumbar level (p = 0.0003). Venous congestion appeared in 1/14 cases (7%) at the CCJ/cervical level and in 23/24 cases (96%) at the thoracolumbar level (p < 0.0001). CONCLUSIONS: The authors reported detailed incidence rates of SAVSs in Japan. There were some differences in clinical characteristics of SAVSs in the upper spinal levels and those in the lower spinal levels.

DOI： 10.3171/2021.7.SPINE21233

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Parkinson's disease (PD) patients often suffer from spinal diseases requiring surgeries, although the risk of complications is high. There are few reports on outcomes after spinal surgery for PD patients with deep brain stimulation (DBS). The objective of this study was to explore the data on spinal surgery for PD patients with precedent DBS. We evaluated 24 consecutive PD patients with 28 spinal surgeries from 2007 to 2017 who received at least a 2-year follow-up. The characteristics and outcomes of PD patients after spinal surgery were compared to those of 156 non-PD patients with degenerative spinal diseases treated in 2013-2017. Then, the characteristics, outcomes, and spinal alignment of PD patients receiving DBS were analyzed in degenerative spinal/lumbar diseases. The mean age at the time of spinal surgery was 68 years. The Hoehn and Yahr score regarding PD was stage 1 for 8 patients, stage 2 for 2 patients, stage 3 for 8 patients, stage 4 for 10 patients, and stage 5 for 0 patient. The median preoperative L-DOPA equivalent daily dose was 410 mg. Thirteen patients (46%) received precedent subthalamic nucleus (STN) DBS. Lumbar lesions with pain were common, and operation and anesthesia times were long in PD patients. Pain and functional improvement of PD patients persisted for 2 years after surgery with a higher complication rate than for non-PD patients. PD patients with STN DBS maintained better lumbar lordosis for 2 years after spinal surgery. STN DBS significantly maintained spinal alignment with subsequent pain and functional amelioration 2 years after surgery. The outcomes of spinal surgery for PD patients might be favorably affected by thorough treatment for PD including DBS.

DOI： 10.2176/nmc.oa.2021-0094

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We developed a new cranioplasty method that utilizes artificial bone made of ultra-high-molecular-weight polyethylene, with a wedge-shaped edge (UHMWPE Wing). This study shows the methods and data of case series and finite element analyses with the UHMWPE Wing. A circumferential wing was preoperatively designed for a custom-made artificial bone made of UHMWPE to achieve high fixed power and to minimize the usage of cranial implants. Here, we present 4 years of follow-up data and finite element analyses for patients treated with the UHMWPE Wing between February 2015 and February 2019. Eighteen consecutive patients underwent cranioplasty using our UHMWPE Wing design. There were no postoperative adverse events in 17 of the patients for at least 18 months. One case of hydrocephalus experienced screw loosening and graft uplift due to shunt malfunction. Placement of a ventriculo-peritoneal shunt immediately returned the artificial bone to normal position. Finite element analyses revealed that a model using the UHMWPE Wing had the highest withstand load and lowest deformation. This is the first report on the UHMWPE Wing method. This method may enable clinicians to minimize dead space and achieve high strength in cranioplasty.

DOI： 10.2176/nmc.oa.2021-0032

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Although surgical site infections(SSIs)are usually controllable, their occasional occurrence is unavoidable. SSIs in neurosurgery comprise surgical-wound infections and surgical-organ/space infections. Data from the Japan Nosocomial Infections Surveillance revealed an overall infection rate of 1.1% during the first half of 2020. Responses to two questionnaire-based surveys on SSI prevention and complications related to cranial implant/artificial bone revealed the real world situation in neurosurgery. In 2020, neurosurgical information was added to the practical guidelines concerning the proper use of prophylactic antibacterial drug for SSIs. COVID-19 hygiene control protocols may have reduced the incidence of SSIs. It may be prudent to continue this stringent hygiene control after the COVID-19 pandemic has abated. Information of medical material on SSI is presented in this article, including the Plus suture®, DuraGen®, DuraSeal®, Adherus®, ultra-high-molecular-weight polyethylene(SKULPIO®, CRANIOFIT-PE®), Bioglide® and Bactiseal® shunt systems, and olanexidine. Minimizing SSIs requires proper knowledge on infection control, taking care while performing neurosurgical procedures, and compassion for the patients. In addition, information and material must be updated over time.

DOI： 10.11477/mf.1436204493

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The effectiveness of adenosine-induced flow arrest in surgical clipping for the cerebral aneurysms with difficulties in temporary clip placement to the proximal main trunk has been reported. This is the first clinical trial to evaluate the safety and feasibility of adenosine-assisted clipping surgery for unruptured cerebral aneurysms (UCAs) in Japan. The inclusion criteria are as follows: patients over 20 years old, patients who agree to be enrolled in this study after providing informed consent, patients who undergo clipping surgery for UCA in our institute, and patients in whom the surgeons (T.H. or I.D.) judge that decompression of the aneurysm is effective. The primary endpoint is a modified Rankin Scale (mRS) score 30 days after surgery. We plan to enroll 10 patients in this study. The original protocol of adenosine administration was established in this trial. Herein, we present the study protocol.

DOI： 10.2176/nmc.st.2021-0018

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BACKGROUND: The major surgical treatment for Parkinson's disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. In this study, we developed a wireless controllable electrical stimulator to examine the efficacy of VNS on PD model rats. METHODS: Adult female Sprague-Dawley rats underwent placement of a cuff-type electrode and stimulator on the vagus nerve. Following which, 6-hydroxydopamine (6-OHDA) was administered into the left striatum to prepare a PD model. VNS was started immediately after 6-OHDA administration and continued for 14 days. We evaluated the therapeutic effects of VNS with behavioral and immunohistochemical outcome assays under different stimulation intensity (0.1, 0.25, 0.5 and 1 mA). RESULTS: VNS with 0.25-0.5 mA intensity remarkably improved behavioral impairment, preserved dopamine neurons, reduced inflammatory glial cells, and increased noradrenergic neurons. On the other hand, VNS with 0.1 mA and 1 mA intensity did not display significant therapeutic efficacy. CONCLUSIONS: VNS with 0.25-0.5 mA intensity has anti-inflammatory and neuroprotective effects on PD model rats induced by 6-OHDA administration. In addition, we were able to confirm the practicality and effectiveness of the new experimental device.

DOI： 10.3390/biomedicines9070789

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BACKGROUND AND PURPOSE: To date, the incidence of intracranial and spinal arteriovenous shunts has not been thoroughly investigated. We aimed to clarify recent trends in the rates of intracranial and spinal arteriovenous shunts in Japan. METHODS: We conducted multicenter hospital-based surveillance at 8 core hospitals in Okayama Prefecture between April 1, 2009 and March 31, 2019. Patients who lived in Okayama and were diagnosed with cerebral arteriovenous malformations, dural arteriovenous fistulas (DAVFs), or spinal arteriovenous shunts (SAVSs) were enrolled. The incidence and temporal trends of each disease were calculated. RESULTS: Among a total of 393 cranial and spinal arteriovenous shunts, 201 (51.1%) cases of DAVF, 155 (39.4%) cases of cerebral arteriovenous malformation, and 34 (8.7%) cases of SAVS were identified. The crude incidence rates between 2009 and 2019 were 2.040 per 100 000 person-years for all arteriovenous shunts, 0.805 for cerebral arteriovenous malformation, 1.044 for DAVF, and 0.177 for SAVS. The incidence of all types tended to increase over the decade, with a notable increase in incidence starting in 2012. Even after adjusting for population aging, the incidence of nonaggressive DAVF increased 6.0-fold while that of SAVS increased 4.4-fold from 2010 to 2018. CONCLUSIONS: In contrast to previous studies, we found that the incidence of DAVF is higher than that of cerebral arteriovenous malformation. Even after adjusting for population aging, all of the disease types tended to increase in incidence over the last decade, with an especially prominent increase in SAVSs and nonaggressive DAVFs. Various factors including population aging may affect an increase in DAVF and SAVS.

DOI： 10.1161/STROKEAHA.120.032052

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Ventriculitis is a rare, serious complication of neurosurgery. A 59-year-old man who had undergone a craniotomy for a paranasal adenocarcinoma, developed a right frontal cystic lesion. We performed a bifrontal craniotomy to remove the lesion. The dura was repaired with non-vascularized free fascia lata in watertight fashion. Ventriculitis occurred 3 days postoperatively. Ventricular drainage, craniectomy, and endoscopic irrigation were undertaken to remove an abscess. The dura and the resection cavity were reconstructed using a vascularized anterolateral thigh adipofascial flap. His symptoms disappeared, indicating that endoscopic irrigation and reconstruction can effectively address ventriculitis even in patients in critical clinical condition.

DOI： 10.18926/AMO/61908

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OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

DOI： 10.1212/WNL.0000000000011450

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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"Diffuse midline glioma (DMG), H3K27M-mutant" was newly classified in the revised World Health Organization (WHO) 2016 classification of central nervous system tumors. Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols. In this study, we report two cases of spinal cord DMG, H3K27M-mutant treated with bevacizumab. The two patients were women in their 40s who initially presented with sensory impairment. MRI showed spinal intramedullary tumors, and each patient underwent laminectomy/laminoplasty and biopsy of the tumors. Histological examination initially suggested low-grade astrocytoma in case 1 and glioblastoma in case 2. Upon further immunohistochemical examination in case 1 and molecular examination in case 2, however, both cases were diagnosed as DMG, H3K27M-mutant. Case 1 was treated with radiation therapy and temozolomide (TMZ) chemotherapy, which induced a transient improvement of symptoms; 3 months after surgery, however, the patient's symptoms rapidly deteriorated. MRI showed tumor enlargement with edema to the medulla. Triweekly administration of bevacizumab improved her symptoms for the following 12 months. Case 2 was treated with bevacizumab from the beginning because of acute deterioration of breathing. After bevacizumab administration, both cases showed tumor regression on MRI and drastic improvement of symptoms within a few days. Although spinal cord DMG, H3K27M-mutant has an aggressive clinical course and poor prognosis, bevacizumab administration may offer the significant clinical benefit of alleviating edema, which improves patient's capacity for activities of daily life.

DOI： 10.2176/nmccrj.cr.2021-0033

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Adhesive arachnoiditis (AA) is a chronic inflammation inside the dura and remains one of the most challenging diseases. We describe a case of treatment-resistant extensive AA that offers insight into surgical treatment selection. The patient had a 2-year history of progressive spastic gait and was diagnosed with syringomyelia caused by extensive AA. Although syringe-subarachnoid and subarachnoid-subarachnoid shunting resulted in recurrence within a short period, syringo- peritoneal shunting improved the symptoms and there was no recurrence. This case suggests that syringo-peritoneal cerebrospinal fluid (CSF) shunt drainage, which has previously been considered a further step, may be a first-surgery option for extensive AA.

DOI： 10.2176/nmccrj.cr.2020-0228

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本脳神経CI学会  

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Ossification of the posterior longitudinal ligament (OPLL) is common in East Asia. Arteriovenous fistula at the craniocervical junction (CCJ-AVF), in contrast, is rare. As OPLL occurs most often in the cervical region, these 2 conditions can coexist in the cervical spinal canal of a single patient. We report a case of CCJ-AVF found after cervical laminoplasty (CLP) for OPLL. A 68-year-old man experienced progressive myelopathy due to cervical OPLL. Magnetic resonance imaging (MRI) revealed a high-intensity area inside the spinal cord. CLP was performed and his symptoms immediately improved. Three months after CLP, however, myelopathy recurred. MRI revealed an exacerbated and enlarged high-intensity area inside the cord from the medulla oblongata to the C4/5 level with a flow void around the cord. Left vertebral artery angiography revealed CCJ-AVF with ascending and descending draining veins. Direct surgery was performed to interrupt shunt flow into the draining veins. The patient's symptoms improved to a limited degree. In this case, increased pressure inside the spinal canal due to OPLL might have decreased the shunt flow of the CCJ-AVF. Thus, the venous congestion induced by CCJ-AVF might have been exacerbated after the pressure was removed by CLP. Magnetic resonance angiography screening could help detect concurrent CCJ-AVF and OPLL.

DOI： 10.14245/ns.2040200.100

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Language：Japanese   Publisher：(一社)日本定位・機能神経外科学会  

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OBJECTIVE: The purpose of the present study was to compare the treatment success rates of primary neurosurgical and endovascular treatments in patients with spinal dural arteriovenous fistulas (dAVFs). METHODS: Data from 199 consecutive patients with thoracic and lumbosacral spinal dAVFs were collected from 18 centers. Angiographic and clinical findings, the rate of initial treatment failure or recurrence by procedures, risk factors for treatment failure, complications, and neurological outcomes were statistically analyzed. RESULTS: Spinal dAVFs were frequently detected in the thoracic region (81%), fed by a single feeder (86%), and shunted into an intradural vein via the dura mater. The fistulous connection between the feeder(s) and intradural vein was located at a single spinal level in 195 patients (98%) and at 2 independent levels in 4 patients (2%). Among the neurosurgical (n = 145), and endovascular (n = 50) treatment groups of single dAVFs (n = 195), the rate of initial treatment failure or recurrence was significantly higher in the index endovascular treatment group (0.68% and 36%). A multivariate analysis identified endovascular treatment as an independent risk factor with significantly higher odds of initial treatment failure or recurrence (OR 69; 95% CI 8.7-546). The rate of complications did not significantly differ between the two treatment groups (4.1% for neurosurgical vs 4.0% for endovascular treatment). With a median follow-up of 26 months, improvements of ≥ 1 point in the modified Rankin Scale (mRS) score and Aminoff-Logue gait and Aminoff-Logue micturition grades were observed in 111 (56%), 121 (61%), and 79 (40%) patients, respectively. Independent risk factors for lack of improvement in the Aminoff-Logue gait grades were multiple treatments due to initial treatment failure or recurrence (OR 3.1) and symptom duration (OR 1.02). CONCLUSIONS: Based on data obtained from the largest and most recently assessed multicenter cohort, the present study shows that primary neurosurgery is superior to endovascular treatment for the complete obliteration of spinal dAVFs by a single procedure.

DOI： 10.3171/2020.6.SPINE20309

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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PURPOSE: Endovascular therapy to the spinal dural arteriovenous fistula (SDAVF) with a common origin of the radiculomedullary artery and the feeder of the shunt has the risk of spinal cord infarction. This study aimed to retrospectively assess the detection rate of normal spinal arteries from the feeder of SDAVF. METHODS: We retrospectively collected the angiographic and clinical data of SDAVFs. This study included 19 patients with 20 SDAVF lesions admitted to our department between January 2007 and December 2018. We assessed the detection rate of normal radiculomedullary artery branched from the feeder of SDAVF between the period using the image intensifier (II) and flat panel detector (FPD) and evaluated the treatment results. RESULTS: The detection rates of the radiculomedullary artery branched from the feeder of SDAVF were 10% (1/10 lesions) during the II period and 30% (3/10 lesions) during the FPD period. During the FPD period, all normal radiculomedullary arteries branched from the feeder were only detected on slab maximum intensity projection (MIP) images of rotational angiography, and we could not detect them in 2D or 3D digital subtraction angiography. All lesions that had a common origin of a normal radiculomedullary artery and the feeder were completely obliterated without complications. There was no recurrence during the follow-up period. CONCLUSIONS: The flat panel detector and slab MIP images seem to show the common origin of the normal radiculomedullary arteries from the feeder more accurately. With detailed analyses, SDAVF can be safety treated.

DOI： 10.1007/s00234-020-02466-0

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Other Link： http://link.springer.com/article/10.1007/s00234-020-02466-0/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Purpose Endovascular therapy to the spinal dural arteriovenous fistula (SDAVF) with a common origin of the radiculomedullary artery and the feeder of the shunt has the risk of spinal cord infarction. This study aimed to retrospectively assess the detection rate of normal spinal arteries from the feeder of SDAVF. Methods We retrospectively collected the angiographic and clinical data of SDAVFs. This study included 19 patients with 20 SDAVF lesions admitted to our department between January 2007 and December 2018. We assessed the detection rate of normal radiculomedullary artery branched from the feeder of SDAVF between the period using the image intensifier (II) and flat panel detector (FPD) and evaluated the treatment results. Results The detection rates of the radiculomedullary artery branched from the feeder of SDAVF were 10% (1/10 lesions) during the II period and 30% (3/10 lesions) during the FPD period. During the FPD period, all normal radiculomedullary arteries branched from the feeder were only detected on slab maximum intensity projection (MIP) images of rotational angiography, and we could not detect them in 2D or 3D digital subtraction angiography. All lesions that had a common origin of a normal radiculomedullary artery and the feeder were completely obliterated without complications. There was no recurrence during the follow-up period. Conclusions The flat panel detector and slab MIP images seem to show the common origin of the normal radiculomedullary arteries from the feeder more accurately. With detailed analyses, SDAVF can be safety treated.

DOI： 10.1007/s00234-020-02466-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECTIVE Spinal arteriovenous shunts are rare vascular lesions and are classified into 4 types (types I-IV). Due to rapid advances in neuroimaging, spinal epidural AVFs (edAVFs), which are similar to type I spinal dural AVFs (dAVFs), have recently been increasingly reported. These 2 entities have several important differences that influence the treatment strategy selected. The purposes of the present study were to compare angiographic and clinical differences between edAVFs and dAVFs and to provide treatment strategies for edAVFs based on a multicenter cohort.METHODS A total of 280 consecutive patients with thoracic and lumbosacral spinal dural arteriovenous fistulas (dAVFs) and edAVFs with intradural venous drainage were collected from 19 centers. After angiographic and clinical comparisons, the treatment failure rate by procedure, risk factors for treatment failure, and neurological outcomes were statistically analyzed in edAVF cases.RESULTS Final diagnoses after an angiographic review included 199 dAVFs and 81 edAVFs. At individual centers, 29 patients (36%) with edAVFs were misdiagnosed with dAVFs. Spinal edAVFs were commonly fed by multiple feeding arteries (54%) shunted into a single or multiple intradural vein(s) (91% and 9%) through a dilated epidural venous plexus. Preoperative modified Rankin Scale (mRS) and Aminoff Logue gait and micturition grades were worse in patients with edAVFs than in those with dAVFs. Among the microsurgical (n = 42), endovascular (n = 36), and combined (n = 3) treat- ment groups of edAVFs, the treatment failure rate was significantly higher in the index endovascular treatment group (7.5%, 31%, and 0%, respectively). Endovascular treatment was found to be associated with significantly higher odds of initial treatment failure (OR 5.72, 95% CI 1.45-22.6). In edAVFs, the independent risk factor for treatment failure after microsurgery was the number of intradural draining veins (OR 17.9, 95% C11.56-207), while that for treatment failure after the endovascular treatment was the number of feeders (OR 4.11, 95% CI 1.23-13.8). Postoperatively, mRS score and Aminoff-Logue gait and micturition grades significantly improved in edAVFs with a median follow-up of 31 months.CONCLUSIONS Spinal epidural AVFs with intradural venous drainage are a distinct entity and may be classified as type V spinal vascular malformations. Based on the largest multicenter cohort, this study showed that primary microsurgery was superior to endovascular treatment for initial treatment success in patients with spinal edAVFs.

DOI： 10.3171/2020.2.SPINE191432

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Cranial implants are commonly used throughout the world, yet the data on complications remain partly clarified. The aim of this study was to gather real data in 2018 on complications related to cranial implants in neurosurgery. The survey population consisted of 1103 institutes supplying neurosurgical treatment. The survey consisted of two-stage questionnaire. First the incidence of complications was investigated, then the secondary questionnaire was e-mailed to the respondents about the detailed of the complications. As the result, the annual incidence of complications related to cranial implants was 0.558% in Japan. Titanium plate and mesh were used predominantly in craniotomy and cranioplasty, respectively. The second survey collected data on 449 cases with complications (infection: 63%, implant exposure: 46%, multiple answer). Postoperative infection was associated with male sex, brain tumor, short interval between surgery and complication, usage of ceramics, hydroxyapatite, resin, and artificial dura, hyponutrition, multiple surgeries, dirty wound, and sinusitis as patient factors, and CSF leakage, ruptured sutures, and sinus maltreatment as surgery factors. Meanwhile, long hospital stay was associated with age, male sex, mRS 3-5 before complication, short interval between initial surgery and complication, large craniotomy, long operative time, usage of ceramics and artificial dura, multiple surgeries and dirty wound as patient factors, ruptured suture as a surgical factor, and bacterial infection, especially MRSA infection, as the complication and treatment consisting of removal as complication factors. In conclusion, this is the first Japanese national survey on complications related to cranial implants in neurosurgery. It is important to recall that complications may arise years after surgery and to be aware of the risk factors associated with complications.

