Hidetoshi Murata

IL-6 up-regulates CNTF mRNA expression and enhances neurite regeneration.

Interleukin-6 (IL-6) is a neurotrophic cytokine, however, its direct effect on nerve regeneration has not been well characterized. We therefore examined the effect of IL-6 on neurite regeneration using the rat dorsal root ganglion. IL-6 significantly enhanced neurite regeneration from transected nerve terminals. We also examined the mRNA expression of IL-6 family cytokines and their receptors during the regeneration. The mRNA expressions of IL-6, IL-6 receptor, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) receptor α, and LIF receptor β showed no significant differences by the addition of IL-6. In contrast, IL-6 enhanced the mRNA expression of gp130 and CNTF. In addition, CNTF significantly increased neurite regeneration when added exogenously. Our data suggest that IL-6 enhanced regeneration via up-regulating CNTF expression.

Altered Blood Flow Distribution in the Rat Spinal Cord under Chronic Compression

Study Design. Sham-operation–controlled animal study to assess alterations in blood flow in the spinal cord in a chronic compression model. Laboratory investigation. Objective. Cervical myelopathy is a common cause of disability in elderly patients. Hypothesis was made that ischemia subsequent to the spinal cord compression plays an important role in the pathogenesis of the spinal cord dysfunction. This study was undertaken to assess alterations in the blood flow of the spinal cord under chronic compression in a rat model. Summary of Background Data. Histologic study of spinal cord from patients with spondylotic myelopathy showed ischemic tissue changes. Experimentally, spinal cord hypoperfusion in combination with chronic spinal cord compression induced myelopathy in dogs. We previously showed that chronic compression of the spinal cord in rats produces gradual deterioration of mobility of the animals accompanied by cord tissue degeneration compatible with ischemic changes. Methods. Chronic compression of the cervical spinal cord was implemented by implantation of a thin urethane polymer sheet under the C5–C6 laminae, which expands by absorbing tissue water over 48–72 hours. The control group underwent sham operation. Twelve weeks later, blood flow to the C3–C4 and C5–C6 spinal cord segments were measured by fluorescent microsphere methods. Results. In the control group, the blood flow in the C5–C6 segment was larger than C3–C4 segment. In the compression group, the blood flow in the C5–C6 was significantly reduced compared to the C3–C4 segment. Conclusion. Under chronic focal spinal cord compression, there was a decrease of the blood flow in the compressed segment in comparison to the rostral segment. Our data are compatible with the hypothesis that alteration in the spinal cord blood flow contributes to pathogenesis of myelopathy.

Experimental gene therapy against subcutaneously implanted glioma with a herpes simplex virus-defective vector expressing interferon-γ

We investigated the feasibility of local treatment or tumor vaccination with a herpes simplex virus (HSV) type 1-defective vector. The vector was engineered to express murine interferon-γ (IFN-γ) for experimental gene therapy against mouse glioma Rous sarcoma virus (RSV). The murine IFN-γ gene was driven by the cytomegalovirus promoter. The helper virus (tsk) was thermosensitive; consequently, this vector could only proliferate at 31°C. A high level of murine IFN-γ expression was confirmed in vitro and in vivo by immunohistochemistry using anti-mouse IFN-γ monoclonal antibody. This engineered vector (dvHSV/MuIFN-γ) inhibited the proliferation of mouse glioma RSV cells in vitro, and an intratumoral (i.t.) local injection of the vector caused i.t. necrosis in vivo. The immunological effect of dvHSV/MuIFN-γ was also examined in a mouse glioma RSV cell implantation model. A subcutaneous (s.c.) implant of 1 × 106 mouse glioma RSV cells after treatment with dvHSV/MuIFN-γ was rejected. However, the implant after treatment with an engineered HSV-defective vector containing an antisense nucleotide sequence of the murine IFN-γ gene was not rejected. In addition, in another group of mice in which RSV cells treated with dvHSV/MuIFN-γ were implanted into a femoral (s.c.) region and nontreated RSV cells were implanted into a contralateral femoral (s.c.) region, the implanted RSV cells were rejected. The rejection of the implanted mouse glioma RSV was blocked by anti-asialo GM1, which was known to inhibit natural killer cell activity. These results revealed that the HSV-defective vector could realize a high efficiency of transfection to glioma cells through short-time treatment, and that the IFN-γ gene transferred to the cells had the effect of tumor vaccination, which was suggested be related to natural killer cells. In conclusion, dvHSV/MuIFN-γ may be useful for the gene therapy of malignant glioma through either i.t. local injection or a practical tumor vaccination with ex vivo gene transfer.

