Anti-high mobility group box-1 antibody therapy for traumatic brain injury.

OBJECTIVE: High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. In this study, we examined the involvement of HMGB1 in traumatic brain injury (TBI) and evaluated the ability of intravenously administered neutralizing anti-HMGB1 monoclonal antibody (mAb) to attenuate brain injury. METHODS: Traumatic brain injury was induced in rats or mice by fluid percussion. Anti-HMGB1 mAb or control mAb was administered intravenously after TBI. RESULTS: Anti-HMGB1 mAb remarkably inhibited fluid percussion-induced brain edema in rats, as detected by T2-weighted magnetic resonance imaging; this was associated with inhibition of HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression, and improvement of motor function. In contrast, intravenous injection of recombinant HMGB1 dose-dependently produced the opposite effects. Experiments using receptor for advanced glycation end product (RAGE)(-/-) , toll-like receptor-4 (TLR4)(-/-) , and TLR2(-/-) mice suggested the involvement of RAGE as the predominant receptor for HMGB1. INTERPRETATION: Anti-HMGB1 mAb may provide a novel and effective therapy for TBI by protecting against BBB disruption and reducing the inflammatory responses induced by HMGB1.

Proteomics-based analysis of invasion-related proteins in malignant gliomas.

One of the insidious biological features of gliomas is their potential to extensively invade normal brain tissue, yet molecular mechanisms that dictate this locally invasive behavior remain poorly understood. To investigate the molecular basis of invasion by malignant gliomas, proteomic analysis was performed using a pair of canine glioma subclones - J3T-1 and J3T-2 - that show different invasion phenotypes in rat brains but have similar genetic backgrounds. Two-dimensional protein electrophoresis of whole-cell lysates of J3T-1 (angiogenesis-dependent invasion phenotype) and J3T-2 (angiogenesis-independent invasion phenotype) was performed. Twenty-two distinct spots were recognized when significant alteration was defined as more than 1.5-fold change in spot intensity between J3T-1 and J3T-2. Four proteins that demonstrated increased expression in J3T-1, and 14 proteins that demonstrated increased expression in J3T-2 were identified using liquid chromatography-mass spectrometry analysis. One of the proteins identified was annexin A2, which was expressed at higher levels in J3T-1 than in J3T-2. The higher expression of annexin A2 in J3T-1 was corroborated by quantitative RT-PCR of the cultured cells and immunohistochemical staining of the rat brain tumors. Moreover, immunohistochemical analysis of human glioblastoma specimens showed that annexin A2 was expressed at high levels in the tumor cells that formed clusters around dilated vessels. These results reveal differences in the proteomic profiles between these two cell lines that might correlate with their different invasion profiles. Thus, annexin A2 may be related to angiogenesis-dependent invasion.

Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats.

BACKGROUND AND PURPOSE: High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity in the extracellular space. We previously demonstrated that intravenous injection of anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by middle cerebral artery occlusion in rats. In the present study, we focused on the protective effects of the mAb on the marked translocation of HMGB1 in the brain, the disruption of the blood-brain barrier (BBB), and the resultant brain edema. METHODS: Middle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with anti-HMGB1 mAb or control IgG intravenously. BBB permeability was measured by MRI. Ultrastructure of the BBB unit was observed by transmission electron microscope. The in vitro BBB system was used to study the direct effects of HMGB1 in BBB components. RESULTS: HMGB1 was time-dependently translocated and released from neurons in the ischemic rat brain. The mAb reduced the edematous area on T2-weighted MRI. Transmission electron microscope observation revealed that the mAb strongly inhibited astrocyte end feet swelling, the end feet detachment from the basement membrane, and the opening of the tight junction between endothelial cells. In the in vitro reconstituted BBB system, recombinant HMGB1 increased the permeability of the BBB with morphological changes in endothelial cells and pericytes, which were inhibited by the mAb. Moreover, the anti-HMGB1 mAb facilitated the clearance of serum HMGB1. CONCLUSIONS: These results indicated that the anti-HMGB1 mAb could be an effective therapy for brain ischemia by inhibiting the development of brain edema through the protection of the BBB and the efficient clearance of circulating HMGB1.

Nonimmersive virtual reality mirror visual feedback therapy and its application for the treatment of complex regional pain syndrome: an open-label pilot study.