DOI： 10.2176/nmc.oa.2020-0051

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Crossed cerebellar diaschisis (CCD) is a state of hypoperfusion and hypometabolism in the contralesional cerebellar hemisphere caused by a supratentorial lesion, but its pathophysiology is not fully understood. We evaluated chronological changes in cerebellar blood flow (CbBF) and gene expressions in the cerebellum using a rat model of transient middle cerebral artery occlusion (MCAO). CbBF was analyzed at two and seven days after MCAO using single photon emission computed tomography (SPECT). DNA microarray analysis and western blotting of the cerebellar cortex were performed and apoptotic cells in the cerebellar cortex were stained. CbBF in the contralesional hemisphere was significantly decreased and this lateral imbalance recovered over one week. Gene set enrichment analysis revealed that a gene set for "oxidative phosphorylation" was significantly upregulated while fourteen other gene sets including "apoptosis", "hypoxia" and "reactive oxygen species" showed a tendency toward upregulation in the contralesional cerebellum. MCAO upregulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the contralesional cerebellar cortex. The number of apoptotic cells increased in the molecular layer of the contralesional cerebellum. Focal cerebral ischemia in our rat MCAO model caused CCD along with enhanced expression of genes related to oxidative stress and apoptosis.

DOI： 10.3390/ijms21114137

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Cell therapy for disorders of the central nervous system has progressed to a new level of clinical application. Various clinical studies are underway for Parkinson's disease, stroke, traumatic brain injury, and various other neurological diseases. Recent biotechnological developments in cell therapy have taken advantage of the technology of induced pluripotent stem (iPS) cells. The advent of iPS cells has provided a robust stem cell donor source for neurorestoration via transplantation. Additionally, iPS cells have served as a platform for the discovery of therapeutics drugs, allowing breakthroughs in our understanding of the pathology and treatment of neurological diseases. Despite these recent advances in iPS, adult tissue-derived mesenchymal stem cells remain the widely used donor for cell transplantation. Mesenchymal stem cells are easily isolated and amplified toward the cells' unique trophic factor-secretion property. In this review article, the milestone achievements of cell therapy for central nervous system disorders, with equal consideration on the present translational obstacles for clinic application, are described.

DOI： 10.1111/cns.13247

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The original version of this article unfortunately contained a mistake. Figure 5a, b were incorrect. The correct figures are given below.

DOI： 10.1007/s12017-020-08594-3

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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Malignant glioma is one of the most common brain cancers in humans, which is very devastating. The expression of reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is decreased in various human cancers. Lately, we have developed a novel second-generation adenoviral vector that expresses REIC/Dkk-3 (Ad-SGE-REIC) and revealed its antiglioma efficacy. The present investigator-initiated clinical trial is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed at Okayama University Hospital, Okayama, Japan. The primary end points are dose-limiting toxicities and the incidence of adverse events. The secondary end points are the objective response rate and immunological assessment. Use of Ad-SGE-REIC will help to improve the prognosis of patients with malignant brain tumors.

DOI： 10.2217/fon-2019-0743

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Although temporary clipping of the parent artery is an indispensable technique in clipping surgery for intracranial aneurysms, the permissive duration of temporary clipping is still not well known. The aim of this study is to confirm the safety of precise motor evoked potential (MEP) monitoring and to estimate the permissive duration of temporary clipping for middle cerebral artery (MCA) aneurysm based on precise MEP monitoring results. Under precise MEP monitoring via direct cortical stimulation every 30 seconds to 1 minute, surgeons released a temporary clip and waited for MEP amplitude to recover following severe (>50%) reduction of MEP amplitude during temporary clipping. Precise MEP monitoring was safely performed. Twenty-eight instances of temporary clipping were performed in 42 MCA aneurysm clipping surgeries. Because precise MEP monitoring could be used to determine when to release a temporary clip even with a severe reduction in MEP amplitude due to lengthy temporary clipping, no patients experienced permanent postoperative hemiparesis. Based on logistic regression analysis, if a temporary clip is applied for 312 seconds or more, there is a higher probability of a severe reduction in MEP amplitude. We should therefore release temporary clips after 5 minutes in order to avoid permanent postoperative hemiparesis.

DOI： 10.1038/s41598-020-60377-9

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In recent years, therapeutic strategies [...].

DOI： 10.3390/ijms21030793

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Background: Spinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients. Objective: Recognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats. Methods: We developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis. Results: The 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group. Conclusions: This study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.

DOI： 10.3389/fnagi.2020.00164

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Mesenchymal stem cells (MSCs) are widely considered good candidates for cell transplantation therapy. Various central nervous system disorders have been suggested as suitable targets for MSC transplantation therapy. In this context, a great deal of basic and clinical research has been conducted to explore its clinical uses. Although depression is one of the most common diseases in the world, the response rate to the currently available treatment is insufficient and new treatments are much needed. Despite the fact that MSC transplantation therapy has the potential to elicit an antidepressant effect, few studies have been conducted on this topic to date and the underlying mechanism remains poorly understood. To address the development of a new treatment for depression, we evaluated the effect of MSCs using the encapsulation technique and Wistar-Kyoto rats. Encapsulation enables dissection of the complicated underlying mechanism of MSC transplantation therapy. Wistar-Kyoto rats that exhibit treatment-resistant depressive-like behaviors allow us to compare the effect of MSCs with that of conventional antidepressant treatment. In this commentary, we briefly summarize our recent published results and discuss future research prospects.

DOI： 10.1177/2633105520959064

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUMANA PRESS INC  

High-mobility group box-1 (HMGB1) is a nuclear protein that promotes inflammation during the acute phase post-stroke, and enhances angiogenesis during the delayed phase. Here, we evaluated whether indirect revascularization surgery with HMGB1 accelerates brain angiogenesis in a chronic cerebral hypoperfusion model. Seven days after hypoperfusion induction, encephalo-myo-synangiosis (EMS) was performed with or without HMGB1 treatment into the temporal muscle. We detected significant increments in cortical vasculature (p<0.01), vascular endothelial growth factor (VEGF) expression in the temporal muscle (p<0.05), and ratio of radiation intensity on the operated side compared with the non-operated side after EMS in the HMGB1-treated group than in the control group (p<0.01). Altogether, HMGB1 with EMS in a chronic hypoperfusion model promoted brain angiogenesis in a VEGF-dependent manner, resulting in cerebral blood flow improvement. This treatment may be an effective therapy for patients with moyamoya disease.

DOI： 10.1007/s12017-019-08541-x

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Parkinson's disease (PD) is a chronic and progressive movement disorder and the second most common neurodegenerative disease. Although many studies have been conducted, there is an unmet clinical need to develop new treatments because, currently, only symptomatic therapies are available. To achieve this goal, clarification of the pathology is required. Attempts have been made to emulate human PD and various animal models have been developed over the decades. Neurotoxin models have been commonly used for PD research. Recently, advances in transgenic technology have enabled the development of genetic models that help to identify new approaches in PD research. However, PD animal model trends have not been investigated. Revealing the trends for PD research will be valuable for increasing our understanding of the positive and negative aspects of each model. In this article, we clarified the trends for animal models that were used to research PD in the 2000s, and we discussed each model based on these trends.

DOI： 10.3390/ijms20215402

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BACKGROUND: Details of the somatotopy within the subthalamic nucleus (STN) are still poorly understood; however, the STN is a common target of deep brain stimulation (DBS) for Parkinson disease. OBJECTIVE: To examine somatotopic organization within the STN and identify optimal stimulation sites from 77 surgical cases with microelectrode recording. METHODS: STN-DBS was performed for 77 patients with Parkinson disease between 2010 and 2014. We performed passive movements of each joint and captured single neuronal activities to identify movement-related cells (MRCs). The sites of MRCs and active contacts were determined by measuring their distances from the first contact of DBS electrode. Their positional correlations were directly and indirectly analyzed. RESULTS: The number of obtained MRCs was 264, of which 151 responded to multiple joints. The average x-, y-, and z-coordinates of the cells of the upper and lower limbs from the midcommisural point were 13.1 ± 1.1 and 12.7 ± 1.2, 0.22 ± 1.3 and -0.45 ± 1.5, and -2.5 ± 1.1 and -3.0 ± 1.4 mm, respectively. Most MRCs were distributed in the upper third of the STN, in its superior, lateral, and posterior regions, along the DBS electrode routes. Active contacts were observed to lie slightly inferior, medial, and posterior to the average MRC position. CONCLUSION: Somatotopic organization of the STN was easier to observe in the present study than in previous studies. Optimal stimulation sites were located inferior, medial, and posterior to the average MRC location. The sites may correspond to associative or motor parts through which fibers from the supplementary motor area pass.

DOI： 10.1093/ons/opy351

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Wistar Kyoto (WKY) rats are a useful animal model of treatment-resistant depression. Lithium is effective for treating recurrent mood disorders or treatment-resistant depression, and lithium augmentation treatment is also useful for treatment-resistant depression. However, the treatment effect of lithium on the depressive behavior of WKY rats remains poorly understood, and whether lithium augments the treatment effect of antidepressants in WKY rats is also unknown. In this study, we evaluated the treatment effect of lithium in WKY rats. We also sought to determine if lithium treatment augments the treatment effect of fluoxetine. Lithium was administered for 15 consecutive days and fluoxetine was administered 23.5, 5, and 1 h before the forced swim test (FST) day 2, based on previous studies. Lithium treatment counteracted depressive behavior in the FST and increased hippocampal neurogenesis. Additionally, co-administration of lithium and fluoxetine augmented the treatment effect observed in the FST and in hippocampal neurogenesis in WKY rats, although fluoxetine monotherapy showed no treatment effect. Lithium prevented an increase in body weight, similar to its effect in human patients. These results are consistent with those of lithium augmentation treatment for human patients with treatment-resistant depression. They suggest that WKY rats are a promising animal model for treatment-resistant depression. However, lithium treatment has various side effects. A new treatment with the same anti-depressive effect as fluoxetine + lithium treatment and fewer side effects compared with lithium would be desirable for patients with treatment-resistant depression.

DOI： 10.1016/j.brainres.2019.04.001

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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BACKGROUND: Hyponatremia generally occurs after transsphenoidal surgery (TSS) in a delayed fashion. Most patients with delayed postoperative hyponatremia (DPH) are asymptomatic or only express non-specific symptoms; consequently, DPH is associated with prolonged hospitalization. No consensus has been reached on which patients are at greatest risk of developing DPH. We reviewed patients with DPH and evaluated predictive factors for DPH. METHODS: We retrospectively analyzed 107 consecutive patients who underwent endoscopic TSS for pituitary adenoma (January 2010-December 2016). Patients with DPH (hyponatremia group) and without DPH (normonatremia group) were compared according to their nadir sodium levels on postoperative days 3 to 10. We documented the patients' demographics, clinical features, and postoperative physiological characteristics. RESULTS: Twenty-five (23.4%) patients developed DPH after endoscopic TSS. The patients' mean age was 54 ± 17 years, and 63.6% of the patients were female. The overall prevalence of DPH was 23.4%. The non-parametric χ2 test and the Mann-Whitney U test revealed statistically significant differences in age, use of antihypertensive drugs, nonfunctioning pituitary adenoma, and higher yet normal preoperative thyroid-stimulating hormone level between the hyponatremia and normonatremia groups (P < 0.05). Logistic regression analysis revealed that only older age was a useful independent predictive factor for DPH (odds ratio, 1.05; 95% confidence interval, 1.01-1.08; P = 0.01). The serum sodium levels on postoperative day 2 were significantly lower in the hyponatremia than normonatremia group (P < 0.01) and were negatively correlated with age (r = - 0.25, P < 0.05). The cut-off age for predicting DPH was 55 years. The hospital stay was significantly longer in the hyponatremia than normonatremia group (P < 0.01). CONCLUSIONS: Age of more than 55 years was an independent predictive factor for DPH even after adjusting for potential confounders. Older age was negatively correlated with the serum sodium level on postoperative day 2. Preventing early decreases in the sodium level could reduce the risk of DPH. TRIAL REGISTRATION: 1707-027.

DOI： 10.1007/s00701-019-03818-3

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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OBJECTIVECervical spondylotic myelopathy (CSM) is one of the most common causes of spinal cord dysfunction. Surgery for CSM is generally effective, but postoperative delirium is a potential complication. Although there have been some studies that investigated postoperative delirium after spine surgery, no useful tool for identifying high-risk patients has been established, and it is unknown if 36-Item Short Form Health Survey (SF-36) scores can predict postoperative delirium. The objective of this study was to evaluate the correlation between preoperative SF-36 scores and postoperative delirium after surgery for CSM.METHODSSixty-seven patients who underwent surgery for CSM at the authors' institution were enrolled in this study. Medical records of these patients were retrospectively reviewed. Patient background, preoperative laboratory data, preoperative SF-36 scores, the preoperative Japanese Orthopaedic Association (JOA) score for the evaluation of cervical myelopathy, and perioperative factors were selected as potential risk factors for postoperative delirium. These factors were evaluated using univariable and multivariable logistic regression analysis.RESULTSTen patients were diagnosed with postoperative delirium. Univariable analysis revealed that the physical functioning score (p = 0.01), general health perception score (p < 0.01), and vitality score (p < 0.01) of the SF-36 were significantly lower in patients with postoperative delirium than in those without. The total number of medications was significantly higher in the delirium group compared with the no-delirium group (p = 0.02). In contrast, there were no significant differences between the delirium group and the no-delirium group in cervical JOA scores (p = 0.20). Multivariable analysis revealed that a low general health perception score was an independent risk factor for postoperative delirium (p = 0.02; odds ratio 0.810, 95% confidence interval 0.684-0.960).CONCLUSIONSSome of the SF-36 scores were significantly lower in patients with postoperative delirium than in those without. In particular, the general health perception score was independently correlated with postoperative delirium. SF-36 scores could help identify patients at high risk for postoperative delirium and aid in the development of prevention strategies.

DOI： 10.3171/2018.11.SPINE181031

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BACKGROUND: High mobility group box 1 (HMGB1) protein plays a key role in triggering inflammatory responses in many diseases. Our previous study showed that HMGB1 is found upstream of secondary damage in traumatic brain injury (TBI). We found that anti-HMGB1 monoclonal antibody (mAb) effectively decreased acute brain damage, including the disruption of the blood-brain barrier, brain edema, and neurologic dysfunction. This effect of anti-HMGB1 mAb lasts for at least 1 week. In this study, we explored subacute effects of anti-HMGB1 mAb after TBI. METHODS: TBI was induced in rats by fluid percussion. Anti-HMGB1 mAb or control mAb was given intravenously after TBI. Histochemical staining, plasma levels of HMGB1, motor activity and memory, and video electroencephalography monitoring were evaluated 2 weeks after fluid percussion injury. RESULTS: Anti-HMGB1 mAb remarkably attenuated accumulation of activated microglia in the rat cortex in the ipsilateral hemisphere after TBI. Anti-HMGB1 mAb also prevented neuronal death in the hippocampus in the ipsilateral hemisphere after TBI. Treatment of rats with anti-HMGB1 mAb inhibited HMGB1 translocation and suppressed impairment of motor function. The beneficial effects of anti-HMGB1 mAb on motor and cognitive function persisted for 14 days after injury. Treatment with anti-HMGB1 mAb also had positive effects on electroencephalography activity. CONCLUSIONS: The beneficial effects of anti-HMGB1 mAb continued during the subacute postinjury phase, suggesting that anti-HMGB1 mAb may prevent cognitive dysfunction after TBI.

DOI： 10.1016/j.wneu.2018.10.164

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Language：Japanese   Publisher：(NPO)日本脳神経外科救急学会  

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DOI： 10.5797/jnet.oa.2018-0082

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OBJECTIVE: In Parkinson's disease (PD), abnormal postures are often accompanied, which interfere with rehabilitation and subsequent functional recovery. This study investigated the relationship between clinical characteristics and improvement in abnormal postures of PD patients who received subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: Seventy-four PD patients were included in this study. Clinical data were analyzed using the patients' functional status at pre- and post-STN-DBS, including anteflexion vs. non-anteflexion, scoliosis vs. non-scoliosis, improved anteflexion vs. non-improved anteflexion, and improved scoliosis vs. non-improved scoliosis. RESULTS: In patients with anteflexion, UPDRS III motor score at off medication was worse than that of patients with non-anteflexion. Patients with scoliosis presented with more comorbid spinal deformity and longer disease duration than those without scoliosis. Cobb angle of patients with asymmetrical psoas major and erector spinal muscles was more than that of patients without the asymmetry. Patients with improved anteflexion after STN-DBS had thicker abdominal oblique muscle and transverse abdominal muscle than those of patients without improved anteflexion. Patients with improved scoliosis were significantly younger at PD onset than those without improvement. CONCLUSIONS: There were only a few prognostic factors recognized in patients with improved postures. The thick abdominal muscle for anteflexion and younger PD onset for scoliosis were significant factors for improvement by STN-DBS. Rehabilitation designed to maintain muscle for correct postures may contribute to the amelioration of abnormal postures by STN-DBS, although multicenter trials are needed.

DOI： 10.1016/j.parkreldis.2018.07.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The primary treatment for hydrocephalus is ventricular shunt placement, and a programmable valve is widely used for ventriculoperitoneal (VP) shunt surgery to reduce over/under drainage of cerebrospinal fluid (CSF). Here, we report a rare case of a patient who developed successive VP shunt malfunction causing spastic muscle weakness in extremities associated cervical epidural venous distension and compressive myelopathy due to over-drainage of CSF through a defective VP shunt valve a decade after the initial shunt was placed. One should be aware and cognizant of this complication and carefully follow the symptoms and potentially utilize brain MRI with and without contrast to look at over drainage stigmata to avoid the development of neurological complications.

DOI： 10.1016/j.inat.2018.08.009

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本脳神経外傷学会  

過去5年間に当院センターへ救急搬送され、開頭血腫除去術を受けた頭部外傷症例26例(男14例、女12例、年齢中央値65歳)を対象に、予後良好群の特徴について検討した。その結果、予後良好群は10例、予後不良群は16例であった。予後良好群では主病変が急性硬膜外血腫であること、術前意識レベルがJCS IあるいはIIであることが特徴であった。

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Despite the advances in pharmacological therapies, only the half of depressed patients respond to currently available treatment. Thus, the need for further investigation and development of effective therapies, especially those designed for treatment-resistant depression, has been sorely needed. Although antidepressant effects of mesenchymal stem cells (MSCs) have been reported, the potential benefit of this cell therapy on treatment-resistant depression is unknown. Cell encapsulation may enhance the survival rate of grafted cells, but the therapeutic effects and mechanisms mediating encapsulation of MSCs remain unexplored. Here, we showed that encapsulation enhanced the antidepressant effects of MSCs by attenuating depressive-like behavior of Wistar Kyoto (WKY) rats, which are considered as a promising animal model of treatment-resistant depression. The implantation of encapsulated MSCs (eMSCs) into the lateral ventricle counteracted depressive-like behavior and enhanced the endogenous neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, whereas the implantation of MSCs without encapsulation or the implantation of eMSCs into the striatum did not show such ameliorative effects. eMSCs displayed robust and stable secretion of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor, fibroblast growth factor-2, and ciliary neurotrophic factor (CNTF), and the implantation of eMSCs into the lateral ventricle activated relevant pathways associated with these growth factors. Additionally, eMSCs upregulated intrinsic expression of VEGF and CNTF and their receptors. This study suggests that the implantation of eMSCs into the lateral ventricle exerted antidepressant effects likely acting via neurogenic pathways, supporting their utility for depression treatment.

DOI： 10.1038/s41380-018-0208-0

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DOI： 10.4103/bc.bc_17_18

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publisher：日本神経麻酔集中治療学会  

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The success of deep brain stimulation (DBS) depends heavily on surgical accuracy, and brain shift is recognized as a significant factor influencing accuracy. We investigated the factors associated with surgical accuracy and showed the effectiveness of a dural sealant system for preventing brain shift in 32 consecutive cases receiving DBS. Thirty-two patients receiving DBS between March 2014 and May 2015 were included in this study. We employed conventional burr hole techniques for the first 18 cases (Group I) and a dural sealant system (DuraSeal) for the subsequent 14 cases (Group II). We measured gaps between the actual positions of electrodes and the predetermined target positions. We then retrospectively evaluated the factors involved in surgical accuracy. The average gap between an electrode's actual and target positions was 1.55 ± 0.83 mm in all cases. Postoperative subdural air volume e, the only factor associated with surgical accuracy (r = 0.536, P < 0.0001), was significantly smaller in Group II (Group I: 43.9 ± 27.7, Group II: 12.1 ± 12.5 ml, P = 0.0006). The average electrode position gap was also significantly smaller in Group II (Group I: 1.77 ± 0.91, Group II: 1.27 ± 0.59 mm, P = 0.035). Use of a dural sealant system could significantly reduce intracranial air volume, which should improve surgical accuracy.