Hyperthermia and chemotherapy using Fe(Salen) nanoparticles might impact glioblastoma treatment

We previously reported that μ-oxo N,N’-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, has direct anti-tumor activity, and generates heat in an alternating magnetic field (AMF). We showed that Fe(Salen) nanoparticles are useful for combined hyperthermia-chemotherapy of tongue cancer. Here, we have examined the effect of Fe(Salen) on human glioblastoma (GB). Fe(Salen) showed in vitro anti-tumor activity towards several human GB cell lines. It inhibited cell proliferation, and its apoptosis-inducing activity was greater than that of clinically used drugs. Fe(Salen) also showed in vivo anti-tumor activity in the mouse brain. We evaluated the drug distribution and systemic side effects of intracerebrally injected Fe(Salen) nanoparticles in rats. Further, to examine whether hyperthermia, which was induced by exposing Fe(Salen) nanoparticles to AMF, enhanced the intrinsic anti-tumor effect of Fe(Salen), we used a mouse model grafted with U251 cells on the left leg. Fe(Salen), BCNU, or normal saline was injected into the tumor in the presence or absence of AMF exposure. The combination of Fe(Salen) injection and AMF exposure showed a greater anti-tumor effect than did either Fe(Salen) or BCNU alone. Our results indicate that hyperthermia and chemotherapy with single-drug nanoparticles could be done for GB treatment.

18F-Fluoride PET/CT allows detection of hyperostosis and osseous involvement in meningioma: initial experience.

Purpose The present study was conducted to assess the diagnostic performance of 18F-fluoride PET/CT in evaluating hyperostosis and osseous involvement in patients with meningioma. Patients and Methods Thirty-four patients with meningioma (mean age, 61 years) underwent 18F-fluoride PET/CT before surgery. In 24 patients (71%), 18F-FDG PET/CT was also given before surgery, and the results were compared. The images were reviewed by 2 board-certified nuclear medicine specialists who were unaware of any clinical information and a consensus was reached. Uptake patterns and measurements of tracers were compared with pathological findings from resected specimens, with hyperostosis and osseous involvement as the reference standard. Results There were 27 grade I tumors (79%) and 7 grade II tumors (21%). The primary tumor focus was identified in each patient using both 18F-fluoroide PET/CT and 18F-FDG PET/CT, but there were no significant correlations in the degree of uptake between the 2 tracers. The SUVmax, SUVmax corrected for lean body mass (SULmax), and tumor metabolic volume (TMV) for 18F-fluoride and 18F-FDG were greater in grade II tumors than in grade I tumors. Hyperostosis and osseous involvement was identified in 12 tumors (38%). The SUVmax, SULmax, and TMV of tumors visualized with 18F-fluoride PET/CT were greater in tumors with hyperostosis and osseous involvement than in those without (P = 0.005, P = 0.003, and P = 0.006, respectively). In contrast, the SUVmax, SULmax, and TMV of tumors visualized with 18F-FDG PET/CT were similar regardless of hyperostosis or osseous involvement. Conclusions 18F-fluoride PET/CT may improve detection of hyperostosis and osseous involvement in patients with meningioma.