OBJECTIVE: Chronic pain conditions such as phantom limb pain and complex regional pain syndrome are difficult to treat, and traditional pharmacological treatment and invasive neural block are not always effective. Plasticity in the central nervous system occurs in these conditions and may be associated with pain. Mirror visual feedback therapy aims to restore normal cortical organization and is applied in the treatment of chronic pain conditions. However, not all patients benefit from this treatment. Virtual reality technology is increasingly attracting attention for medical application, including as an analgesic modality. An advanced mirror visual feedback system with virtual reality technology may have increased analgesic efficacy and benefit a wider patient population. In this preliminary work, we developed a virtual reality mirror visual feedback system and applied it to the treatment of complex regional pain syndrome. DESIGN: A small open-label case series. Five patients with complex regional pain syndrome received virtual reality mirror visual feedback therapy once a week for five to eight sessions on an outpatient basis. Patients were monitored for continued medication use and pain intensity. RESULTS: Four of the five patients showed >50% reduction in pain intensity. Two of these patients ended their visits to our pain clinic after five sessions. CONCLUSION: Our results indicate that virtual reality mirror visual feedback therapy is a promising alternative treatment for complex regional pain syndrome. Further studies are necessary before concluding that analgesia provided from virtual reality mirror visual feedback therapy is the result of reversing maladaptive changes in pain perception.

[Embolization for aneurismal dilatation associated with ruptured dissecting anterior inferior cerebellar artery aneurysm with preservation of the parent artery: case report].

We report a rare case of a ruptured dissecting anterior inferior cerebellar artery (AICA) aneurysm treated by endosaccular embolization with a Guglielmi detachable coil (GDC). An 85-year-old female presented with headache. Computed tomographic (CT) scan showed subarachnoid hemorrhage and intraventricular hemorrhage in the fourth ventricule. Cerebral angiography and 3D-CT angiography revealed an aneurysmal dilatation at the anterior pontine segment of the right AICA with a diagnosis of arterial dissection. The right posterior inferior cerebellar artery (PICA) was absent and the right AICA supplied the territory normally nourished by the right PICA. The aneurismal dilatation was occluded by endosacullar embolization with preservation of the AICA. The distal AICA aneurysm is rare and only seven cases treated with endovascular embolization have been reported. In these, six cases were treated by parent artery occlusion with coil and the subsequent three cases presented with ischemic complications. Only one case was treated by endosaccular embolization with GDC. To our knowledge, this is the second report of the distal AICA aneurysm treated by endosaccular embolization with GDC. Distal AICA aneurysms are briefly discussed while reviewing the literature.

[A case of cervical endodermal cyst].

A very rare case involving an endodermal cyst of the cervical spinal canal was documented. In 1999, a 28-year-old male presented with mild tetraplegia due to a traffic accident and consequently, he was admitted to another hospital. Magnetic resonance imaging (MRI) performed at that time demonstrated a cervical cord cyst. He was treated conservatively and as a result, complete resolution of symptoms was achieved. Five years later, he presented with progressive right hemiparesis and was referred to our institute. MRI at the time of admission exhibited an intradural extramedullary cystic lesion on the ventral side of the spinal cord at the C5-6 levels, which was characterized by low intensity on T1-weighted, and by high intensity on T2-weighted images. The cyst, which had increased in size, compressed the spinal cord remarkably backward. The anterior central vertebrectomy approach was performed. Subtotal resection of the cyst wall was conducted due to its tight partical adhesion to the spinal cord. The vertebral defect was reconstructed with an autogenous iliac graft. According to histological findings the cyst wall consisted of a single layer of columnar epithelial cells with secretory granules and immunohistochemical examination revealed that the cyst wall was positive for cytokeratin 7. Symptoms improved immediately. Subsequently, the patient was discharged with good performance status. Endodermal cysts are very rare developmental cysts derived from the embryonic endodermal layer. Moreover, these lesions are usually located intradurally in the cervical and upper dorsal spine ventral to the spinal cord. Total removal of the cyst is recommended if it is possible. However, total resection is often difficult due to adhesion of the cyst wall to the neural tissue so invasive resection should be avoided. In such cases, follow-up MRI is necessary in order to exclude recurrence of the remnant lesion.

Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma.

We have established a pair of animal models (J3T-1 and J3T-2) with different invasive and angiogenic phenotypes, and demonstrated that annexin A2 is expressed at higher levels in J3T-1 than J3T-2 cells. The function of annexin A2 in relation to angiogenesis and invasion was investigated using these models. Stable silencing or overexpression of annexin A2 in J3T-1 and J3T-2 cells (J3T-1shA and J3T-2A cells) was established and used. Thirty human glioblastoma samples were evaluated for expression of annexin A2, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Immunohistochemical and quantitative reverse-transcription polymerase chain reaction analyses revealed higher expression of annexin A2, VEGF and PDGF in J3T-1 and J3T-2A cells. Cultured J3T-1 and J3T-2A cells exhibited higher adhesive ability to endothelial cells. Histopathological analysis of animal brain tumors revealed that J3T-1 and J3T-2A tumors displayed marked angiogenesis and invasion along the neovasculature, whereas J3T-2 and J3T-1shA tumors exhibited diffuse, infiltrative invasion without angiogenesis. Positive expression of annexin A2 was observed in tumor cells surrounding dilated vessels in 25/30 human glioblastoma specimens. Our results reveal that the phenotype of glioma invasion is closely related to angiogenesis. We identify annexin A2 as a factor regulating angiogenesis and invasion of malignant gliomas.