DOI： 10.2176/nmc.oa.2017-0242

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OBJECTIVE: Optimal placement of electrodes is important for spinal cord stimulation. Factors affecting the difficulty of percutaneous electrode placement are not well known. In this study, we retrospectively evaluated the factors affecting the difficulty of percutaneous electrode placement. METHODS: We performed a retrospective analysis of 90 consecutive procedures of percutaneous cylindrical electrode implantation at the first author's institution. Age, sex, smoking state, body mass index, the duration of time from the beginning of pain syndrome to operation, diagnosis, the number of previous electrode placements, the previous electrode implantation period, the presence of axial low back pain, the electrode tip level, the pattern of electrode placement, and the reason for reimplantation were selected as factors associated with the success of electrode placement or the operation time of electrode placement. RESULTS: The number of previous electrode placements and the electrode tip level were independently associated with the operation time of electrode placement. According to both univariable and multivariable regression analyses, 1 previous electrode placement lengthened the operation time by approximately 15 minutes. No factors were significantly associated with the success of electrode placement. The more frequently that previous electrode placement was performed, the more difficult electrode placement tended to be. However, electrode reimplantation can be successful given extra time. CONCLUSIONS: This is the first study to evaluate factors affecting the difficulty of percutaneous electrode placement. A history of percutaneous cylindrical electrode placement did not affect the success of current placement, although it lengthened the operation time.

DOI： 10.1016/j.wneu.2018.02.040

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Language：Japanese   Publisher：(一社)日本脳神経外科コングレス  

症例は側頭葉てんかんを発症した13歳男児。頭部MRIで右側頭葉内広範囲、基底核、深部白質、側脳室内などに多発する病変を認め、さらに経時的に造影病変は変化した。Fluorodeoxyglucose-positron emission tomography(FDG-PET)で悪性を示唆する所見はなく、subtraction ictal single-photon emission computed tomography coregistered to MRI(SISCOM)と発作時脳波で右側頭葉が発作焦点であると判断し、一期的に右側頭葉切除を行った。病理学的診断はdysembryoplastic neuroepithelial tumorであった。現時点で術後半年経過したが、発作は消失し、残存病変についても増大していない。多発性DNTは非常にまれであり、変化に富む画像所見とあわせて、治療方針の決定に難渋した。本症例はてんかんの治療目的に手術を行ったが、複雑な病態であっても、治療目的を明確にし、それに応じた検査、手術を行うことが重要である。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J02632&link_issn=&doc_id=20180403310006&doc_link_id=10.7887%2Fjcns.27.317&url=https%3A%2F%2Fdoi.org%2F10.7887%2Fjcns.27.317&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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The spinal extradural arachnoid cyst is a rare entity. Obtaining the correct diagnosis and detecting the fistula location are critical for providing effective treatment. A 41-year-old man had numbness in the soles of his feet for 2 years with accompanying gait disturbance, and a defecation disorder. Computed tomography myelography performed at another hospital revealed an epidural arachnoid cyst from Th11 to L2. He received a subarachnoid-cyst shunt at the rostral part of the cyst. However, his symptoms worsened and he was admitted to our hospital. Neuroradiological investigations revealed the correct location of the fistula at the level of Th12. We performed partial removal of the cyst wall with fistula closure via right hemilaminectomy of Th11 and 12. The complete closure of the fistula was confirmed by intrathecal infusion of artificial cerebrospinal fluid through the shunt tube. The shunt tube was removed with the sutures. The patient's symptoms improved, although numbness remained in his bilateral heels. There has been no recurrence in 15 months since the surgery. Fistula closure may work as a balanced therapeutic strategy for spinal extradural arachnoid cyst, and intrathecal cerebrospinal fluid infusion is useful for the confirmation of complete fistula closure.

DOI： 10.18926/AMO/55666

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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Several reports have shown that long-term potentiation (LTP) per se effectively enhances neurogenesis in the hippocampus of intact animals. If LTP can enhance neurogenesis in chronic hypoperfusion, this approach could potentially become a new therapeutic strategy for the restoration of cognitive function and for prevention from deterioration of mild cognitive impairment (MCI). Using an in vivo LTP model of rats, we examined whether LTP per se can enhance neurogenesis in hypoperfusion rats that underwent permanent bilateral common carotid artery occlusion (permanent 2-vessel occlusion, P2VO). High frequency stimulation (HFS) in the subacute phase after P2VO enhanced hippocampal cell proliferation and neurogenesis. However, most enhanced cell proliferation and neurogenesis was seen in the hypoperfusion rats that received HFS and for which LTP could finally be induced. In contrast, the same effect was not seen in the LTP induction in the chronic phase. The present findings, which reveal that most enhanced neurogenesis was seen in hypoperfusion rats for which LTP could be finally induced, could explain the ability of LTP-like activities such as learning paradigms and environmental stimuli to increase the rate of neurogenesis in the hippocampus even under hypoperfusion conditions. Moreover, the present findings, which reveal that LTP induction in the chronic phase after P2VO could not effectively enhance neurogenesis in the hypoperfusion rats, could indicate that patients with MCI and even middle-aged healthy control individuals should start LTP-like activities as early as possible and continue with these activities to prevent age-related deterioration of hippocampal function.

DOI： 10.3389/fnagi.2018.00029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Neurolymphomatosis is a rare form of extranodal malignant lymphoma defined as the infiltration of malignant lymphocytes into the central or peripheral nerve. We herein report a case of neurolymphomatosis in the cauda equina diagnosed by an open surgical biopsy. He presented with muscle weakness, atrophy, numbness and hypoesthesia in the bilateral lower extremities with the accumulation of (18)fluoro-2-deoxyglucose (FDG) in the bilateral cauda equina. Cerebrospinal fluid cytology (three times) and flow cytometry (two times) and biopsies of the left rural nerve, bone marrow, paranasal sinus and left testis were all negative for malignancy, so finally we performed a surgical open biopsy of the cauda equina by laminectomy and diagnosed him with diffuse large B-cell lymphoma in the cauda equina. He was successfully treated with the disappearance of the FDG accumulation for a long time. The present case suggested that an early open biopsy of the cauda equina may be considered for cases of suspected neurolymphomatosis in the cauda equina for a good outcome.

DOI： 10.2169/internalmedicine.1049-18

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Congress of Neurological Surgeons  

Dysembryoplastic neuroepithelial tumor (DNT) is a type of brain tumor that causes refractory epilepsy. We present the case of a 13-year-old boy with temporal lobe epilepsy. Magnetic resonance imaging (MRI) revealed multiple lesions in the right temporal lobe, basal ganglia, deep white matter, and lateral ventricle. Serial MRI showed morphological changes of contrast-enhanced lesions, but fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed hypometabolic lesions. Subtraction ictal single-photon emission computed tomography coregistered to MRI (SISCOM) and ictal electroencephalography (EEG) suggested the seizure onset zone might be located in the right temporal lobe. We performed right temporal lobectomy, and pathological diagnosis confirmed DNT. At one year post-surgery, the patient has achieved seizure-free status, and the remaining lesions have not increased. Multifocal DNT is extremely rare, and treatment strategy was difficult to determine in this case. Surgery should be performed when appropriate after clarifying the treatment purpose.

DOI： 10.7887/jcns.27.317

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Language：Japanese   Publisher：(一社)日本脳卒中の外科学会  

症例1:9歳女児。左片麻痺で発症し、右内包後脚脳梗塞と診断された。aspirin内服を行い、24ヵ月再発なく外来加療中である。症例2:13歳男児。けいれん発作、意識障害、左片麻痺が生じ、動脈炎として加療開始された。右中大脳動脈領域に脳梗塞を認めたため外減圧術を施行したが、第62病日に頭蓋骨形成術を施行後に意識障害が生じ、けいれん重積状態となった。barbitalを用いた2週間にわたる鎮静・呼吸循環管理にて徐々に改善したが、左不全麻痺の悪化、右不全麻痺を生じた。17ヵ月経過現在、両杖をついた歩行訓練を行っている。症例3:10ヵ月女児。左不全片麻痺で発症し、3日後に意識障害が生じた。右側の血栓性脳梗塞と考えaspirin内服を開始したが、脳梗塞の再発、左側に新規の脳梗塞を来たした。warfarinとaspirinの内科加療を開始し、16ヵ月再発なく経過している。症例4:2歳女児。Klippel-Trenaunay症候群として経過観察されていた。繰り返す左片麻痺とけいれん発作が生じ、右内頸動脈の閉塞ないし狭窄に伴う脳虚血と診断し、aspirin内服加療を開始した。16ヵ月間再発なく経過している。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J02079&link_issn=&doc_id=20171211180009&doc_link_id=%2Fcp4strok%2F2017%2F004506%2F009%2F0476-0482%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcp4strok%2F2017%2F004506%2F009%2F0476-0482%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

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Cell therapy for Parkinson's disease (PD) began in 1979 with the transplantation of fetal rat dopamine-containing neurons that improved motor abnormalities in the PD rat model with good survival of grafts and axonal outgrowth. Thirty years have passed since the 2 clinical trials using cell transplantation for PD patients were first reported. Recently, cell therapy is expected to develop as a realistic treatment option for PD patients owing to the advancement of biotechnology represented by pluripotent stem cells. Medication using levodopa, surgery including deep brain stimulation, and rehabilitation have all been established as current therapeutic strategies. Strong therapeutic effects have been demonstrated by these treatment methods, but they have been unable to stop the progression of the disease. Fortunately, cell therapy might be a key for true neurorestoration. This review article describes the historical development of cell therapy for PD, the current status of cell therapy, and the future direction of this treatment method.

DOI： 10.1177/0963689717735411

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Several targets and targeting methods are utilized in stereotactic surgery to achieve tremor suppression for patients with intractable tremor. Recent developments in magnetic resonance imaging, including diffusion tensor imaging, have enabled the setting of appropriate targets in stereotactic surgery. In this retrospective study, the optimal target to suppress tremors in stereotactic surgery was explored using diffusion tensor image-based fiber tractography. Four tracts were focused on in this study, namely: the cerebello-thalamo-premotor cortical fiber tract, cerebello-thalamo-primary motor cortical fiber tract, spino-thalamo-somatosensory cortical fiber tract, and pyramidal tract. In 10 patients with essential tremor, we evaluated the thalamotomy lesions and active contacts of the lead in thalamic stimulation by diffusion tensor image-based fiber tractography to reveal which part of the cerebral cortex is most affected by stereotactic surgery. Tremor suppression and adverse events were also evaluated in the patients involved in this study. Consequently, the good tremor suppression was achieved in all patients. There had been no permanent adverse events 3 months after surgery. Twelve lesions in thalamotomy patients or active contacts of the lead in thalamic stimulation patients were on the cerebello-thalamo-premotor cortical fiber tract (12/14 lesions or active contacts: 86%). In conclusion, the cerebello-thalamo-premotor cortical fiber tract may be an optimal target for tremor suppression. Diffusion tensor image-based fiber tractography may enable us to both determine the optimal target to achieve strong tremor suppression and to reduce the number of adverse events by keeping lesions or electrodes away from important fiber tracts, such as the pyramidal tract and spinothalamic fibers.

DOI： 10.2176/nmc.oa.2016-0277

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To date, many animal studies have indicated the neuroprotective effects of mesenchymal stem cell (MSC) transplantation in ischemic stroke. Several clinical studies have also revealed the safety, feasibility, and neuroprotective effects in ischemic stroke patients. In this review, we present the main approaches of MSC transplantation in ischemic stroke, the mechanisms of MSC therapy, and the current clinical studies on MSC transplantation in ischemic stroke patients. We also explore the safety of MSC transplantation and conclude that MSC therapy will play an important role in the future treatment of ischemic stroke. The optimal timing, approach, and cell dose in the transplantation are important issues for successful clinical application.

DOI： 10.18926/AMO/55302

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The hippocampus is thought to be an important region for depression. However, the relationship between hippocampal neurogenesis and depression is still controversial. Wistar Kyoto (WKY) rats are frequently used as a depression model. WKY rats are known to show physiologically abnormal features, and these features resemble abnormalities seen in depressed patients. However, the neurogenesis of WKY rats is still unknown. In this study, we first evaluated the neurogenesis of WKY rats and compared it to that of Wistar (WIS) rats. No strain effect was observed in the number of cells positive for 5-bromo-2'-deoxyuridine (BrdU) and BrdU/Doublecortin (Dcx) in the subventricular zone (SVZ). However, the number of BrdU- and BrdU/Dcx-positive cells in the dentate gyrus (DG) of the hippocampus was significantly lower in WKY rats than in WIS rats. Next, we evaluated the correlation between neurogenesis and behavior tests. Behavior tests did not affect neurogenesis in either strain. Hippocampal neurogenesis correlated negatively with the results of a forced swim test (FST) on day 2 in each strain. That is, rats with a lower level of native neurogenesis in the DG showed a higher level of learned helplessness induced by the inescapable stress of the FST on day 1. Our findings indicate that hippocampal neurogenesis in WKY rats is congenitally impaired in contrast to that in WIS rats. Native cell proliferation and neurogenesis in the DG are correlated with stress resistance. These findings may be useful for developing new targets for depression treatment.

DOI： 10.1016/j.bbr.2017.04.046

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Newly published clinical practice guidelines recommend intracranial pressure (ICP) monitoring in critical care for the management of pediatric acute encephalopathy (pAE), but the utility of ICP monitoring for pAE has been poorly studied. We recently performed direct ICP monitoring for two patients. We observed that although the direct ICP monitoring had clinical benefits with less body weight gain and no vasopressor use in both cases, this monitoring technique is still invasive. Future studies should determine the utility of non-invasive ICP monitoring systems in pAE to further improve the quality of intensive-care management.

DOI： 10.18926/AMO/54987

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Language：Japanese   Publisher：The Japan Stroke Society  

<p>Rehabilitation is one of the essential treatments for the patients with stroke to achieve good functional recovery and subsequent social participation of the patients. In this mini review, we show two basic researches of our laboratory. One is neuroprotective effects of rehabilitation for Parkinson's disease model of rats and the other is decreased neurogenesis by the lack of exercise through hindlimb suspension of rats. Finally, the significance of rehabilitation with future direction of regenerative medicine for the patients with stroke in this field is stressed.</p>

DOI： 10.3995/jstroke.10482

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Language：English   Publishing type：Research paper (scientific journal)  

Unexpected injuries can have a profound effect on a surgeon's performance and thus on patients and surgical departments. Here we describe a technique for performing surgery in the standing position, as done by a surgeon with an Achilles tendon rupture. During his prescribed 45-day non-weight-bearing period for the left ankle after surgery for an Achilles tendon rupture, the surgeon was able to participate in 15 surgeries as an operator or assistant, due to his use of a combination of injured-leg genuflection on a stool and a 'Surgical Body Support' device. Similarly injured surgeons may benefit from such support.

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Study Design Retrospective comparative study. Objective To evaluate the accuracy of percutaneous pedicle screw (PPS) placement and intraoperative imaging time using dual fluoroscopy units and their differences between surgeons with more versus less experience. Methods One hundred sixty-one patients who underwent lumbar fusion surgery were divided into two groups, A (n = 74) and B (n = 87), based on the performing surgeon's experience. The accuracy of PPS placement and radiation time for PPS insertion were compared. PPSs were inserted with classic technique under the assistance of dual fluoroscopy units placed in two planes. The breach definition of PPS misplacement was based on postoperative computed tomography (grade I: no breach; grade II: <2 mm; grade III: ≤2 to <4 mm). Results Of 658 PPSs, only 21 screws were misplaced. The breach rates of groups A and B were 3.3% (grade II: 3.4%, grade III: 0%) and 3.1% (grade II: 2.6%, grade III: 0.6%; p = 0.91). One patient in grade III misplacement had a transient symptom of leg numbness. Median radiation exposure time during PPS insertion was 25 seconds and 51 seconds, respectively (p < 0.01). Conclusions Without using an expensive imaging support system, the classic technique of PPS insertion using dual fluoroscopy units in the lumbar and sacral spine is fairly accurate and provides good clinical outcomes, even among surgeons lacking experience.

DOI： 10.1055/s-0035-1563405

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Delayed symptomatic vasospasm after clipping surgery for unruptured aneurysm is rarely reported. We report a case of a 62-year-old woman who presented with symptomatic vasospasm 11 days after clipping surgery for an unruptured aneurysm. We could not predict the existence of vasospasm until ischemic symptoms developed. We retrospectively found mild vasospasm in the computed tomography angiogram taken 8 days after the operation. The patient complained of a prolonged unexpected headache 1 week after the operation. We should recognize prolonged unexpected headache as a warning sign of vasospasm.

DOI： 10.1016/j.jstrokecerebrovasdis.2015.11.029

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Language：Japanese   Publisher：(一社)日本脳卒中の外科学会  

当院のHybrid operating room(Hybrid OR)の特徴や具体的な使用方法について検討した。手術室の敷地面積の広さを最大の特徴とする当院のHybrid ORで治療を行った連続14症例(男6例、女8例、平均年齢51.1歳)における各支援機器の使用頻度は術中血管撮影79%、indocyanine green蛍光血管撮影86%、Doppeler血流検査86%、motor evoked potential 75%、navigation 21%であった。血管撮影装置は診断目的にのみ使用したが、術中血管撮影は安全に反復して施行でき、他の手術支援機器との併用も可能で、小型病変のarteriovenous malformation(AVM)の局在把握やAVM摘出後の微細な残存病変の評価に有用であった。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J02079&link_issn=&doc_id=20160408210007&doc_link_id=%2Fcp4strok%2F2016%2F004402%2F007%2F0125-0131%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcp4strok%2F2016%2F004402%2F007%2F0125-0131%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1 day and astrocytes at 7 days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

DOI： 10.1016/j.expneurol.2015.11.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN NEUROSURGICAL SOC  

Perioperative management is critical for positive neurosurgical outcomes. In order to maintain safe and authentic perioperative management, a perioperative management center (PERIO) was introduced to patients of our Neurosurgery Department beginning in June 2014. PERIO involves a multidisciplinary team consisting of anesthesiologists, dentists/dental hygienists/technicians, nurses, physical therapists, pharmacists, and nutritionists. After neurosurgeons decide on the course of surgery, a preoperative evaluation consisting of blood sampling, electrocardiogram, chest X-ray, and lung function test was performed. The patients then visited the PERIO clinic 7-14 days before surgery. One or two days before surgery, the patients without particular issues enter the hospital and receive a mouth cleaning one day before surgery. After surgery, postoperative support involving eating/swallowing evaluation, rehabilitation, and pain control is provided. The differences in duration from admission to surgery, cancellation of surgery, and postoperative complications between PERIO and non-PERIO groups were examined. Eighty-five patients were enrolled in the PERIO group and 131 patients in the non-PERIO group. The duration from admission to surgery was significantly decreased in the PERIO group (3.6 +/- 0.3 days), compared to that in the non-PERIO group (4.7 +/- 0.2 days). There was one cancelled surgery in the PERIO group and six in the non-PERIO group. Postoperative complications and the overall hospital stay did not differ between the two groups. The PERIO system decreased the duration from admission to surgery, and it is useful in providing high-quality medical service, although the system should be improved so as not to increase the burden on medical staff.

DOI： 10.2176/nmc.oa.2016-0085

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INTRODUCTION: Superior ophthalmic vein thrombosis is a rare entity, but is associated with significant morbidities. We describe a case in which superior ophthalmic vein thrombosis occurred shortly after severe facial trauma. CASE PRESENTATION: A 77-year-old Japanese man was transferred to our tertiary hospital after a motor vehicle accident. Le Fort III facial bone fractures and a minor cerebral contusion were detected. Follow-up computed tomography scans detected dilatation of his left superior ophthalmic vein on day 3 and thrombosis on day 12; however, no causative carotid cavernous fistula was observed. As he did not present with any symptoms other than slight conjunctival congestion, a conservative management strategy was adopted along with anticoagulant therapy against deep venous thrombosis. The superior ophthalmic vein thrombosis resolved spontaneously and the conjunctival congestion also improved. CONCLUSIONS: Superior ophthalmic vein thrombosis should be taken into consideration and managed properly after severe facial injuries, and further investigation of its cause is necessary to prevent morbidities.