Limaprost Alfadex, a Prostaglandin E1 Derivative, Prevents Deterioration of Forced Exercise Capability in Rats with Chronic Compression of the Spinal Cord

Study Design. Basic animal research. Objective. Cervical spondylotic myelopathy is a common condition among elderly and often treated by surgery. To explore possibility of pharmacologic treatment, limaprost alfadex, a prostaglandin E1 derivative with vasodilatory and antiplatelet action, was tried in a rat chronic spinal cord compression model. Summary of Background Data. Limaprost increased the blood flow of cauda equina and improved motor functions in animal models of lumbar stenosis. The drug is clinically used to treat neurogenic intermittent claudication. Methods: Forty-two rats were allocated to four groups: (A) sham operation without permanent cord compression, given 5 mL/kg of distilled water twice a day (n = 6); (B) sham operation, receiving 300 &mgr;g/kg limaprost twice a day (n = 6); (C) cord compression, receiving the vehicle (n = 15); and (D) cord compression receiving the drug (n = 15). A thin polyurethane sheet that expands by absorbing water was implanted under the C5–C6 laminae to produce cord compression. For sham operation, the sheet was immediately removed. Exercise tests were repeated on a rotating treadmill until 26 weeks after surgery, and then the animals were killed and the spinal cord harvested for motor neurons counts. Results. Treadmill endurance (seconds, mean ± standard error of mean) 2 weeks after surgery was 497.7 ± 2.3, 434.5 ± 65.5, 423.1 ± 33.0, and 480.5 ± 19.5 in groups A, B, C, and D, respectively. At 26th week, the duration was 497.7 ± 2.3, 421.2 ± 78.8, 21.3 ± 11.7, and 441.3 ± 40.4 (P < 0.0001 for the decrease in C group, multivariate analysis of variance with correction for multiple measures.) The motor neuron counts were 38.3 ± 3.6, 38.2 ± 2.6, 32.6 ± 1.9, and 36.2 ± 2.3 in groups A, B, C, and D (P = 0.34), respectively. Conclusion. Limaprost alfadex prevented decline of forced locomotion capability in rats with chronic compression of the cervical cord.

Granulocyte Colony-Stimulating Factor Improves Motor Function in Rats Developing Compression Myelopathy.

Study Design. Basic animal research. Objective. The effects of granulocyte colony-stimulating factor (G-CSF) were assessed in a rat chronic spinal cord compression model to explore the potential of G-CSF as a pharmacological treatment for cervical spondylotic myelopathy. Summary of Background Data. G-CSF is a hematopoietic cytokine used clinically to treat neutropenia. Recently, neuroprotective effects of G-CSF have been reported in spinal cord disorders. Methods. To introduce the chronic cervical cord compression, thin polyurethane sheets were implanted under C5-C6 laminae of rats and gradually expanded by absorbing water. This model reproduces delayed compressive myelopathy of the cervical spine. In sham operations, the sheets were immediately removed. G-CSF (15 &mgr;g/kg) or normal saline (NS) was administered subcutaneously 5 days a week. Experimental groups were sham operation given NS; cord compression given NS; and cord compression given G-CSF. To assess motor functions, rotarod performance, and grip strength were measured. Twenty-six weeks after surgery, cervical spinal cords were examined histopathologically. In the prevention experiment, G-CSF or NS administration was started immediately after surgery. In the treatment experiment, their administration was started 8 weeks after surgery. In another experiment, in three groups in the prevention experiment, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick end labeling staining was performed to assess apoptotic cell death at 8 weeks after surgery. Results. In the prevention experiment, administration of G-CSF preserved the motor functions and motor neurons throughout the 26 weeks, and significantly decreased the number of apoptotic cells at 8 weeks. In the treatment experiment, G-CSF administration from 8 weeks after surgery markedly restored the motor function temporarily to a level equal to the sham group. Conclusion. G-CSF prevents the decline in motor functions and preserves motor neurons in the rat chronic cord compression model. G-CSF also improves motor function in the progressive phase of compression myelopathy. Level of Evidence: N/A

Bow Hunter's Syndrome by Nondominant Vertebral Artery Compression: A Case Report, Literature Review, and Significance of Downbeat Nystagmus as the Diagnostic Clue