[Preoperative embolization of metastatic spinal tumors].

The authors reviewed their clinical experience with preoperative embolization of metastatic spinal tumors. Between October 2000 and September 2003, 20 patients (13 men and 7 women; average age 68.3 years, range 44-82 years) underwent 24 spinal operations for 22 spinal metastatic tumors. Nineteen spinal operations (79%) were planned preoperative embolization with polyvinyl alcohol particles. In 3 cases, there was no tumor stain. Fifty percent of the C4-T2 lesions and 76% of the T3-L3 lesions were embolized preoperatively. The level of lesions determined which embolization procedure should be used. With C7-T2 or sacral lesions, feeding arteries were superselectively catheterized, then particles were injected via a microcatheter. With T3-L3 lesions, selective catheterization of the corresponding segmental arteries was performed. Particles were injected via 4 or 5Fr catheters. No complications were encountered during embolization. Embolizing from the origin of the segmental arteries is effective for reducing intraoperative blood loss because feeding vessels in the anterior part of the spinal body are able to be embolized. Preoperative embolization is not a very complicated procedure and careful catheterization can avoid complications. Based on tumor histology, size of the spinal body, depth of the operative field and operative approach, preoperative embolization can be performed with positive results.

Novel animal glioma models that separately exhibit two different invasive and angiogenic phenotypes of human glioblastomas.

OBJECTIVE: Invasive behaviors of malignant gliomas are fundamental traits and major reasons for treatment failure. Delineation of invasive growth is important in establishing treatment for gliomas and experimental neuro-oncology could benefit from an invasive glioma model. In this study, we established two new cell line-based animal models of invasive glioma. METHODS: Two cell lines, J3T-1 and J3T-2, were derived from the same parental canine glioma cell line, J3T. These cells were inoculated to establish brain tumors in athymic mice and rats. Pathologic samples of these animal gliomas were examined to analyze invasive patterns in relation to angiogenesis, and were compared with human glioblastoma samples. The molecular profiles of these cell lines were also shown. RESULTS: Histologically, J3T-1 and J3T-2 tumors exhibited different invasive patterns. J3T-1 cells clustered around newly developed vessels at tumor borders, whereas J3T-2 cells showed diffuse single cell infiltration into surrounding healthy parenchyma. In human malignant glioma samples, both types of invasion were observed concomitantly. Molecular profiles of these cell lines were analyzed by immunocytochemistry and with quantitative reverse transcription polymerase chain reaction. Vascular endothelial growth factor, matrix metalloproteinase-9, hypoxia-inducible factor-1, and platelet-derived growth factor were overexpressed in J3T-1 cells rather than in J3T-2 cells, whereas integrin αvß3, matrix metalloproteinase-2, nestin, and secreted protein acidic and rich in cysteine were overexpressed in J3T-2 cells rather than in J3T-1 cells. CONCLUSIONS: These animal models histologically recapitulated two invasive and angiogenic phenotypes, namely angiogenesis-dependent and angiogenesis-independent invasion, also observed in human glioblastoma. These cell lines provided a reproducible in vitro and in vivo system to analyze the mechanisms of invasion and angiogenesis in glioma progression.

"Double-stick tape" technique for transposition of an offending vessel in microvascular decompression: technical case report.

BACKGROUND AND IMPORTANCE: Severe hemifacial spasm caused by compression by a tortuous vertebral artery (VA) often is encountered and is difficult to treat. We describe a patient with hemifacial spasm caused by compression of the facial nerve by a tortuous VA. A simple and effective transposition approach, a "double-stick tape" technique, to the offending artery using a fibrin tissue-adhesive collagen fleece product (TachoComb) is reported. CLINICAL PRESENTATION: A 65-year-old woman presented with an 8-year history of right-sided facial spasms, including the orbicularis oculi and orbicularis oris muscles. MRI revealed a tortuous right VA indented into the pontomedullary junction. The right anterior inferior cerebellar artery (AICA) also contacted the proximal portion of the facial nerve. Surgical exploration with standard retrosigmoid craniotomy was performed. The offending VA was dissected away from the pontomedullary junction toward the cranial base. A small piece of TachoComb, with fibrin glue applied on the non-coated side of the fleece to make a "double-stick tape," was then placed on the ventral surface of the VA. Until the glue hardened, the VA was held away from the brainstem onto the dura of the petrous pyramid. After this procedure, AICA transposition was performed. The patient's symptoms were completely resolved immediately after surgery, and she remained asymptomatic at her 1 year follow-up visit. CONCLUSION: The advantage of our "double-stick tape" technique is the simplicity of the procedure. The present technique is a feasible alternative for the treatment of hemifacial spasm caused by a tortuous VA.

Primary germinoma in the medulla oblongata - case report - .

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.

Striatal stimulation nurtures endogenous neurogenesis and angiogenesis in chronic-phase ischemic stroke rats.

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.