DOI： 10.1186/s13256-015-0737-y

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Language：Japanese   Publisher：(株)メディカ出版  

圧迫性脊髄症に対するC1椎弓切除術後、数ヵ月の経過でC1前弓骨折を生じた3症例を報告した。症例1(72歳男)、症例2(60歳男)、症例3(66歳男)で、いずれも強い頸部痛にて受診し、頸椎CTにてC1前弓骨折を認めた。術後数ヵ月での発症、日常生活動作で受傷、頸部の動きで増悪する疼痛、神経症状の悪化なしという共通点を有し、いずれもC2棘突起および付着筋群への侵襲がアライメントの更なる悪化の一因と思われた。3症例とも装具による外固定により頸部痛は軽減し、骨癒合は得られていないものの症候性の不安定を呈することなく慎重な画像フォローのもと保存的加療を継続している。

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Spinal dural arteriovenous fistulas(S-dAVFs)are rare vascular malformations of the spine. We experienced a case that presented with rapidly progressive brainstem dysfunction due to venous congestion of cervical dAVFs. A 56-year-old man diagnosed with cervical dAVF four years prior presented with gait disturbance and abnormal thermal nociception on his right side. In addition to the high-intensity lesion from the lower pons to the medulla oblongata on T2-weighted magnetic resonance imaging, diffusion-weighted imaging demonstrated cerebral infarction of the left ventrolateral medulla oblongata. Left vertebral angiography revealed that a feeding artery supplied by the radicular artery at the C4 level formed a fistula with the dilated ascending anterior perimedullary vein. We made a diagnosis of venous congestion due to cervical dAVFs. Numbness on the left upper limb occurred five days after the first symptom. Subsequently, hemiparesis on the left upper limb and swallowing disturbance occurred two weeks after the first symptom. The patient underwent surgical ligation of the dilated abnormal vein, with gradual improvement of his symptoms. Myelopathy due to venous congestion of S-dAVFs usually progresses slowly for several years. However, this case report warns about the possibility that some cases of S-dAVF with rapidly exacerbated symptoms may require prompt therapy.

DOI： 10.11477/mf.1436202944

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Language：Japanese   Publisher：The Japanese Society of Spinal Surgery  

DOI： 10.2531/spinalsurg.29.323

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Other Link： http://search.jamas.or.jp/link/ui/2016163799

Language：Japanese   Publisher：The Japanese Society of Spinal Surgery  

DOI： 10.2531/spinalsurg.29.77

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Other Link： http://search.jamas.or.jp/link/ui/2015237853

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Intra-arterial stem cell transplantation exerts neuroprotective effects for ischemic stroke. However, the optimal therapeutic time window and mechanisms have not been completely understood. In this study, we investigated the relationship between the timing of intra-arterial transplantation of allogeneic mesenchymal stem cells (MSCs) in ischemic stroke model in rats and its efficacy in acute phase. METHODS: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. MSCs (1 × 10(6) cells/ 1 ml PBS) were intra-arterially injected at either 1, 6, 24, or 48 hours (1, 6, 24, 48 h group) after MCAO. PBS (1 ml) was intra-arterially injected to control rats at 1 hour after MCAO. Behavioral test was performed immediately after reperfusion, and at 3, 7 days after MCAO using the Modified Neurological Severity Score (mNSS). Rats were euthanized at 7 days after MCAO for evaluation of infarct volumes and the migration of MSCs. In order to explore potential mechanisms of action, the upregulation of neurotrophic factor and chemotactic cytokine (bFGF, SDF-1α) induced by cell transplantation was examined in another cohort of rats that received intra-arterial transplantation at 24 hours after recanalization then euthanized at 7 days after MCAO for protein assays. RESULTS: Behavioral test at 3 and 7 days after transplantation revealed that stroke rats in 24h group displayed the most robust significant improvements in mNSS compared to stroke rats in all other groups (p's<0.05). Similarly, the infarct volumes of stroke rats in 24h group were much significantly decreased compared to those in all other groups (p's<0.05). These observed behavioral and histological effects were accompanied by MSC survival and migration, with the highest number of integrated MSCs detected in the 24h group. Moreover, bFGF and SDF-1α levels of the infarcted cortex were highly elevated in the 24h group compared to control group (p's<0.05). CONCLUSIONS: These results suggest that intra-arterial allogeneic transplantation of MSCs provides post-stroke functional recovery and reduction of infarct volumes in ischemic stroke model of rats. The upregulation of bFGF and SDF-1α likely played a key mechanistic role in enabling MSC to afford functional effects in stroke. MSC transplantation at 24 hours after recanalization appears to be the optimal timing for ischemic stroke model, which should guide the design of clinical trials of cell transplantation for stroke patients.

DOI： 10.1371/journal.pone.0127302

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Regenerative medicine for Parkinson’s disease (PD) is expected to develop dramatically with the advancement of biotechnology as represented by induced pluripotent stem cells. Existing therapeutic strategy for PD consists of medication using L-DOPA, surgery such as deep brain stimulation and rehabilitation. Current treatment cannot stop the progression of the disease, although there is definite therapeutic effect. True neurorestoration is strongly desired by regenerative medicine. This review article describes the historical development of regenerative medicine for PD, with a focus on fetal nigral cell transplantation and glial cell line-derived neurotrophic factor infusion. Subsequently, the current status of regenerative medicine for PD in terms of cell therapy and gene therapy are reviewed. In the end, the future direction to realize regenerative medicine for PD is discussed.

DOI： 10.2176/nmc.ra.2014-0264

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Language：English   Publishing type：Research paper (scientific journal)  

Regenerative medicine for Parkinson's disease (PD) is expected to develop dramatically with the advancement of biotechnology as represented by induced pluripotent stem cells. Existing therapeutic strategy for PD consists of medication using L-DOPA, surgery such as deep brain stimulation and rehabilitation. Current treatment cannot stop the progression of the disease, although there is definite therapeutic effect. True neurorestoration is strongly desired by regenerative medicine. This review article describes the historical development of regenerative medicine for PD, with a focus on fetal nigral cell transplantation and glial cell line-derived neurotrophic factor infusion. Subsequently, the current status of regenerative medicine for PD in terms of cell therapy and gene therapy are reviewed. In the end, the future direction to realize regenerative medicine for PD is discussed.

DOI： 10.2176/nmc.ra.2014-0264

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Other Link： http://search.jamas.or.jp/link/ui/2015374130

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Objective: We wished to relate severity of Parkinson's disease (PD) with cognitive function in relation to cerebral blood flow (CBF).
Methods: Eighty-one consecutive PD patients were enrolled in this study. We used Mini-Mental State Examination (MMSE) and Wechsler Adult Intelligence Scale-Third edition (WAIS-III) to evaluate cognitive functions, and three-dimensional stereotactic ROI template (3DSRT) and Statistical Parametric Mapping (SPM) 8 to evaluate single photon emission CT (SPECT) recordings of regional CBF.
Results: The mean MMSE score of PD patients was 27.4 +/- 2.4. The scores of most patients were higher than 23/30. On the other hand, the mean Full-scale IQ of PD patients was 88.4 +/- 17.3 in WAIS-III, which was lower than that of normal controls. In particular, visuospatial function score of most patients was lower. There was significant correlation between cognitive scores and Hoehn & Yahr stage and hallucinatory episodes. PD Patients with stage III and IV showed significant deterioration in cognitive functions compared to stage II patients. Analysis of CBF revealed relative reductions in perfusion in the cerebral cortex relative to that in normal control. SPM 8 showed that cognitive functions in PD patients were positively correlated with rCBF in the thalamus and cingulate gyrus.
Conclusions: This is the study to demonstrate the cognitive impairments in PD patients using WAIS-III. Visuospatial dysfunction might be caused by decrease in rCBF in the parietal and occipital lobes and dorsolateral prefrontal cortex. The severity of cognitive impairments in PD patients was correlated with disease severity and hallucinatory episodes. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.parkreldis.2014.01.002

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Language：Japanese   Publisher：(一社)日本脊髄外科学会  

症例はパーキンソン病加療中の61歳女性で、増悪する体動時の腰痛を主訴に受診した。MRI、CT所見および二重エネルギーX線吸収法による大腿骨頸部の骨密度測定により、骨粗鬆症性L2椎体骨折と診断し、Ballon kyphoplasty(BKP)を施行した。術後疼痛は軽減し、術後20日で歩行器にて見守り歩行の状態で回復期リハビリテーション病院に転院した。術後122日目の腰椎単純X線にて骨セメントの前方移動および立位でL2レベルに強い局所後彎(後彎角36度)を認めた。仰臥位では椎体内に骨セメントが戻り、CTでは椎体が前後に離断してしまい椎体前部もろとも骨セメントが移動していることが確認された。コルセットによる外固定を継続したが、術後158日目に両下肢疼痛のため再び歩行困難となったため、術後182日目にT10-L5後側方固定術を施行した。再手術後に下肢痛は消失し、再手術後88日目に歩行器で自宅退院となり、術後16ヵ月で前方骨架橋が完成した。

DOI： 10.2531/spinalsurg.28.52

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Language：Japanese   Publisher：(一社)日本脊椎脊髄病学会  

2011年1月にballoon kyphoplasty(BKP)が保険収載され、当院でも2012年8月までに28例32椎体に施行した。施術は正面側面2方向の透視下に経皮的両側経椎弓根的に行い、有害な周術期合併症は認められなかった。術後3ヵ月の時点で疼痛および椎体高の有意な改善が維持されたが、後彎の改善はみられなかった。経過観察可能であった26例中6例に隣接椎体骨折をきたし、1例で骨セメントの前方脱出をきたした。当院での経験を省みてBKPの問題点を検討する。(著者抄録)

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In clinical practice, deep brain stimulation (DBS) is effective for treatment of motor symptoms in Parkinson's disease (PD). However, the mechanisms have not been understood completely. There are some reports that electrical stimulation exerts neuroprotective effects on the central nervous system diseases including cerebral ischemia, head trauma, epilepsy and PD, although there are a few reports on neuroprotective effects of spinal cord stimulation (SCS). We investigated the neuroprotective effects of high cervical SCS on PD model of rats. Adult female Sprague-Dawley rats received hour-long SCS (2, 50 or 200 Hz) with an epidural electrode at C1-2 level for 16 consecutive days. At 2 days after initial SCS, 6-hydroxydopamine (6-OHDA) was injected into the right striatum of rats. Behavioral evaluations of PD symptoms were employed, including cylinder test and amphetamine-induced rotation test performed at 1 and 2 weeks after 6-OHDA injection. Animals were subsequently euthanized for immunohistochemical investigations. In order to explore neurotrophic and growth factor upregulation induced by SCS, another cohort of rats that received 50 Hz SCS was euthanized at 1 and 2 weeks after lesion for protein assays. Behavioral tests revealed that the number of amphetamine-induced rotations decreased in SCS groups. Immunohistochemically, tyrosine hydroxylase (TH)-positive fibers in the striatum were significantly preserved in SCS groups. TH-positive neurons in the substantia nigra pars compacta were significantly preserved in 50 Hz SCS group. The level of vascular endothelial growth factor (VEGF) was upregulated by SCS at 1 week after the lesion. These results suggest that high cervical SCS exerts neuroprotection in PD model of rats, at least partially by upregulation of VEGF. SCS is supposed to suppress or delay PD progression and might become a less invasive option for PD patients, although further preclinical and clinical investigations are needed to confirm the effectiveness and safety.

DOI： 10.1371/journal.pone.0101468

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The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson's test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

DOI： 10.3390/ijms141121513

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Traumatic brain injury (TBI) sustained in a traffic accident or a fall is a major cause of death that affects a broad range of ages. The aim of this study was to investigate the therapeutic effects of intra-arterial transplantation of mesenchymal stem cells (MSCs) combined with hypertonic glycerol (25%) or mannitol (25%) in a TBI model of rats. TBI models were produced with a fluid percussion device. At 24h after TBI, MSCs (1×10(6)cells/100μl) with glycerol or mannitol were administered via the right internal carotid artery. Rats were evaluated behaviorally and immunohistochemically, and hyperpermeability of the blood-brain barrier (BBB) induced by hypertonic solutions was explored. Compared to PBS or glycerol, the administration of mannitol resulted in increased BBB disruption. The mannitol-treated rats showed significant improvement in motor function. Intra-arterial transplantation of MSCs caused no thromboembolic ischemia. Immunohistochemically, more MSCs were observed in the injured brain tissues of mannitol-treated rats than in glycerol or PBS-treated rats at 24h after transplantation. Intra-arterial transplantation of MSCs combined with mannitol is an effective treatment in a TBI model of rats. This technique might be used for patients with diseases of the central nervous system including TBI.

DOI： 10.1016/j.neulet.2013.08.058

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Language：Japanese   Publisher：(一社)日本脊髄外科学会  

65歳以上の高齢者の非骨傷性頸髄損傷25例(男性16例、女性9例、平均74.4歳)について検討した。受傷原因は転倒16例、転落6例、交通障害3例で、全例が脊柱管狭窄症(頸椎症19例、後縦靱帯骨下症6例)を合併していた。主な損傷高位はC3/4:14例、C4/5:6例、C5/6:5例、入院時のFrankel分類はA:3例、B:3例、C:12例、D:7例であった。治療は保存的加療のみ11例、保存的加療後に外科的加療14例(前方徐圧固定術2例、椎弓形成術12例)であり、受傷から手術までの期間は平均20.1日であった。退院時のFrankel分類はA:3例、B:0例、C:4例、D:16例、E:2例であった。入院時A:3例は保存的加療で神経症状の改善が得られず、外科的加療群は保存的加療群に比べ改善度が高い傾向にあり、入院時にMRI T2強調で髄内高輝度変化と椎体前面の血腫が認められた10例では、他の15例に比べ改善度が低い傾向であった。

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Language：Japanese   Publisher：(株)メディカ出版  

胸腰椎椎体破裂骨折に対する筋間アプローチによる椎弓根スクリュー固定術について検討した。double C arm techniqueで刺入した椎弓根スクリュー218本(自験42例、単一術者)について、CTを用いて、誤刺入・スクリューのずれをretrospectiveに検討した。誤刺入例は0本であった。スクリューのずれに関しては、最大で2mm以内であり、2本(0.9%)に認めた(grade B)。いずれもスクリュー刺入に伴う神経損傷や、血管損傷などの合併症を認めなかった。他のスクリューはすべて椎弓根内に挿入されており、grade Aと評価された。自験42例については、フォロー期間がまだ短いが、1年以上の経過において1例もinstrument faliureを認めておらず、抜釘に至った症例も42例中、約半数の20例を超えた。

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Language：Japanese   Publisher：(一社)日本脊髄外科学会  

症例は40歳女性で、薬物治療歴はなく、アルコール多飲があった。自家用車内で約3分間の全身強直性痙攣を来たし、救急搬送された。脳神経外科に入院し翌日意識清明となったが、強い腰痛を訴え脊髄脊椎外科を紹介受診した。X線立位側面像でL3椎体上部の圧潰および椎体上部のずれを、正面像では同椎体に右6度の椎体楔状変形が認められた。MRIでも椎弓根部に及ぶ輝度変化としてT2強調画像脂肪抑制で高輝度、T1強調画像で低輝度を呈した。骨密度はやや低下していたが骨粗鬆症ではなかった。非外傷性腰椎椎体骨折と診断し、半硬性コルセットによる外固定を中心とした保存的加療を行い、疼痛がやや改善したため発症12日に自宅退院したが、除痛加療を希望したため第30病日にballoon kyphoplastyを施行した。椎体は既に右側の局所硬化が進み、バルーン拡張が不十分であったが、疼痛は完全に消失して術後4日目に独歩退院した。

DOI： 10.2531/spinalsurg.27.57

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Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons. Thus the development of therapeutic neuroprotection and neurorescue strategies to mitigate disease progression is important. In this study we evaluated the neuroprotective/rescue effects of erythropoietin Fc fusion protein (EPO-Fc) and carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Adult female Sprague-Dawley rats received intraperitoneal injection of EPO-Fc, CEPO-Fc or PBS. Behavioral evaluations consisted of rota-rod, cylinder and amphetamine-induced rotation tests. In the neuroprotection experiment, the CEPO-Fc group demonstrated significant improvement compared with the EPO-Fc group on the amphetamine-induced rotation test throughout the four-week follow-up period. Histologically, significantly more tyrosine hydroxylase (TH)-positive neurons were recognized in the substantia nigra (SN) pars compacta in the CEPO-Fc group than in the PBS and EPO-Fc groups. In the neurorescue experiment, rats receiving CEPO-Fc showed significantly better behavioural scores than those receiving PBS. The histological data concerning striatum also showed that the CEPO-Fc group had significantly better preservation of TH-positive fibers compared to the PBS and EPO-Fc groups. Importantly, there were no increases in hematocrit or hemoglobin levels in the CEPO-Fc group in either the neuroprotection or the neurorescue experiments. In conclusion, the newly developed CEPO-Fc might confer neuroprotective and neurorescue benefits in a rat model of Parkinson's disease without the side effects associated with polycythemia. CEPO-Fc might be a therapeutic tool for patients with Parkinson's disease.

DOI： 10.1016/j.brainres.2013.01.042

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PURPOSE: Cervical disc herniation (CDH) is found more frequently at the lower cervical spine than at the upper or middle level. However, there is scarcity of data about the laterality of CDH. The aim of this study is to detect the laterality of CDH. METHODS: We retrospectively evaluated preoperative computed tomography myelograms and magnetic resonance images of 75 cases of CDH who underwent single level anterior cervical discectomy and fusion at C4-5, C5-6, or C6-7 levels from 2008 to 2010 in our institute. Statistical analyses were performed using the Chi-square test. RESULTS: Eleven cases were found at C4-5 level, 42 cases at C5-6 level, and 22 cases at C6-7 level. At C4-5 level, CDH was recognized at the right side in 2 cases, at the left side in 2 cases, and at the center in 7 cases. At C5-6 level, CDH was found at the right side in 20 cases and at the left side in 22 cases. At C6-7 level, CDH was found at the right side in 3 cases and at the left side in 19 cases with significantly high frequency of left-sided CDH (p < 0.025). CONCLUSIONS: In this study, it was revealed that the left-sided CDH was more frequent than the right-sided CDH at C6-7 level.

DOI： 10.1007/s00586-012-2565-8

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Some cases with lumbar degenerative diseases require multi-level fusion surgeries. At our institute, 27 and 4 procedures of 3- and 4-level fusion were performed out of a total 672 posterior lumbar interfusions (PLIFs) on patients with lumbar degenerative disease from 2005 to 2010. We present 2 osteoporotic patients who developed proximal vertebral body fracture after 4-level fusion. Both cases presented with gait disability for leg pain by degenerative lumbar scoliosis and canal stenosis at the levels of L1/2-4/5. After 4-level fusion using L1 as the upper instrumented vertebra, proximal vertebral body fractures were found along with the right pedicle fractures of L1 in both cases. One of these patients, aged 82 years, was treated as an outpatient using a hard corset for 24 months, but the fractures were exacerbated over time. In the other patient, posterolateral fusion was extended from Th10 to L5. Both patients can walk alone and have been thoroughly followed up. In both cases, the fracture of the right L1 pedicle might be related to the subsequent fractures and fusion failure. In consideration of multi-level fusion, L1 should be avoided as an upper instrumented vertebra to prevent junctional kyphosis, especially in cases with osteoporosis and flat back posture.

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Magnetic resonance imaging is used with increasing frequency to provide accurate clinical information in cases of acute brain injury, and it is important to ensure that intracranial pressure (ICP) monitoring devices are both safe and accurate inside the MRI suite. A rare case of thermal brain injury during MRI associated with an overheated ICP transducer is reported. This 20-year-old man had sustained a severe contusion of the right temporal and parietal lobes during a motor vehicle accident. An MR-compatible ICP transducer was placed in the left frontal lobe. The patient was treated with therapeutic hypothermia, barbiturate therapy, partial right temporal lobectomy, and decompressive craniectomy. Immediately after MRI examination on hospital Day 6, the ICP monitor was found to have stopped working, and the transducer was subsequently removed. The patient developed meningitis after this event, and repeat MRI revealed additional brain injury deep in the white matter on the left side, at the location of the ICP transducer. It is suspected that this new injury was caused by heating due to the radiofrequency radiation used in MRI because it was ascertained that the tip of the transducer had been melted and scorched. Scanning conditions--including configuration of the transducer, MRI parameters such as the type of radiofrequency coil, and the specific absorption rate limit--deviated from the manufacturer's recommendations. In cooperation with the manufacturer, the authors developed a precautionary tag describing guidelines for safe MR scanning to attach to the display unit of the product. Strict adherence to the manufacturer's guidelines is very important for preventing serious complications in patients with ICP monitors undergoing MRI examinations.