BACKGROUND Bow hunters syndrome (BHS) is rare and typically induced by mechanical compression of the dominant vertebral artery (VA) during head rotation. We report a case of BHS induced by nondominant VA compression in which contralateral VA patency was preserved. Definite diagnosis of BHS is not often feasible because of transient symptoms and nonspecific clinical features, such as vertigo or dizziness, especially in nondominant VA compression. We discuss the diagnostic clues of BHS and clinical features of BHS caused by nondominant VA compression through a literature review. CASE DESCRIPTION A 65-year-old man suffered repeated bouts of dizziness whenever his head was rotated to the left. This dizziness was consistently accompanied by downbeat nystagmus (DBN). Radiography revealed left VA compression by a lateral osteophyte at the C3-C4 level only during left head rotation. In contrast, patency of the right VA, which was almost equivalent in size to the left VA, was preserved during head rotation. The distinctive clinical finding of head rotation-induced DBN, which is usually associated with lesions involving the caudal midline cerebellum, was observed. Symptoms disappeared immediately after left VA decompression with osteophytectomy and C3-C4 fusion. CONCLUSIONS Despite excellent flow through the contralateral VA, occlusion of the nondominant VA occasionally induces BHS. According to a review of the literature, BHS cases do not always depend on the VA on one side for blood supply. Head rotation-induced DBN can be useful for diagnosis of BHS, even in cases of nondominant VA compression.

Initial Treatment Strategy for Intracranial Mycotic Aneurysms: 2 Case Reports and Literature Review

BACKGROUND Intracranial mycotic aneurysm (IMA) is a rare neurovascular disease and a well-known complication after infective endocarditis. IMAs potentially carry a high mortality risk resulting from intracranial hemorrhage. Therefore, initial treatment is crucial for IMA patients, but an optimal treatment strategy remains unknown. Herein, we report 1 cases of IMA patients treated with the current usual modalities, and we provide a comprehensive literature review to propose an optimal initial treatment strategy for IMAs. CASE DESCRIPTIONS Case 1: An 80-year-old man received a diagnosis of ruptured IMA. He immediately underwent trapping surgery and was discharged without neurologic deficit. Case 2: A 36-year-old man with previous aortic root replacement received a diagnosis of ruptured IMA. His general condition was considered too unstable to allow him to undergo direct surgery, and the angiographic access route was limited because of the previous aortic replacement surgery. Therefore, we selected conservative therapy; however, the patient subsequently died after complications from a huge intracerebral hemorrhage during medical treatment. CONCLUSIONS On the basis of 129 IMA cases across 54 reports published from 2006 to 2016, we propose initial surgical intervention as an optimal treatment for patients with ruptured, and even unruptured, IMAs. Regarding surgical intervention, there was no significant difference in postoperative modified Rankin scale scores between direct surgery and endovascular treatment. By contrast, because antibiotic treatment significantly decreased IMA size in unruptured IMAs, antibiotic treatment might be a reasonable alternative for patients with unruptured IMAs, depending on the patients situation.

Surgical Treatment of Gorham’s Disease with Massive Osteolysis of the Skull and Cervical Spine: A Case Report and Review of Literature

Gorham’s disease is a rare disorder of unknown etiology and variable clinical presentation and is characterized by the proliferation of lymphatic vessels associated with massive regional osteolysis. Although 10 cases involving the skull and cervical spine have been reported in the literature, little is available concerning the surgical treatment of either atlantoaxial dislocation or basilar impression. Most cases have experienced universally unsuccessful treatment with bone grafts, which have led to dissolution. This case report describes the clinical course, and radiotherapeutic, medical, and surgical treatment for Gorham’s disease with basilar impression and massive osteolysis of the skull and upper cervical spine. The case of a 27-year-old man with progressive massive osteolysis of the skull and cervical spine is reported. Multiple surgical treatments to decompress the spinal cord and stabilize the skull and upper cervical spine with autologous fibular grafts were performed in order to prevent the progression of atlantoaxial dislocation and basilar impression. Pathologically, radiotherapy failed to show any effect. The efficacy of antiresorptive therapy with bisphosphonates could not be confirmed either clinically or radiologically. Although solid bone fusion was not obtained, the patient has achieved a satisfactory functional outcome and remains completely active after repeated surgeries. Surgical treatment is extremely difficult in cases of Gorham’s disease involving the skull and upper cervical spine. Fibular bone grafts seem to show resistance to erosion to osteolytic tissue.