DOI： 10.3171/2012.9.JNS12738

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

胸腰椎椎体骨折4椎間固定における筋間アプローチによる椎弓根スクリュー固定術(A群:12例)とOpen PLF(B群:3例)の成績を比較検討した。その結果、手術時間は両群間で有意差を認めなかった。しかし一方、術中出血量および手術1週間後における傍脊柱筋のMRI T2高信号域の割合はA群で有意な減少が確認された。

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Language：Japanese   Publisher：(NPO)日本脳神経外科救急学会  

われわれのグループ(社会医療法人財団池友会、巨樹の会)で運用している民間医療搬送用ヘリ(以下ホワイトバード)は、2008年10月1日より運航を開始し、2011年12月までに491例の患者搬送を行ってきた。その内、脊髄脊椎疾患に関する搬送は121例であった。疾患の内訳は、外傷(脊髄損傷、脊椎骨折)48例、変性疾患(頸椎症性脊髄症、腰部脊柱管狭窄症、椎間板ヘルニアなど)55例、その他(化膿性脊椎炎、硬膜外血腫、脊椎腫瘍、脊髄梗塞など)18例であった。ホワイトバードは、重症患者や緊急性を要する患者の搬送はもちろんであるが、軽症患者の搬送や術後患者の下り搬送にも利用できる。脊髄脊椎疾患におけるホワイトバードの運航状況について、症例をまじえて報告する。(著者抄録)

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DOI： 10.4044/joma.124.111

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Human umbilical cord blood (HUCB) cells are rich source of immature stem cells, which have the potential to repair lost tissue. Intractable central nervous system (CNS) disorders are important targets for regenerative medicine, and the application of HUCB cells is being investigated in animal models of CNS disorders. Transplantation of HUCB has induced functional improvements in these animal models due to multiple therapeutic effects including neuroprotection, anti-inflammation, angiogenesis, and neurogenesis. HUCB cells are easily available and safer than other stem cells used in transplantation therapy. In this review, we focus on HUCB transplantation as an encouraging therapeutic approach for animal models of neonatal hypoxic-ischemic brain injury and ischemic stroke.

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A 69-year-old woman presented with a rare case of multiple supra- and infratentorial intracranial hemorrhages after cervical laminoplasty for cervical spondylotic myelopathy without intraoperative liquorrhea. A wound drainage tube under negative pressure was placed with subsequent 380 ml of drainage in the first 12 hours. She had no complaint of headache and nausea at that time. Computed tomography of the brain obtained at 15 hours after surgery demonstrated cerebellar hemorrhage, acute subdural hemorrhage, subarachnoid hemorrhage, supratentorial intraparenchymal hemorrhage, and pneumocephalus. She was treated medically without consequent neurological deficits other than right hemianopsia. Overdrainage of cerebrospinal fluid through an occult dural tear might cause severely low intracranial pressure with subsequent multiple intracranial hemorrhages. Wound drainage should be controlled thoroughly even in patients without intraoperative liquorrhea.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Cell transplantation has been shown to be an effective therapy for central nervous system disorders in animal models. Improving the efficacy of cell transplantation depends critically on improving grafted cell survival. We investigated whether glial cell line-derived neurotrophic factor (GDNF)-pretreatment of neural stem cells (NSCs) enhanced grafted cell survival in a rat model of Parkinson&apos;s disease (PD). We first examined the neuroprotective effects of GDNF on oxygen-glucose deprivation (OGD) in NSCs. Cells were pretreated with GDNF for 3 days before subjecting them to OGD. After 12 h of OGD, GDNF-pretreated NSCs showed significant increases in survival rates compared with PBS-pretreated NSCs. An apoptosis assay showed that the number of apoptotic cells was significantly decreased in GDNF-pretreated NSCs at 1 h and 6 h after OGD. A PD rat model was then established by unilateral injection of 6-hydroxydopamine (6-OHDA, 9 pig) into the medial forebrain bundle. Two weeks after 6-OHDA injection, GDNF-pretreated NSCs, PBS-pretreated NSCs, or PBS were injected into PD rat striatum. The survival of grafted cells in the striatum was significantly increased in the GDNF-pretreated NSC group compared with the control groups. GDNF pretreatment increased survival of NSCs following transplantation, at least partly through suppression of cell apoptosis. (C) 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2011.05.019

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Increased oxidative stress contributes to pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the oxidation product most frequently measured as an indicator of oxidative DNA damage. Several studies have shown increased 8-OHdG in PD patients. There are few basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we utilized hemiparkinsonian model of rats induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). The urinary 8-OHdG level was measured in relation to behavioral and pathological deficits arising from 6-OHDA-induced neurotoxic effects on the nigrostriatal dopaminergic pathway. All rats were subjected to a series of behavioral tests for 42 days after 6-OHDA injection. We collected urine samples with subsequent measurement of 8-OHdG level using ELISA kits. For immunohistochemical evaluation, tyrosine hydroxylase (TH) staining was performed. Significant increments in urinary 8-OHdG level were observed continuously from day 7 until day 35 compared to control group, which showed a trend of elevation as early as day 3. Such elevated urinary 8-OHdG level significantly correlated with all of the behavioral deficits measured here, suggesting that urinary 8-OHdG level provides a good index of severity of parkinsonism. Urinary 8-OHdG level also had a significant positive correlation with the survival rate of dopaminergic fibers or neurons, advancing the concept that oxidative stress during the early phase of 6-OHDA neurotoxicity may correspond to disease progression closely approximating neuronal degeneration in the nigrostriatal dopaminergic system. The present results demonstrate that alterations in urinary 8-OHdG level closely approximate onset and disease progression in PD.

DOI： 10.1002/jcp.22467

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DOI： 10.1016/j.clineuro.2010.10.014

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Posterior reversible encephalopathy syndrome (PRES) is a clinico-neuroradiological entity with typical symptoms and symmetric high-signal intensity lesions in the bilateral parieto-occipital lobes on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. We described three patients with PRES of varied etiologies. Patient 1 was a young man with severe hypertension who presented with headache and visual disturbance. Patient 2 had leukemia and was receiving umbilical cord blood cell transplantation with immunosuppressant, and developed PRES with convulsions. Patient 3 was a pregnant woman with renal failure, who repeatedly developed PRES with convulsions. FLAIR and apparent diffusion coefficient mapping were useful in detecting PRES lesions in our patients, although diffusion-weighted imaging and CT scans had limited use in the diagnosis. Adequate and prompt treatment with antihypertensive medication immediately ameliorated the symptoms, with improvement of abnormal MRI findings. In previous reports, delayed diagnosis might have affected the prognosis. Further work on the clinical manifestations of PRES and its therapy is required.

DOI： 10.1016/j.jocn.2010.06.011

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A case of a Chiari malformation with an extraordinarily thick occipital bone is described. The thick occipital bone might make the posterior fossa narrow with consequent herniation of the cerebellar tonsils to the foramen magnum and formation of a syrinx. At dural plasty, well-developed marginal and occipital sinuses should be deliberately handled with the preservation of normal venous drainage. This case gives us the essence of the occurrence mechanisms of Chiari malformation and foramen magnum decompression.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Brain-derived neurotrophic factor (BDNF) is a well neurotrophic factor with neuroprotective potentials for various diseases in the central nervous system. However several previous studies demonstrated that BDNF might deteriorate symptoms for epilepsy model of animals by progression of abnormal neurogenesis. We hypothesized that continuous administration of BDNF at low dose might be more effective for epilepsy model of animals because high dose of BDNF was used in many studies. BDNF-secreting cells were genetically made and encapsulated for transplantation. Rats receiving BDNF capsule showed significant amelioration of seizure stage and reduction of the number of abnormal spikes at 7 days after kainic acid administration, compared to those of control group. The number of BrdU and BrdU/doublecortin positive cells in the hippocampus of BDNF group significantly increased, compared to that of control group. NeuN positive cells in the CA1 and CA3 of BDNF group were significantly preserved, compared to control group. In conclusion, low dose administration using encapsulated BDNF-secreting cells exerted neuroprotective effects with enhanced neurogenesis on epilepsy model of rats. These results might suggest the importance of the dose and administrative way of this neurotrophic factor to the epilepsy model of animals.

DOI： 10.1016/j.brainres.2010.10.054

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Language：Japanese   Publisher：(NPO)日本脳神経外科救急学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本脳神経外科救急学会  

再生医療と救急医療は現時点で大きなOverlapはないが、今後、急性期に治療効果を有する再生医療が救急医療の現場で行われる可能性は十分ある。凍結保存細胞移植はその有望な候補であり、その概念ならびに我々の基礎研究結果を示し、今後の展望を述べた。(著者抄録)

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A 29-year-old man presented with a rare case of far-out foraminal stenosis with radiculopathy caused by osteophyte formation secondary to an anomalous articulation between the transverse process and the sacral ala. Diagnosis of unilateral far-out foraminal entrapment of the L5 spinal nerve below a transitional vertebra (TV) depended on selective radiculography and nerve root block. Computed tomography after selective radiculography clearly demonstrated foraminal entrapment of the L5 nerve root via the osteophytes. The patient underwent posterior decompression by resection of the osteophytes using an operating microscope and experienced good relief of radicular pain. This case illustrates the effectiveness and some refinements of posterior decompression for radicular pain caused by far-out foraminal stenosis below a TV and compression of the L5 spinal nerve.

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A 27-year-old woman presented with a case of primary medulla oblongata germinoma manifesting as sleep apnea, aspiration pneumonia, and left hemiparesis. Magnetic resonance (MR) imaging revealed a dorsal mass in the medulla oblongata with heterogeneous enhancement by gadolinium (Gd). Emergent biopsy and foramen magnum decompression with C1 laminectomy were performed because of rapid worsening of her symptoms. The histological diagnosis was germinoma. Subsequently she received chemoradiation therapy with subsequent amelioration of her neurological deficits and disappearance of enhancement on MR imaging with Gd. Primary medulla oblongata germinoma is rare and difficult to diagnose preoperatively. However, correct diagnosis and subsequent adequate chemoradiation therapy is possible by understanding the common characteristics of the disease. Germinoma should be included in the differential diagnosis of midline medullary lesion in young patients, and biopsy should be considered.

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A 11-year-old female with Noonan syndrome presented with occipito-atlantal dislocation and upper cervical cord compression due to C1 dysplasia and basilar invagination. Computed tomography (CT) of the cervical spine showed dysplasia of the C1 posterior arch and bilateral dislocation of the occipito-atlantal joints. Dynamic lateral radiography revealed no instability at the occipito-atlantal joints. CT also demonstrated basilar invagination. The tip of the odontoid process extended above the Chamberlain line by 9 mm and the McGregor line by 10 mm. Whole spinal radiography showed no scoliosis. C1 laminectomy was performed with instrumented occipito-C2 fixation. The postoperative course was uneventful, and magnetic resonance imaging revealed sufficient decompression of the upper cervical cord at 2 months after surgery. CT demonstrated solid bony fusion between the occipital bone and C2 at 8 months after surgery. Cervical neuraxial malformations are rare in patients with Noonan syndrome.

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A 78-year-old man presented with a rare massive subarachnoid hematoma (SAH) in the cervical spine after coronary stenting for angina pectoris. Chest pain and electrocardiographic changes were resolved after administration of coronary dilator and coronary stenting, but shoulder pain persisted. At 6 hours after stenting, left hemiparesis was found with deteriorated shoulder pain. Computed tomography and magnetic resonance imaging revealed massive SAH in the cervical spine. Emergent hematoma evacuation with laminoplasty was performed because of rapid progression of the hemiparesis and pain. The hemiparesis was ameliorated after surgery. Spinal hematoma should be considered in the differential diagnosis in patients receiving anti-platelet or anti-coagulant drugs with rapid progression of pain.

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Deep brain stimulation (DBS) is used to treat a variety of neurological disorders including Parkinson's disease. In this study, we explored the effects of striatal stimulation (SS) in a rat model of chronic-phase ischemic stroke. The stimulation electrode was implanted into the ischemic penumbra at 1 month after middle cerebral artery occlusion (MCAO) and thereafter continuously delivered SS over a period of 1 week. Rats were evaluated behaviorally coupled with neuroradiological assessment of the infarct volumes using magnetic resonance imaging (MRI) at pre- and post-SS. The rats with SS showed significant behavioral recovery in the spontaneous activity and limb placement test compared to those without SS. MRI visualized that SS also significantly reduced the infarct volumes compared to that at pre-SS or without SS. Immunohistochemical analyses revealed a robust neurogenic response in rats that received SS characterized by a stream of proliferating cells from the subventricular zone migrating to and subsequently differentiating into neurons in the ischemic penumbra, which exhibited a significant GDNF upregulation. In tandem with this SS-mediated neurogenesis, enhanced angiogenesis was also recognized as revealed by a significant increase in VEGF levels in the penumbra. These results provide evidence that SS affords neurorestoration at the chronic phase of stroke by stimulating endogenous neurogenesis and angiogenesis.

DOI： 10.3727/096368910X544915

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The "mist irrigation system" (MIS) is a new and effective method at drilling in spinal surgery. In this report, MIS is introduced with subsequent demonstration that visibility at drilling is better with MIS because of the reduction of smoke, blood and irrigation water. Additionally using a 5 mm-thick acryl plate, the time for perforation by drilling and temperature after drilling with MIS, drip-irrigation (DI) or no irrigation, were measured respectivily. Using the acryl plate significantly reduced drilling time and high temperature after perforation in the group without irrigation were recognized, compared to cases in the groups with MIS or DI. The results might indicate that the high temperature of the drill might melt the acryl plate immediately. As a conclusion, MIS might help surgeons to drill in the deep and narrow operative field. Additionally it might help to reduce the risks of heat injury to neuronal tissue by cooling efficiently.

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The cortex is a key brain region vulnerable to intracerebral hemorrhage (ICH) associated with stroke and head trauma. Animal models of ICH, via blood or collagenase infusion, have been developed most commonly to target the striatum. Here, we show that stereotaxic injection of collagenase type IV into two sites of the right cortex of adult C57BL6 mice produced hemorrhage to the cortex, subcortical white matter and hippocampus at day 1 post-injury, followed by cortical volume decrement by day 7. Reductions in MAP2- and NeuN-positive neurons were detected at day 1 and 7 post-injury in the core and peri-hemorrhagic cortex, respectively. Fluoro-Jade positive degenerating neurons were observed at day 1 in the peri-hemorrhagic area. An aberrant aggregation of GFAP-positive astrocytes and a significant reduction in RIP-positive oligodendroglial cells were detected at day 7 post-injury in the cortical area. In addition, a significant decrement in retrogradely Cholera Toxin Subunit B-labeled corticospinal neurons was recognized at day 14 post-injury in the ipsilateral cortex. Among the behavioral tests employed, the pole climb movement test robustly detected significant motor dysfunction at day 1, 3, and 7 post-injury that positively but inversely correlated with cortical volume at day 1 and 7 post-injury, respectively. The consistent observation of neuronal cell loss in the hemorrhagic core that subsequently extended to degeneration of neurons in the peri-hemorrhagic area, with accompanying motor abnormalities at least up to the subacute phase, advances this cortical hemorrhage model as a platform for examining the pathophysiology of and experimental treatments for ICH.

DOI： 10.1016/j.brainres.2010.07.101

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BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1alpha (SDF-1alpha) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1alpha were explored. 6-hydroxydopamine (6-OHDA, 20 microg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 x 107 cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1alpha were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. RESULTS: Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the in vitro study, SDF-1alpha treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. CONCLUSIONS: Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1alpha. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

DOI： 10.1186/1471-2202-11-52

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We recently demonstrated that blood-brain barrier permeabilization using mannitol enhances the therapeutic efficacy of systemically administered human umbilical cord blood (HUCB) by facilitating the entry of neurotrophic factors from the periphery into the adult stroke brain. Here, we examined whether the same blood-brain barrier manipulation approach increases the therapeutic effects of intravenously delivered HUCB in a neonatal hypoxic-ischaemic (HI) injury model. Seven-day-old Sprague-Dawley rats were subjected to unilateral HI injury and then at day 7 after the insult, animals intravenously received vehicle alone, mannitol alone, HUCB cells (15k mononuclear fraction) alone or a combination of mannitol and HUCB cells. Behavioural tests at post-transplantation days 7 and 14 showed that HI animals that received HUCB cells alone or when combined with mannitol were significantly less impaired in motor asymmetry and motor coordination compared with those that received vehicle alone or mannitol alone. Brain tissues from a separate animal cohort from the four treatment conditions were processed for enzyme-linked immunosorbent assay at day 3 post-transplantation, and revealed elevated levels of GDNF, NGF and BDNF in those that received HUCB cells alone or when combined with mannitol compared with those that received vehicle or mannitol alone, with the combined HUCB cells and mannitol exhibiting the most robust neurotropic factor up-regulation. Histological assays revealed only sporadic detection of HUCB cells, suggesting that the trophic factor-mediated mechanism, rather than cell replacement per se, principally contributed to the behavioural improvement. These findings extend the utility of blood-brain barrier permeabilization in facilitating cell therapy for treating neonatal HI injury.

DOI： 10.1111/j.1582-4934.2009.00671.x

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Recent studies demonstrate that rehabilitation ameliorates physical and cognitive impairments of patients with stroke, spinal cord injury, and other neurological diseases and that rehabilitation also has potencies to modulate brain plasticity. Here we examined the effects of compulsive exercise on Parkinson's disease model of rats. Before 6-hydroxydopamine (6-OHDA, 20 microg) lesion into the right striatum of female SD rats, bromodeoxyuridine (BrdU) was injected to label the proliferating cells. Subsequently, at 24 h after the lesion, the rats were forced to run on the treadmill (5 days/week, 30 min/day, 11 m/min). As behavioral evaluations, cylinder test was performed at 1, 2, 3, and 4 weeks and amphetamine-induced rotational test was performed at 2 and 4 weeks with consequent euthanasia for immunohistochemical investigations. The exercise group showed better behavioral recovery in cylinder test and significant decrease in the number of amphetamine-induced rotations, compared to the non-exercise group. Correspondingly, significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and TH-positive neurons in the substantia nigra pars compacta (SNc) was demonstrated, compared to the non-exercise group. Additionally, the number of migrated BrdU- and Doublecortin-positive cells toward the lesioned striatum was increased in the exercise group. Furthermore, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the striatum by exercise. The results suggest that exercise exerts neuroprotective effects or enhances the neuronal differentiation in Parkinson's disease model of rats with subsequent improvement in deteriorated motor function.

DOI： 10.1016/j.brainres.2009.10.075

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A 2-month-old infant presented with a cervical intramedullary spinal cord cavernous angioma manifesting as left hemiparesis caused by hematomyelia. Osteoplastic laminotomy of the cervical spine was carried out with subsequent microsurgical excision of the intramedullary spinal cord cavernous angioma. Magnetic resonance imaging revealed no residual tumor. At 25 months after the surgery, she presented no neurological deficit without recurrence and cervical deformity. This case of infantile intramedullary spinal cord cavernous angioma presenting with cervical hematomyelia shows osteoplastic laminotomy of the cervical spine might be helpful to prevent consequent cervical deformity in pediatric cases.

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Gene transfection with Notch 1 intracellular domain and subsequent growth factor treatment stimulate neuron-like differentiation of bone marrow stromal cells (BMSCs). Here, we examined the potential of transplanting Notch-induced BMSCs to exert therapeutic effects in a rat model of chronic ischemic stroke. In experiment 1, Notch-induced rat BMSCs were intrastriatally transplanted in rats at 1 month after being subjected to transient occlusion of middle cerebral artery (MCAo). Compared to post-stroke/pretransplantation level, significant improvements in locomotor and neurological function were detected in stroke rats that received 100 k and 200 k BMSCs, but not in those that received 40 k BMSCs. Histological results revealed 9%-15% graft survival, which dose-dependently correlated with behavioral recovery. At 5 weeks post-transplantation, some grafted BMSCs were positive for the glial marker GFAP (about 5%), but only a few cells (2-5 cells per brain) were positive for the neuronal marker NeuN. However, at 12 weeks post-transplantation, where the number of GFAP-positive BMSCs was maintained (5%), there was a dramatic increase in NeuN-positive BMSCs (23%). In experiment 2, Notch-induced human BMSCs were intrastriatally transplanted in rats at 1 month following the same MCAo model. Improvements in both locomotor and neurological function were observed from day 7 to day 28 post-transplantation, with the high dose (180 k) displaying significantly better behavioral recovery than the low dose (90 k) or vehicle. There were no observable adverse behavioral effects during this study period that also involved chronic immunosuppression of all animals. Histological analyses revealed a modest 5%-7% graft survival, with few (<1%) cells expressing an intermediate MAP2 neuronal marker, but not glial or oligodendroglial markers. In addition, striatal peri-infarct cell loss was significantly reduced in transplanted stroke animals compared to vehicle-treated stroke animals. The present study demonstrates the potential of Notch-induced BMSC cell therapy for patients presenting with fixed ischemic stroke.

DOI： 10.1089/scd.2009.0011

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We explored the effects of exogenous and endogenous erythropoietin (EPO) in a seizure model of rat. Adult male Fischer 344 rats received continuous intraventricular infusion of EPO dissolved in saline containing 1mg/ml of rat serum albumin, anti-EPO antibody, saline containing 1mg/ml of rat serum albumin or combined EPO and neuropeptide Y (NPY) Y2-receptor antagonist. Animals were behaviorally evaluated for seizure development over 6h after kainic acid injection followed by immunohistochemical assays. Mortality rate, seizure severity, apoptotic cell death and abnormal cell proliferation in the hippocampus of EPO-treated epileptic rats were significantly attenuated, compared to control rats. Anti-EPO antibody in non-EPO-treated animals worsened seizures and CA1 neuronal cell death, while NPY Y2-receptor antagonist cancelled the therapeutic effects of exogenous EPO. Both exogenous and endogenous EPO might modulate seizure severity and protect the hippocampal neurons in epileptic rats, via novel mechanistic pathways involving blockade of epileptogenic cell formation coupled with NPY receptor modulation in the hippocampus.

DOI： 10.1016/j.brainres.2009.08.025

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BACKGROUND AND PURPOSE: Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood. METHODS: Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 microA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats. RESULTS: Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex. CONCLUSIONS: These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.

DOI： 10.1161/STROKEAHA.109.563627

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Adult neural stem cells (NSCs) possess the potentials to self-renew and exert neuroprotection. In this study, we examined whether adult NSCs had anti-epileptic effects in rats with status epilepticus (SE) induced by kainic acid (KA) and whether co-administration of erythropoietin (EPO) enhanced anti-epileptic effects or cell survival. Adult NSCs were transplanted into KA-lesioned hippocampus with or without intracerebroventricular EPO infusion. Electronic encephalography (EEG) was recorded for 3 weeks after transplantation. The frequency of abnormal spikes in rats with NSC transplantation decreased significantly compared to those of rats without NSC transplantation. Most of the transplanted NSCs differentiated into GFAP-positive astrocytes. EPO infusion significantly enhanced the survival of NSCs, but not neuronal differentiation or migration. NSC transplantation increased the number of neuropeptide Y (NPY) and glutamic acid decarboxylase 67 (GAD67)-positive interneurons. NSC transplantation also suppressed mossy fiber sprouting into the inner molecular layer with subsequent reduction of hippocampal excitability, which finally prevented the development of spontaneous recurrent seizures in adult rats after KA-induced SE. This study might shed light on the cytoarchitectural mechanisms of temporal lobe epilepsy as well as clarify the effect of adult NSC transplantation with intracerebroventricular EPO infusion for temporal lobe epilepsy.

DOI： 10.1016/j.brainres.2009.07.079

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BACKGROUND: Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting. RESULTS: Here, we demonstrate that minocycline attenuates both in vitro (oxygen glucose deprivation) and in vivo (middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury. CONCLUSION: The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.

DOI： 10.1186/1471-2202-10-126

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We investigated a non-human primate (NHP) transient global ischemia (TGI) model which was induced by clipping the arteries originating from the aortic arch. Previously we demonstrated that our TGI model in adult Rhesus macaques (Macaca mulatta) results in marked neuronal cell loss in the hippocampal region, specifically the cornu Ammonis (CA1) region. However, we observed varying degrees of hippocampal cell loss among animals. Here, we report for the first time an anomaly of the aortic arch in some Rhesus macaques that appears as a key surgical factor in ensuring the success of the TGI model in this particular NHP. Eleven adult Rhesus macaques underwent the TGI surgery, which involved 10-15-minute clipping of both innominate and subclavian arteries. Animals were allowed to survive between 1 day and 28 days after TGI. Because of our experience and knowledge that Japanese macaques exhibited only innominate and subclavian arteries arising from the aortic arch, macroscopic visualization of these two arteries alone in the Rhesus macaques initially assured us that clipping both arteries was sufficient to produce TGI. During the course of one TGI operation, however, we detected 3 arterial branches arising from the aortic arch, which prompted us to subsequently search for 3 branches in succeeding TGI surgeries. In addition, we performed post-mortem examination of the heart to confirm the number of arterial branches in the aortic arch. Finally, in order to reveal the pathological effect of the aortic arch anomaly, we compared the hippocampal cell loss between animals found to have 3 arterial branches but had all or only two branches clipped during TGI operation. Post-mortem examination revealed that eight NHPs had the typical two arterial aortic branches, but three NHPs displayed an extra arterial aortic branch, indicating that about 30% of Rhesus macaques had 3 arterial branches arising from the aorta. Histological analyses using Nissl staining showed that in NHPs with the aortic arch anomaly clipping only two of three arterial branches led to a partial cell loss and minimal alteration in number of cell layers in the hippocampal region when compared with clipping all three branches, with the hippocampal cell death in the latter resembling the pathological outcome achieved by clipping the two arterial branches in NHPs displaying the typical two-artery aortic arch. The finding that 3 of 11 NHPs exhibited an extra arterial aortic branch recognizes this aortic arch anomaly in Rhesus macaques that warrants a critical surgical maneuver in order to successfully produce consistent TGI-induced hippocampal cell loss.

DOI： 10.1016/j.brainres.2009.06.015

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Language：Japanese   Publisher：The Japanese Society of Child Neurology  

DOI： 10.11251/ojjscn.41.197

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Other Link： http://search.jamas.or.jp/link/ui/2009199216

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The relationship between neurogenesis and epilepsy remains to be solved so far, although aberrant electric circuit recognized in epilepsy might be involved in neurogenesis. In this study, neurogenesis and the proliferation of astrocytes in the subgranular zone of the hippocampus were explored using unilateral amygdala-kindled rats with or without muscimol, a gamma-aminobutyric acid a (GABAa) agonist injection into the bilateral anterior thalamic nuclei (AN). Muscimol injection significantly ameliorated the behavioral scores of epilepsy without any significant alteration on the electroencephalography recorded at the stimulated basolateral amygdala, thus suggesting that muscimol injection might affect the secondary generalization, but not the initial discharge itself. The number of bromodeoxyuridine (BrdU), BrdU/doublecortin and BrdU/glial fibrillary acidic protein-positive cells in the subgranular zone of kindled animals increased markedly. Muscimol injection significantly suppressed neurogenesis, but not the proliferation of astrocyte, in the subgranular zone of the non-stimulated side, probably through the suppression of secondary generalization via AN. The results might indicate the underlying relationships between neurogenesis and epilepsy, that epileptic propagation in unilateral amygdala-kindled rats might go through AN into the contralateral side with subsequent neurogenesis, although further studies need to clarify the hypothesis.

DOI： 10.1179/174313208X346125

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Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neuronal systems. Several therapeutic tools for PD include medication using L-DOPA and surgeries such as deep brain stimulation are established. However, the therapies are considered as symptomatic therapy, but not basic remedy for PD and a new regenerative therapy would be desired to explore. In this study, the neuroprotective/rescue effects of erythropoietin (EPO), a well known hematopoietic hormone, on dopaminergic neurons were explored with neurogeneic potencies of EPO. EPO (100 IU/day) was continuously administered with micro-osmotic pump for a week to PD model of rats induced by intrastriatal 6-hydroxydopamine (6-OHDA) injection with subsequent behavioral and immunohistochemical investigations. The number of amphetamine-induced rotations of EPO-treated rats significantly decreased, compared to the control rats. The preservation of dopaminergic neurons of EPO-treated rats were confirmed by tyrosine hydroxylase staining and Fluoro-Gold staining. The number of bromodeoxyuridine (BrdU)/polysialic acid-neural cell adhesion molecule (PSA-NCAM) double positive cells in the subventricular zone of EPO treated rats significantly increased with migratory potencies to the damaged striatum,compared to the control rats. Furthermore, TUNEL staining and phosphorylated Akt staining revealed that the neuroprotective/rescue effects of EPO might be mediated by anti-apoptotic effects through the increase of phosphorylated Akt. These results suggest that continuous low dose infusion of EPO exerts neuroprotective/rescue effects with neurogeneic potentials. EPO might be a strong tool for PD therapy, although the further experiments should be added.

DOI： 10.1016/j.brainres.2008.11.094

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For many years, it was recognized that brain and spinal cord tissues could not be regenerated once they were damaged. Recently, this concept has been challenged and many basic and clinical studies regarding neural regeneration and transplantation have been reported. In this review, we will summarize the clinical studies using cell transplantation for the treatment of Parkinson's disease and cerebral ischemia. Then, we will report the recent advancement of basic studies using cell lines and neural stem cells as donor tissue. Cell line grafting can be done by encapsulating desired cell line in semipermeable polymer hollow fibers, and neurotransmitter and neurotrophic factors can be delivered into the brain. Neural stem cells, especially those of adult origin, have the advantage that autologous cell transplantation can be done. The biological features of various types of stem cells have been widely investigated and will be applied to the treatment of neurological disorders through cell transplantation.

DOI： 10.1007/s10047-008-0441-4

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Parkinson's disease is characterized by the degeneration of the nigrostriatal dopaminergic neurons with the manifestation of tremor, rigidity, akinesia, and disturbances of postural reflexes. Medication using L-DOPA and surgeries including deep brain stimulation are the established therapies for Parkinson's disease. Cell therapies are also effective and have rapidly developed with the recent advancement in molecular biological technology including gene transfer. In this review, ex vivo gene therapy using genetically engineered cell transplantation for Parkinson's disease model of animals is described, including catecholamine/neurotrophic factor-secreting cell transplantation with or without encapsulation, as well as in vivo gene therapy using direct injection of viral vector to increase dopamine-production, ameliorate the survival of dopaminergic neurons, correct the deteriorated microenvironment, or normalize genetic abnormality. Furthermore, the future directions for clinical application are described together with recent clinical trials of gene therapy.

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Once hypoxic-ischemic (HI) injury ensues in the human neonate at birth, the resulting brain damage lasts throughout the individual's lifetime, as no ameliorative treatments are currently available. We have recently shown that intracerebral transplantation of multipotent adult progenitor cells (MAPCs) results in behavioral improvement and reduction in ischemic cell loss in neonatal rat HI-injury model. In an attempt to advance this cellular therapy to the clinic, we explored the more practical and less invasive intravenous administration of MAPCs. Seven-day-old Sprague-Dawley rats were initially subjected to unilateral HI injury, then 7 days later received intracerebral or intravenous injections of allogeneic rat MAPCs. On post-transplantation days 7 and 14, the animals that received MAPCs via the intracerebral or intravenous route exhibited improved motor and neurologic scores compared with those that received vehicle infusion alone. Immunohistochemical evaluations at day 14 after transplantation revealed that both intracerebrally and intravenously transplanted MAPCs were detected in the ischemic hippocampal area. The degree of hippocampal cell preservation was almost the same in the two treatment groups and greater than that in the vehicle group. These results show that intravenous delivery of MAPCs is a feasible and efficacious cell therapy with potential for clinical use.

DOI： 10.1038/jcbfm.2008.68

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Cell therapy using stem cells is awaited by stroke patients with impaired movement and cognitive functions, although intravenous alteplase-administration ameliorated outcomes of patients receiving the therapy within 3 h of onset. In this study, we explored the therapeutic effects of neural progenitor cells (NPC) upon middle cerebral artery occlusion (MCAO) model of rats with exploration of the differences between adult and embryonic NPCs in therapeutic effects. GFP-labeled adult or embryonic NPCs were transplanted for transient MCAO model of rats at 1h after reperfusion. Rats were examined behaviorally using limb placement test, rotarod test and cylinder test with neuroradiological assessment using magnetic resonance imaging (MRI). Consequently after euthanasia, rats were immunohistochemically investigated to explore graft survival and immune reaction. MRI of rats receiving NPCs revealed significant reduction of infarct volumes, compared to vehicle-treated rats with corresponding behavioral amelioration. The transplanted cells were surviving in rats receiving NPCs, although the number of embryonic NPCs was significantly higher than that of adult NPCs. Iba-1-positive inflammatory cells of rats receiving adult NPCs were prominent, compared to those receiving embryonic NPCs, which might be a rationale for the differences between rats receiving adult and embryonic NPCs in the number of surviving NPCs. On the contraries, adult NPCs surely demonstrated therapeutic effects with a few surviving cells, thus indicating that the therapeutic effects might be due to trophic/growth factor-secretion from transplanted NPCs, rather than replacement of damaged host neurons. Therapeutic effects of NPCs for MCAO model of rats were clarified in this study. Transplantation of NPCs will be a hopeful strategy for stroke patients, although further studies are required for the patient safety and underlying mechanisms.

DOI： 10.1016/j.brainres.2008.07.086

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BACKGROUND: Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses. RESULTS: In vitro study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining in vivo might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration. CONCLUSION: Edaravone exerts neuroprotective effects on PD model both in vitro and in vivo. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.

DOI： 10.1186/1471-2202-9-75

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This review article discusses recent progress on the use of teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N cells, also called hNT cells) as graft source for cell transplantation in stroke. Laboratory evidence has demonstrated the therapeutic potential of NT2N cells in stroke therapy. Phase I and II clinical trials have shown the cells' feasibility, safety and tolerability profiles in stroke patients. Despite these novel features of NT2N cells, the transplantation regimen remains to be optimized. Moreover, determining the mechanisms underlying the grafts' beneficial effects, specifically demonstrating functional synaptic connections between host brain and NT2N cell grafts, warrants further examination. The major limiting factor for initiating a large clinical trial is the cells' highly potent proliferative property due to their cancerous origin, thereby raising the concern that these cells may revert to a neoplastic state over time after transplantation. To this end, we explored a proof-of-concept "retroviral" strategy to further establish the post-mitotic status of NT2N cells by transfecting these cells with the transcription factor Nurr1, in addition to the standard treatment with retinoic acid and mitotic inhibitors. This new cell line NT2N.Nurr1 displays an expedited neuronal commitment and secretes a high level of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF), and when transplanted into the rodent stroke brain expressed neuronal phenotype and reduced behavioral impairments which are comparable, if not more robust, than those produced by NT2N cells. Such highly potent neuronal lineage commitment and neurotrophic factor secretory function of NT2.Nurr1 cells make them an appealing graft source for transplantation therapy.

DOI： 10.1016/j.pneurobio.2008.04.005

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Metabotropic glutamate receptors (mGluRs) have been recently implicated as robust therapeutic targets for Parkinson's disease (PD). Here, we explored how activation of mGluRs in globus pallidus (GP) affected the amphetamine-induced rotational behavior in the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. The amphetamine-induced rotations were completely suppressed by the ipsilateral intrapallidal injection of the non-selective mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) and the selective group I mGluR agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), but not the selective group III mGluR agonist, l-2-amino-4-phosphonobutyric acid (l-AP4). The suppressive effects were detected at 2, 4, 6, 8, and 12 h after ACPD injection, but returned to the control level at 24 h. A remarkable c-fos expression was found in the lesioned side of GP, subthalamic nucleus (STN), and substantia nigra pars reticulata (SNr) of rats that received the ACPD or DHPG injection, compared to rats treated with L-AP-4 or phosphate buffer-injection. The results indicate that the blockade of amphetamine-induced rotations might be at least partially mediated by group I mGluR activation. This study advances the use of selective group I mGluRs directed toward the GP for PD treatment.

DOI： 10.1016/j.brainres.2008.01.051

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This study examined whether dietary supplementation can be used to protect against ischemic stroke. Two groups of adult male Sprague-Dawley rats initially received NT-020, a proprietary formulation of blueberry, green tea, Vitamin D3, and carnosine (n = 8), or vehicle (n = 7). Dosing for NT-020 and vehicle consisted of daily oral administration (using a gavage) over a 2-week period. On day 14 following the last drug treatment, all animals underwent the stroke surgery using the transient 1-hour suture occlusion of middle cerebral artery (MCAo). To reveal the functional effects of NT-020, animals were subjected to established behavioral tests just prior to stroke surgery and again on day 14 post-stroke. ANOVA revealed significant treatment effects (p < 0.05), characterized by reductions of 11.8% and 24.4% in motor asymmetry and neurologic dysfunction, respectively, in NT-020-treated stroke animals compared to vehicle-treated stroke animals. Evaluation of cerebral infarction revealed a significant 75% decrement in mean glial scar area in the ischemic striatum of NT-020-treated stroke animals compared to that of vehicle-treated stroke animals (p < 0.0005). Quantitative analysis of subventricular zone's cell proliferative activity revealed at least a one-fold increment in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0005). Similarly, quantitative analysis of BrdU labeling in the ischemic striatal penumbra revealed at least a three-fold increase in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0001). In addition, widespread double labeling of cells with BrdU and doublecortin was detected in NT-020-treated stroke brains (intact side 17% and ischemic side 75%), which was significantly higher than those seen in vehicle-treated stroke brains (intact side 5% and ischemic side 13%) (p < 0.05). In contrast, only a small number of cells in NT-020-treated stroke brains double labeled with BrdU and GFAP (intact side 1% and ischemic side 2%), which was significantly lower than those vehicle-treated stroke brains (intact side 18% and ischemic side 35%) (p < 0.0001). Endogenous neurogenic factors were also significantly upregulated in the ischemic brains of NT-020-treated stroke animals. These data demonstrate the remarkable neuroprotective effects of NT-020 when given prior to stroke, possibly acting via its neurogenic potential.

DOI： 10.1089/rej.2007.0608

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OBJECTIVES: The therapeutic effects of adult and embryonic neural precursor cells (NPCs) were evaluated and their therapeutic potential compared in a rat model of Parkinson disease. METHODS: Adult NPCs were obtained from the subventricular zone and embryonic NPCs were taken from the ganglionic eminence of 14-day-old embryos. Each NPC type was cultured with epidermal growth factor. The in vitro neuronal differentiation rate of adult NPCs was approximately equivalent to that of embryonic NPCs after two passages. Next, the NPCs were transfected with either green fluorescent protein or glial cell line-derived neurotrophic factor (GDNF) by adenoviral infection and transplanted into the striata in a rat model of Parkinson disease (PD) induced by unilateral intrastriatal injection of 6-hydroxydopamine. An amphetamine-induced rotation test was used to evaluate rat behavioral improvement, and immunohistochemical analysis was performed to compare grafted cell survival, differentiation, and host tissue changes. RESULTS: The rats with GDNF-transfected NPCs had significantly fewer amphetamine-induced rotations and less histological damage. Except for the proportion of surviving grafted cells, there were no significant differences between adult and embryonic NPCs. CONCLUSIONS: Adult and embryonic NPCs have a comparable therapeutic potential in a rat model of PD.

DOI： 10.3171/JNS/2008/108/01/0149

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.4044/joma.120.153

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Other Link： http://ousar.lib.okayama-u.ac.jp/13259

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SPRINGER  

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Laboratory and clinical studies have provided evidence of feasibility, safety and efficacy of cell transplantation to treat a wide variety of diseases characterized by tissue and cell dysfunction ranging from diabetes to spinal cord injury. However, major hurdles remain and limit pursuing large clinical trials, including the availability of a universal cell source that can be differentiated into specific cellular phenotypes, methods to protect the transplanted allogeneic or xenogeneic cells from rejection by the host immune system, techniques to enhance cellular integration of the transplant within the host tissue, strategies for in vivo detection and monitoring of the cellular implants, and new techniques to deliver genes to cells without eliciting a host immune response. Finding ways to circumvent these obstacles will benefit considerably from being able to understand, visualize, and control cellular interactions at a sub-micron level. Cutting-edge discoveries in the multidisciplinary field of nanotechnology have provided us a platform to manipulate materials, tissues, cells, and DNA at the level of and within the individual cell. Clearly, the scientific innovations achieved with nanotechnology are a welcome strategy for enhancing the generally encouraging results already achieved in cell transplantation. This review article discusses recent progress in the field of nanotechnology as a tool for tissue engineering, gene therapy, cell immunoisolation, and cell imaging, highlighting its direct applications in cell transplantation therapy.

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We exposed adult Rhesus (Macaca mulatta) to a transient global ischemia, which was induced by clipping the innominate and subclavian arteries that originated from the aortic arch. NHP1 received 20-min, while NHP2 and NHP3, were exposed to a 15-min transient global ischemia and were euthanized at day 1 (NHP1), day 5 (NHP2) or day 30 (NHP3) after ischemia, respectively. NHP1 displayed severe paralysis and rigidity, and intermittent convulsions over the next 24 h. Although histological examination of the brain revealed no detectable gross brain damage (i.e., swelling) and only minimal cell loss in the hippocampus, the acute survival time after surgery likely prevented the cerebral ischemia to fully develop and to be morphologically manifested. Nonetheless, the 20-min ischemia might have been too severe and caused a systemic multiple organ collapse that produced the abnormal behavioral symptoms. On the other hand, NHP2 and NHP3 which received 15-min ischemia only exhibited minor hindlimb paralysis. Indeed, by 48 h after ischemia, both animals appeared fully recovered with only fine motor deficits. Immunohistochemical examination revealed that NHP2 and 3, but not NHP1, had a marked neuronal cell loss in the hippocampal region, specifically the cornu Ammonis (CA1) region. The cell loss in these two ischemic NHP hippocampi was further confirmed by direct comparison with a normal Rhesus brain. These findings replicate the brain pathology seen in Japanese macaques exposed to the same ischemia model [T. Tsukada, M. Watanabe, T. Yamashima, Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus, J. Neurochem. 79 (2001) 1196-1206; T. Yamashima, Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates, Prog. Neurobiol. 62 (2000) 273-295; T. Yamashima, Y. Kohda, K. Tsuchiya, T. Ueno, J. Yamashita, T. Yoshioka, E. Kominami, Inhibition of ischemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on calpain-cathepsin hypothesis, Eur. J. Neurosci. 10 (1998) 1723-1733; T. Yamashima, T.C. Saido, M. Takita, A. Miyazawa, J. Yamano, A. Miyakawa, H. Nishijyo, J. Yamashita, S. Kawashima, T. Ono, T. Yoshioka, Transient brain ischemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys, Eur. J. Neurosci. 8 (1996) 1932-1944; T. Yamashima, A.B. Tonchey, T. Tsukada, T.C. Saido, S. Imajoh-Ohmi, T. Momoi, E. Kominami, Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates, Hippocampus 13 (2003) 791-800]. The present minimally invasive transient global ischemia model using Rhesus shows many histopathological symptoms seen in human patients who experienced global ischemia, and should allow translational validation of experimental therapeutics for ischemic injury. Additional studies are warranted to reveal behavioral deficits associated with this ischemia model.

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Adult neural stem and progenitor cells (NSPCs) are important autologous transplantation tools in regenerative medicine, as they can secrete factors that protect the ischemic brain. We investigated whether adult NSPCs genetically modified to secrete more glial cell line-derived neurotrophic factor (GDNF) could protect against transient ischemia in rats. NSPCs were harvested from the subventricular zone of adult Wistar rats and cultured for 3 weeks in the presence of epidermal growth factor. The NSPCs were treated with fibre-mutant Arg-Gly-Asp adenovirus containing the GDNF gene (NSPC-GDNF) or enhanced green fluorescent protein (EGFP) gene (NSPC-EGFP; control group). In one experiment, cultured cells were transplanted into the right ischemic boundary zone of Wistar rat brains. One week later, animals underwent 90 min of intraluminal right middle cerebral artery occlusion followed by magnetic resonance imaging and behavioural tests. The NSPC-GDNF group had higher behavioural scores and lesser infarct volume than did controls at 1, 7 and 28 days postocclusion. In the second experiment, we transplanted NSPCs 3 h after ischemic insult. Compared to controls, rats receiving NSPC-GDNF had decreased infarct volume and better behavioural assessments at 7 days post-transplant. Animals were killed on day 7 and brains were collected for GDNF ELISA and morphological assessment. Compared to controls, more GDNF was secreted, more NSPC-GDNF cells migrated toward the ischemic core and more NSPC-GDNF cells expressed immature neuronal marker. Moreover, the NSPC-GDNF group showed more effective inhibition of microglial invasion and apoptosis. These findings suggest that NSPC-GDNF may be useful in treatment of cerebral ischemia.

DOI： 10.1111/j.1460-9568.2007.05776.x

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Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.

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Many studies using animals clarify that glial cell line-derived neurotrophic factor (GDNF) has strong neuroprotective and neurorestorative effects on dopaminergic neurons. Several pilot studies clarified the validity of continuous intraputaminal GDNF infusion to patients with Parkinson's disease (PD), although a randomized controlled trial of GDNF therapy published in 2006 resulted in negative outcomes, and controversy remains about the efficacy and safety of the treatment. For a decade, our laboratory has investigated the efficacy and the most appropriate method of GDNF administration using animals, and consequently we have obtained some solid data that correspond to the results of clinical trials. In this review, we present an outline of our studies and other key studies related to GDNF, the current state of the research, problems to be overcome, and predictions regarding the use of GDNF therapy for PD in the future.

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8-Hydroxy-2'-deoxyguanosine (8-OHdG), the predominant marker of oxidative DNA damage, may be a good biomarker for monitoring the progression of Parkinson's disease (PD). Unfortunately, there are no basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we demonstrate that rats lesioned with 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle display significantly elevated 8-OHdG levels in urine, serum, and substantia nigra, but not cerebrospinal fluid and striatum, compared to sham controls. These increments in 8-OHdG levels were detected at 2 days, but not at 7 days after the lesion suggesting that oxidative stress is restricted to the acute phase of 6-OHDA neurotoxicity. The present results support 8-OHdG as a biomarker that may aid both in the diagnosis and in the documentation of progression in PD.

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Over the last decade, molecular biology has progressively developed, leading to new technology with subsequent clinical application for various cerebral diseases including Parkinson's disease (PD), one of the most investigated neurodegenerative disorders. The therapy for PD is mainly composed of medication, including drug replacement therapy, surgical treatment, and cell transplantation. Cell therapy for PD has been explored by using fetal nigral cells as an allo- or xenograft, autologous sympathetic ganglion, adrenal medulla, and carotid body in clinical settings. In addition, neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF), have a strong potency to rescue degenerating dopaminergic cells. Protein and/or gene therapy also might be a therapeutic option for PD. In this review, genetically engineered cell transplantation for animal models of PD, including catecholamine/neurotrophic factor-secreting cell transplantation with or without encapsulation, as performed in our laboratories, and their potential future as clinical applications are described with recent clinical studies in this field.

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Stroke remains a major cause of death in the US and around the world. Over the last decade, stem cell therapy has been introduced as an experimental treatment for stroke. Transplantation of stem cells or progenitors into the injured site to replace the nonfunctional cells, and enhancement of proliferation or differentiation of endogenous stem or progenitor cells stand as the two major cell-based strategies. Potential sources of stem/progenitor cells for stroke include fetal neural stem cells, embryonic stem cells, neuroteratocarcinoma cells, umbilical cord blood-derived nonhematopoietic stem cells, and bone marrow-derived stem cells. The goal of this article is to provide an update on the preclinical use of bone marrow-derived stem cells with major emphasis on mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) because they are currently most widely applied in experimental stroke studies and are now being phased into early clinical trials. The phenotypic features of MSCs and MAPCs, as well as their application in stroke, are described.

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Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 microl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.

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We established a PC12 cell line (PC12TH Tet-Off) in which human tyrosine hydroxylase (TH) expression can be negatively controlled by Doxycycline (Dox). First, dopamine (DA)-secretion from PC12TH Tet-Off cells was controlled by Dox-administration in a dose-responsive manner ranging from 0 to 100 ng/ml for 70 days in vitro. Furthermore, Parkinson's disease model of rats receiving encapsulated PC12TH Tet-Off cells displayed a significant decrease of dopamine concentration in the cerebrospinal fluid (CSF) and increase of the number of apomorphine-induced rotations by Dox-administration, as compared to transplanted rats without Dox-administration, although the significant decrease of the reduction ratio of DA concentration in the CSF with Dox-administration was recognized over time. At 2 months post-implantation, concentration of dopamine in the implanted striatum and from the retrieved capsules demonstrated that the control of DA-secretion could be partially achieved for 2 months in vivo. Our results support both the value of cell therapy using Tet-Off system and the technique of encapsulation might be a feasible option for Parkinson's disease especially in resolving the problem of dopamine oversupply in the future, although a more efficient way to control DA-secretion with quicker regulation and much titration of dose should be explored before clinical application.

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Cell therapy is thought to have a central role in restorative therapy, which aims to restore function to the damaged nervous system. The purpose of this study was to establish an autologous neural stem cell (NSC) transplantation model using adult rats and to compare survival, migration, and differentiation between this system and allogeneic NSC transplantation. Furthermore, we compared the immunologic response of the host tissue between autologous and allogeneic transplantation. NSCs were removed from the subventricular zone of adult Fischer 344 rats using stereotactic methods. NSCs were expanded and microinjected into normal hippocampus in the autologous brain. Allogeneic NSC (derived from adult Wistar rats) transplantation was performed using the same procedure, and hippocampal sections were analyzed immumohistologically 3 weeks post-transplantation. The cell survival and migration rate were higher for autologous transplantation than for allogeneic transplantation, and the neuronal differentiation rate in the autologous transplanted cells far exceeded that of allogeneic transplantation. Furthermore, there was less astrocyte and microglia reactivity in the host tissue of the autologous transplantation compared with allogeneic transplantation. These findings demonstrate that immunoreactivity of the host tissue strongly influences cell transplantation in the CNS as the autologous transplantation did not induce host tissue immunoreactivity; the microenvironment was essentially maintained in an optimal condition for the transplanted cells. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2005.12.004

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Expressions of various neurotrophic factors or their receptors fluctuate after stroke, which in part prompted investigations into the efficacy of neurotrophic factors as treatment modality for stroke. The methods to deliver neurotrophic factors into the brain can be categorized into: 1) the surgical route of administration, such as intracerebral, intraventricular, intra-arterial, or intravenous systemic administration and 2) the manipulation of the therapeutic molecules via ex vivo or in vivo techniques. With ex vivo method, genetically engineered cells, including the use of autologous cells, have been explored. In this review, the potent therapeutic applications of neurotrophic factors in stroke are described, with emphasis on ex vivo methods, especially transplantation of encapsulated stem cells modified with adenovirus. Neurotrophic factor delivery, combined with ex vivo method, poses as novel treatment for stroke, although additional safety and efficacy studies remain to be examined.

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The use of neuroteratocarcinoma cells for transplantation therapy in stroke has emerged as a strategy for cell replacement therapy that has begun its transition from basic science laboratories to a clinical setting. Procurement logistics and novel neuroprotective functions associated with these cells allow neuroteratocarcinoma cells to serve as efficacious alternatives to using fetal cells as donor cell grafts for stroke therapy, although the optimal transplantation regimen must still be determined. In particular, the limitations of current stroke treatments and management reveal an urgent need to examine the efficacy of experimental treatments, such as neural transplantation, in order to develop better treatment therapies. This chapter will discuss the characteristics of NT2N cells, the role of the host brain microenvironment and NT2N cell grafts, laboratory research and clinical trials for the intracerebral transplantation of NT2N cells in stroke, the mechanisms underlying the grafts' effects, and NT2N cell grafts and the need for immunosuppression. This chapter will also highlight some of the most recent findings regarding NT2N cells.

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There is currently no treatment for neonatal hypoxic-ischemic (HI) injury. Although limited clinical trials of stem cell therapy have been initiated in a number of neurological disorders, the preclinical evidence of a cell-based therapy for neonatal HI injury remains in its infancy. Stem cell therapy, via stimulation of endogenous stem cells or transplantation of exogenous stem cells, has targeted neurogenic sites, such as the hippocampus, for brain protection and repair. The hippocampus has also been shown to secrete growth factors, especially during the postnatal period, suggesting that this brain region presents a highly conducive microenvironment for cell survival. Based on its neurogenic and neurotrophic factor-secreting features, the hippocampus stands as an appealing target for stem cell therapy. In the present study, we investigated the efficacy of intrahippocampal transplantation of multipotent adult progenitor cells (MAPCs), which are pluripotent progenitor cells with the ability to differentiate into a neuronal lineage. Seven-day old Sprague-Dawley rats were initially subjected to unilateral HI injury, that involved permanent ligation of the right common carotid artery and subsequent exposure to hypoxic environment. At day 7 after HI

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Children born with hypoxic-ischemic (HI) brain injury account for a significant number of live births wherein no clinical treatment is available. Limited clinical trials of stem cell therapy have been initiated in a number-of neurological disorders, but the preclinical evidence of a cell-based therapy for neonatal HI injury remains in its infancy. One major postulated mechanism underlying therapeutic benefits of stem cell therapy involves stimulation of endogenous neurogenesis via transplantation of exogenous stem cells. To this end, transplantation has targeted neurogenic sites, such as the hippocampus, for brain protection and repair. The hippocampus has been shown to secrete growth factors, especially during the postnatal period, suggesting that this brain region presents as highly conducive microenvironment for cell survival. Based on its neurogenic and neurotrophic factor-secreting features, the hippocampus stands as an appealing target for stem cell therapy. Here, we investigated the efficacy of intrahippocampal transplantation of multipotent progenitor cells (MPCs), which are pluripotent progenitor cells with the ability to differentiate into a neuronal lineage. Seven-day-old Sprague-Dawley rats were initially subjected to unilateral HI injury, which involved permanent ligation of the right common carotid artery and subsequent exposure to hypoxic environment. At day 7 after HI injury, animals received stereotaxic hippocampal injections of vehicle or cryopre-served MPCs (thawed just prior to transplantation) derived either from Sprague-Dawley rats (syngeneic) or Fisher rats (allogeneic). All animals were treated with daily immunosuppression throughout the survival period. Behavioral tests were conducted on posttransplantation days 7 and 14 using the elevated body swing test and the rotarod to reveal general and coordinated motor functions. MPC transplanted animals exhibited reduced motor asymmetry and longer time spent on the rotarod than those that received the vehicle infusion. Both syngeneic and allogeneic MPC transplanted injured animals did not significantly differ in their behavioral improvements at both test periods. Immunohistochemical evaluations of graft survival after behavioral testing at day 14 posttransplantation revealed that syngeneic and allogeneic transplanted MPCs survived in the hippocampal region. These results demonstrate for the first time that transplantation of MPCs ameliorated motor deficits associated with HI injury. In view of comparable behavioral recovery produced by syngeneic and allogeneic MPC grafts, allogeneic transplantation poses as a feasible and efficacious cell replacement strategy with direct clinical application. An equally major finding is the observation lending support to the hippocampus as an excellent target brain region for stem cell therapy in treating HI injury.

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DOI： 10.3727/000000005783982774

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Vascular endothelial growth factor (VEGF) has been shown to display neuroprotective effects on dopaminergic (DA) neurons. Here, we investigated the neurorescue effects of VEGF on 6-hydroxydopamine (6-OHDA)-treated DA neurons in vitro and in vivo. Initially, we examined in vitro whether 1, 10, or 100 ng/ml of VEGF administration at 2 or 4 h after 6-OHDA treatment rescued DA neurons derived from E14 murine ventral mesencephalon. The earlier treatment of VEGF suppressed 6-OHDA-induced loss of DA neurons more than the delayed treatment. Next, we examined whether the continuous infusion of VEGF had neurorescue effects in a rat model of Parkinson's disease. We established a human VEGF secreting cell line (BHK-VEGF) and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally transplanted into the striatum of adult rats at 1 or 2 weeks after 6-OHDA lesions, and animals subsequently underwent behavioral and immunohistochemical evaluations. Compared to lesioned rats that received BHK-Control capsules, lesioned rats transplanted with BHK-VEGF capsules showed a significant reduction in the number of amphetamine-induced rotations, a significant preservation of TH-positive neurons in the substantia nigra pars compacta, and a remarkable glial proliferation in the striatum, with the earlier transplantation exerting much more benefits than the delayed transplantation. Parallel studies revealed that the observed in vitro and in vivo neurorescue effects were likely mediated by VEGF's angiogenic and glial proliferative effects, as well as its direct effects on the neurons. Our results suggest that VEGF is a highly potent neurorescue molecule for Parkinson's disease therapy.

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OBJECT: The authors evaluated the neuroprotective and angiogenic effects of a continuous and low-dose infusion of vascular endothelial growth factor (VEGF)-165 on cerebral ischemia in rats. METHODS: The authors introduced VEGF complementary (c)DNA into baby hamster kidney (BHK) cells and established a cell line that produces human VEGF165 (BHK-VEGF). The BHK-VEGF cells and BHK cells that had been transfected with an expression vector that did not contain human VEGF165 cDNA (BHK-control) were encapsulated. Both capsules were implanted into rat striata. Six days after capsule implantation, the right middle cerebral artery (MCA) was occluded. Some animals were killed 24 hours after occlusion to measure the volume of the resulting infarct and to perform immunohistochemical studies. Other animals were used for subsequent behavioral studies 1, 7, and 14 days after MCA occlusion. The encapsulated BHK-VEGF cell grafts significantly reduced the volume of the infarct and the number of apoptotic cells in the penumbral area when compared with the effect of the BHK-control cell capsule. In addition, angiogenesis and gliogenesis significantly increased in the region around the capsule in animals that received BHK-VEGF cell capsules without an increase in focal cerebral blood flow; this did not occur in animals that received the BHK-control cell capsule. In behavioral studies rats that received the BHK-VEGF cell capsule displayed significant recovery while participating in the accelerating rotarod test after stroke. CONCLUSIONS: Continuous intracerebral administration of low-dose VEGF165 through encapsulated grafts of VEGF-producing cells produces neuroprotective and angiogenic effects. These effects improve subsequent motor function.

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OBJECTIVE: Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells into brain parenchyma reduces histological brain damage following hypoxic-ischemic stress in neonatal rats. We examined the effect of glial cell line-derived neurotrophic factors on long-term learning and memory impairment and morphological changes up to 18 weeks after hypoxic-ischemic stress in neonatal rats. STUDY DESIGN: Baby hamster kidney cells were transfected with expression vector either including (glial cell line-derived neurotrophic factor-hypoxic-ischemic group; n = 10) or not including (control-hypoxic-ischemic group; n = 8) human glial cell line-derived neurotrophic factor cDNA, encapsulated in semipermeable hollow fibers, and implanted into the left brain parenchyma of 7-day-old Wistar rats. Two days after implantation the rats received hypoxic-ischemic stress, and their behavior was then examined in several learning tasks: the 8-arm radial maze, choice reaction time, and water maze tasks, which examine short-term working memory, attention process, and long-term reference memory, respectively. The rats were killed 18 weeks after the hypoxic-ischemic insult for evaluation of brain damage. Two additional control groups were used: the control group (n = 15), which underwent no treatment, and the glial cell line-derived neurotrophic factor group (n = 6), which underwent implantation of the glial cell line-derived neurotrophic factor capsule but did not undergo hypoxic-ischemic stress. RESULTS: The decrease in the size of the cerebral hemisphere was significantly less in the glial cell line-derived neurotrophic factor-hypoxic-ischemic group, compared with the control-hypoxic-ischemic group, and improved performance was observed in all three tasks for the glial cell line-derived neurotrophic factor-hypoxic-ischemic group: for the control-hypoxic-ischemic group versus the glial cell line-derived neurotrophic factor-hypoxic-ischemic group, respectively, in the 8-arm radial maze test, average number of correct choices was 6.2 +/- 0.1 versus 6.9 +/- 0.1 ( P < .01); in the choice reaction time test, average reaction time for a correct response was 2.35 +/- 0.1 seconds versus 1.97 +/- 0.09 seconds ( P < .01); in the water maze test, average swimming length was 1120.0 +/- 95.2 cm versus 841.6 +/- 92.1 cm ( P < .01). All results for the glial cell line-derived neurotrophic factor group were similar to those for the control group. CONCLUSION: Glial cell line-derived neurotrophic factor treatment is effective in not only reducing brain damage but also inhibiting learning and memory impairment, following hypoxic-ischemic insult in neonatal rats. No adverse effects in learning and memory tests were observed in the glial cell line-derived neurotrophic factor group.

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OBJECTIVE: It has been reported that an infarcted area is reduced by the injection of glial cell line-derived neurotrophic factor into brain parenchyma after hypoxic/ischemic insult in neonatal rats. For use of glial cell line-derived neurotrophic factor in humans, we have developed a system for the delivery of a constant supply of glial cell line-derived neurotrophic factor to the brain. The aim of this study was to examine the neuroprotective effect of glial cell line-derived neurotrophic factor with the use of this delivery system. STUDY DESIGN: Baby hamster kidney cells were transfected with human glial cell line-derived neurotrophic factor complementary DNA, encapsulated in semipermeable hollow fibers, and implanted into the left cerebrum of 12-day-old Wistar rats (glial cell line-derived neurotrophic factor group, 11 rats). Nontransfected baby hamster kidney cells served as controls (control group, 9 rats). Two days after implantation, the rats received a hypoxic/ischemic stress, with a modification of Levine's method. Seven days later the rats were killed, and coronal brain slices were cut 2, 4, 6, 8, and 10 mm from the anterior pole. The cortex, hippocampus, striatum, and thalamus were evaluated for damage severity. The serum concentrations of glial cell line-derived neurotrophic factor were also determined. RESULTS: The left brain hemispheric area was significantly larger; the neuronal damage to each brain region was significantly less, and the serum glial cell line-derived neurotrophic factor concentrations were significantly higher in the glial cell line-derived neurotrophic factor group, compared with the control group. CONCLUSION: Grafting of encapsulated glial cell line-derived neurotrophic factor-secreting cells is a promising way to protect the neonatal brain from hypoxic/ischemic insult.

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Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects on dopaminergic (DA) neurons. In this study, we investigated whether the effects of VEGF were dose-dependent or not. First, VEGF was shown to be neuroprotective on 6-hydroxydopamine (6-OHDA)-treated murine DA neurons in vitro, although the 1 ng/ml of VEGF displayed more neuroprotective effects than 100 ng/ml. Furthermore, using 2 sizes of capsules (small/large) with different secreting quantities, 6-OHDA-treated rats receiving the small capsule filled with VEGF-secreting cells (BHK-VEGF) into the striatum showed a significant decrease in amphetamine-induced rotational behavior in number and a significant preservation of TH-positive fibers compared to those receiving the large BHK-VEGF capsule as well as those receiving BHK-Control capsule. Rats receiving the large BHK-VEGF capsule showed much more glial proliferation, angiogenesis, and brain edema around the capsule than those with the small one. High-dose administration of VEGF might cause poor circulation related to brain edema, although low-dose administration of VEGF displays neuroprotective effects on DA neurons. Our results demonstrate the importance of administration dose of VEGF, suggesting that low-dose administration of VEGF might be desirable for Parkinson's disease.

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OBJECT: Glial cell line-derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vitro and in vivo. METHODS: First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA-induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. CONCLUSIONS: These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor alpha1. The results of this study support a role for this grafting technique in the treatment of PD.

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We describe a case of Pseudoxanthoma elasticum (PXE) in a 14-year-old girl. This case is especially rare because of its association with carotid rete mirabile (CRM). Only three cases have been reported previously in the literature. Although the relation between P. elasticum and carotid rete mirabile is unclear, both disorders are believed to be major risk factors for cerebrovascular disease.

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Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects following ischemia, suggesting that VEGF may potentially be applied as a neuroprotective agent for the treatment of other neurological diseases. In this study, we investigated the neuroprotective capacity of VEGF in a model of Parkinson's disease. VEGF was found to be neuroprotective against cell death of primary E14 murine ventral mesencephalic neurons induced by 6-hydroxydopamine (6-OHDA) treatment in vitro. Further, rats receiving a continuous infusion of VEGF into the striatum via encapsulated hVEGF-secreting cells (baby hamster kidney-VEGF) displayed a significant decrease in amphetamine-induced rotational behavior and a significant preservation of tyrosine hydroxylase-positive neurons and fibers compared with control animals. VEGF likely functions via direct mechanisms by signaling through the neuropilin receptor expressed upon dopaminergic neurons in response to 6-OHDA treatment. Further, VEGF is likely to promote neuroprotection indirectly by activating the proliferation of glia and by promoting angiogenesis. Our results support a potential neuroprotective role for VEGF in the treatment of Parkinson's disease.

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During the past decade, vascular endothelial growth factor (VEGF) has been widely investigated, and reported to have pleiotropic functions in the central nervous system (CNS) and its supporting physiological environment. VEGF is involved in not only such well-known functions as angiogenesis, accentuation of vessel permeability, and glial proliferation, but also more recently acknowledged functions such as neuroprotection and even neurogenesis itself. Most recently, the neurogenesis function has attracted much attention, and a number of research groups have taken up the challenge of elucidating this activity. In keeping with this trend, our knowledge of VEGF receptors has increased, and certain suggestions concerning the mechanisms of neuroprotection have come to light in the course of the ongoing work, though at times what the researchers had to work with was only a tiny percent of the signal transduction of VEGF. Together with flt-1 (VEGF receptor 1) and flk-1 (VEGF receptor 2), neuropilin (NP) is frequently described as being involved in the neuroprotective effects of VEGF. In this review, both the direct and indirect neuroprotective effects of VEGF, including various signaling pathways as well as the neurogenesis induced by this factor, are discussed in the context of the newly emerging insights into the biological mechanisms of VEGF and closely related, interacting molecules.

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A 47-year-old woman presented with headache and left homonymous hemianopsia. T1-weighted magnetic resonance (MR) imaging with contrast medium showed a mass lesion with ring-like enhancement in the right temporo-occipital lobe. The patient underwent surgery, focal irradiation, and chemotherapy. The histological diagnosis was glioblastoma. Four months after the operation, the patient again developed headache and left homonymous hemianopsia in addition to vomiting and mild left hemiparesis. MR imaging showed recurrence of the tumor and hydrocephalus. The patient underwent a second craniotomy and placement of a ventriculoperitoneal shunt. Intraoperative findings revealed that the transverse-sigmoid sinus was occluded by tumor invasion. The patient died of intraventricular dissemination 2 months after the second operation. Autopsy revealed metastases in the spleen and lungs. Glioblastoma with metastases to the spleen is very rare. The prognosis for patients is poor. Excessive therapy should not be used for patients with extracranial metastases from glioblastoma.

PubMed

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 58-year-old woman complaining of a mild headache was admitted to our hospital. MRI 3 months before admission revealed a round lesion at the right quadrigeminal cistern. Cerebral angiograms demonstrated a fusiform aneurysm arising from the parietooccipital artery, which is the distal branch of the right posterior cerebral artery. Repeated MRI and cerebral angiograms performed on admission demonstrated complete thrombosis of an aneurysm and the parent artery without any clinical symptoms. This is the first case of complete spontaneous thrombosis of an aneurysm of the distal posterior cerebral artery. The mechanism of its development and spontaneous thrombosis in a fusiform aneurysm is discussed.

PubMed

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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The authors describe a unique presentation of Wegener granulomatosis (WG) manifesting predominantly as meningitis. Magnetic resonance imaging demonstrated diffuse meningeal enhancement, including the pia mater, in a 28-year-old man with meningitis. A diagnosis of atypical WG was based on the findings of a dural biopsy sample and an elevated cytoplasmic antineutrophil cytoplasmic antibody (cANCA) titer, although the patient did not have any of the lesions common to WG. Immunosuppressive therapy was quite effective. With treatment, the meningeal enhancement resolved and the cANCA titer normalized. Meningeal granulomatosis as the sole lesion in WG has never been reported in the literature. This atypical course of WG should be noted.

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

The authors describe a case of de novo formation and rupture of an aneurysm located at the junction of the left internal carotid artery and the superior hypophyseal artery in a middle-aged woman 2 months after another aneurysm, located on the anterior communicating artery, had been clipped. This case is rare because of the short interval between the last angiographic study performed at the first operation and the diagnosis of the de novo aneurysm; in this case the interval was only 47 days, compared with other cases in the literature in which the intervals were 3 to 34 years. Aneurysms can enlarge considerably in 2 to 4 weeks and can rupture at or soon after their formation. This case provides insight into aneurysm formation and rupture.

PubMed

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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J-GLOBAL

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Language：Japanese   Publisher：(公社)日本リハビリテーション医学会  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：WOLTERS KLUWER MEDKNOW PUBLICATIONS  

Angiogenesis involves new blood vessels sprouting from preexisting blood vessels. This process may serve to improve brain circulation. Moyamoya disease (MMD) is a cerebrovascular disorder causing intracranial stenosis which significantly reduces the blood supply to the brain. Mainly stroke is the first symptom of the disorder, so treatments that reduce the risk of stroke are used for patients with MMD. To prevent stroke for those with chronic cerebral hypoperfusion, more blood needs to flow to the brain, which was thought to be achieved by enhancing angiogenesis. Indirect bypass surgery, such as encephalo-myo-synangiosis (EMS), is used for revascularization. However, EMS alone sometimes cannot provide enough circulation to avoid ischemic strokes. The current study examined if EMS combined with high-mobility group box-1 (HMGB1) and vascular endothelial growth factor (VEGF) enhanced angiogenesis and increased cerebral circulation. The results indicated that HMGB1 administered with EMS increased angiogenesis through a VEGF-dependent mechanism. In addition, exercising and stem cell transplantation possess possible means to increase angiogenesis. Overall, EMS with gene therapy, maintaining fitness, and stem cell utilization may prevent or help one recover from stroke by enhancing brain angiogenesis. Thus, these treatments may be applicable for patients with MMD. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed.

DOI： 10.4103/bc.bc_33_19

Web of Science

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English  

BACKGROUND/AIMS: Bone marrow stromal cells (BMSCs) transplantation is an important strategy for the treatment of ischemic stroke. Currently, there are no effective methods to guide BMSCs toward the targeted site. In this study, we investigated the effect of electrical stimulation on BMSCs migration in an ischemic model of rats. METHODS: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. BMSCs (2.5×105 cells/ 4 µl PBS) were stereotaxically injected into the left corpus callosum at 1 day after MCAO. After BMSCs injection, a plate electrode with a diameter of 3 mm connected to an implantable electrical stimulator was placed on the right frontal epidural space and a counter electrode was placed in the extra-cranial space. Electrical stimulation at preset current (100 µA) and frequency (100 Hz) was performed for two weeks. Behavioral tests were performed at 1, 4, 8, and 15 days after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at 15 days after MCAO for evaluation of infarction area and the migration distance and area of BMSCs found in the brain tissue. After evaluating cell migration, we proceeded to explore the mechanisms guiding these observations. MCAO rats without BMSCs transplantation were stimulated with same current and frequency. At 1 and 2 weeks after MCAO, rats were euthanized to evaluate stromal cell-derived factor 1 alpha (SDF-1α) level of brain tissues in the bilateral cortex and striatum. RESULTS: Behavioral tests at 4, 8, and 15 days after MCAO revealed that stimulation group displayed significant amelioration in mNSS and cylinder test compared to control group (p<0.05). Similarly, the infarction areas of stroke rats in stimulation group were significantly decreased compared to control group (p<0.05). Migration distance and area of transplanted BMSCs were significantly longer and wider respectively in stimulation group. An increased concentration gradient of SDF-1α in stimulation group accompanied this enhanced migration of transplanted cells. CONCLUSIONS: These results suggest that electrical stimulation enhances migratory ability of transplanted BMSCs in ischemic stroke model of rats. If we can direct the implanted BMSCs to the site of interest, it may lead to a greater therapeutic effect.

DOI： 10.1159/000488409

PubMed

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Language：Japanese   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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DOI： 10.1016/j.jns.2016.12.040

Scopus

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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Atypical teratoid/rhabdoid tumor(AT/RT)is a rare and lethal childhood cancer. Although radiation therapy in children less than three years of age is generally deferred because of its neural toxicity, recent studies have shown that multimodal therapies, including radiation therapy, are effective in pediatric patients with AT/RT less than three years of age. We treated four infant AT/RT patients and investigated the impact of radiation therapy and genetic classification on the prognosis. The mean age at the time of the operation was 9.3 months and all patients were female. All patients underwent surgical resection. Of the four patients, two received combined irradiation and chemotherapy. Specifically, one patient received conformal craniospinal radiation therapy and the other received craniospinal irradiation with proton beams. Immunohistochemical analyses of tumor specimens revealed that the two patients were positive for ASCL1, a regulator of Notch signaling. Patients who received radiation therapy and exhibited ASCL1-positive tumors had a better prognosis. We conclude that radiation therapy may prolong survival in AT/RT patients who are less than 3 years of age. However, further study is required to evaluate long-term functional outcomes.

DOI： 10.11477/mf.1436203466

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DOI： 10.2531/spinalsurg.31.53

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

分子生物学的発達により、様々な難治性の中枢神経系疾患に対する再生医療が可能になる日を想像することができるようになった。てんかんに対しては、抗けいれん剤を用いた内科的治療を軸として、海馬扁桃体切除・焦点切除・脳梁離断・迷走神経刺激を始めとする外科的治療が行われている。しかし治療抵抗性を有する一部の難治性てんかんが存在する。本稿では、てんかん治療の現状に続き、てんかん動物モデルについて概説する。その後、細胞療法、神経保護作用を有する薬物治療、および電気刺激について述べる。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2017004125

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：COGNIZANT COMMUNICATION CORP  

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Language：Japanese   Publisher：(一社)日本定位・機能神経外科学会  

【背景】最近、ventro oralis posterior nucleus(VOP)やposterior subthalamic area(PSA)を標的にした難治性振戦に対する治療の有効性が報告されている。当科でも、難治性振戦に対してPSAを標的とした手術を行っており、この部位の手術に関するdiffusion tensor imaging based fiber tractography(DTI-FT)による解析を試みた。【目的】PSAにおける神経線維の走行を解析し、難治性振戦に対する最適な標的について検討する。【方法】2013年7月から2014年10月までに難治性振戦に対する脳深部刺激療法を行った患者を対象とした。男性2名、女性2名、平均年齢は69.8歳(66〜75歳)であった。術前に3T-MRIでナビゲーション用の画像と共にDTIも撮像した。術中にVIM(ventro intermedial neucleus)、PSA刺激を行い、振戦抑制効果の高い部位に電極を留置した。Stealth Navigation StealthViz上で術前MRI、fiber tractography、術後MRIのfusion画像を作成し、視床VL(ventro lateral)核、PSA(posterior subthalamic area)周囲を走行する神経線維と活動電極の位置関係について検討を行った。【結果】全例で良好な振戦の抑制が得られた。DTI-FTで、視床VL核、PSAを通過する神経線維を明瞭に描出することが可能であった。活動電極はDTI-FTから想定される視床VL核およびPSAを走行する神経線維上にあった。【結論】難治性振戦に対する定位脳手術の標的決定において、DTI-FTは有用であることが示唆された。(著者抄録)

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Language：Japanese   Publisher：(一社)日本脳神経外傷学会  

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Language：Japanese   Publisher：The Japanese Society of Spinal Surgery  

Spinal hemangioblastomas are benign, and total surgical resection is the standard treatment method used. However, hypervascular tumors may have excessive operative blood loss if the tumors are divided. We encountered a case of cauda equina hemangioblastoma with extraordinary blood supply, which was treated with preoperative embolization. A 49-year-old woman with von Hippel-Lindau disease who had undergone multiple surgeries for intracranial/extracranial hemangioblastomas had lumbago and leg pain. Magnetic resonance images revealed intradural spinal tumors at the L4-S1 vertebral level, with remarkable gadolinium enhancement. The patient was referred to our hospital, after a plan of total resection had been abandoned elsewhere because of the high flow feeders and high pressure of the tumors. Preoperative embolization was performed with consequent disappearance of the arterial blood supply to the tumor. Two days later, the tumor was resected subtotally with reduced tension and a little blood loss. The patient's symptoms resolved soon after surgery. Selective preoperative embolization for a spinal hemangioblastoma with a rich blood supply is a valid option as an adjuvant to the complete surgical resection of a tumor.

DOI： 10.2531/spinalsurg.29.53

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Other Link： http://search.jamas.or.jp/link/ui/2015281939

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Bedridden patients develop atrophied muscles, their daily activities greatly reduced, and some display a depressive mood. Patients who are able to receive physical rehabilitation sometimes show surprising clinical improvements, including reduced depression and attenuation of other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for CNS disorders, namely, transplantation of exogenous stem cells and amplification of endogenous neurogenesis. The latter strategy embraces a natural way of reinnervating the damaged brain and correcting the neurological impairments. In this study, we discussed how immobilization-induced disuse atrophy, using the hindlimb suspension model, affects neurogenesis in rats. The overarching hypothesis is that immobilization suppresses neurogenesis by reducing the circulating growth or trophic factors, such as vascular endothelial growth factor or brain-derived neurotrophic factor. That immobilization alters neurogenesis and stem cell differentiation in the CNS requires characterization of the stem cell microenvironment by examining the trophic and growth factors, as well as stress-related proteins that have been implicated in exercise-induced neurogenesis. Although accumulating evidence has revealed the contribution of "increased" exercise on neurogenesis, the reverse paradigm involving "lack of exercise," which mimics pathological states (e.g., stroke patients are often immobile), remains underexplored. This novel paradigm will enable us to examine the effects on neurogenesis by a nonpermissive stem cell microenvironment likely produced by lack of exercise. BrdU labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid and brain levels of trophic factors, growth factors, and stress-related proteins are proposed as indices of neurogenesis, while quantitative measurements of spontaneous movements will reveal psychomotor components of immobilization. Studies designed to reveal how in vivo stimulation, or lack thereof, alters the stem cell microenvironment are needed to begin to develop treatment strategies for enhancing neurogenesis in bedridden patients.

DOI： 10.3727/096368915X687723

PubMed

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Language：Japanese   Publisher：日本定位・機能神経外科学会事務局  

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Other Link： https://search.jamas.or.jp/link/ui/2016123797

Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese   Publisher：(NPO)日本小児外科学会  

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Accumulating preclinical evidence suggests the use of amnion as a source of stem cells for investigations of basic science concepts related to developmental cell biology, but also for stem cells' therapeutic applications in treating human disorders. We previously reported isolation of viable rat amniotic fluid-derived stem (AFS) cells. Subsequently, we recently reported the therapeutic benefits of intravenous transplantation of AFS cells in a rodent model of ischemic stroke. Parallel lines of investigations have provided safety and efficacy of stem cell therapy for treating stroke and other neurological disorders. This review article highlights the need for investigations of mechanisms underlying AFS cells' therapeutic benefits and discusses lab-to-clinic translational gating items in an effort to optimize the clinical application of the cell transplantation for stroke.

DOI： 10.3389/fncel.2014.00227

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Other Link： http://search.jamas.or.jp/link/ui/2015166907

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Epilepsy is a chronic neurological disorder, which presents with various forms of seizures. Traditional treatments, including medication using antiepileptic drugs, remain the treatment of choice for epilepsy. Recent development in surgical techniques and approaches has improved treatment outcomes. However, several epileptic patients still suffer from intractable seizures despite the advent of the multimodality of therapies. In this article, we initially provide an overview of clinical presentation of epilepsy then describe clinically relevant animal models of epilepsy. Subsequently, we discuss the concepts of regenerative medicine including cell therapy, neuroprotective agents, and electrical stimulation, which are reviewed within the context of our data.

DOI： 10.3390/ijms141223390

PubMed

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：(株)金芳堂  

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On average, every four minutes an individual dies from a stroke, accounting for 1 out of every 18 deaths in the United States. Approximately 795,000 Americans have a new or recurrent stroke each year, with just over 600,000 of these being first attack [1]. There have been multiple animal models of stroke demonstrating that novel therapeutics can help improve the clinical outcome. However, these results have failed to show the same outcomes when tested in human clinical trials. This review will discuss the current in vivo animal models of stroke, advantages and limitations, and the rationale for employing these animal models to satisfy translational gating items for examination of neuroprotective, as well as neurorestorative strategies in stroke patients. An emphasis in the present discussion of therapeutics development is given to stem cell therapy for stroke.

DOI： 10.1007/s12975-012-0241-2

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