Kazuhide Furuya

Genome-Wide Gene Expression Analysis for Induced Ischemic Tolerance and Delayed Neuronal Death following Transient Global Ischemia in Rats:

enome-wide gene expression analysis of the hippocampal CA1 region was conducted in a rat global ischemia model for delayed neuronal death and induced ischemic tolerance using an oligonucleotide-based DNA microarray containing 8,799 probes. The results showed that expression levels of 246 transcripts were increased and 213 were decreased following ischemia, corresponding to 5.1% of the represented probe sets. These changes were divided into seven expression clusters using hierarchical cluster analysis, each with distinct conditions and time-specific patterns. Ischemic tolerance was associated with transient up-regulation of transcription factors (c-Fos, JunB Egr-1, −2, −4, NGFI-B), Hsp70 and MAP kinase cascade-related genes (MKP-1), which are implicated cell survival. Delayed neuronal death exhibited complex long-lasting changes of expression, such as up-regulation of proapoptotic genes (GADD153, Smad2, Dral, Caspase-2 and −3) and down-regulation of genes implicated in survival signaling (MKK2, and PI4 kinase, DAG/PKC signaling pathways), suggesting an imbalance between death and survival signals. Our study provides a differential gene expression profile between delayed neuronal death and induced ischemic tolerance in a genome-wide analysis, and contributes to further understanding of the complex molecular pathophysiology in cerebral ischemia.

Cerebrovascular hemodynamics and ischemic tolerance : Lipopolysaccharide-induced resistance to focal cerebral ischemia is not due to changes in severity of the initial ischemic insult, but is associated with preservation of microvascular perfusion

Lipopolysaccharide (LPS), administered 72 hours before middle cerebral artery (MCA) occlusion, confers significant protection against ischemic injury. For example, in the present study, LPS (0.9 mg/kg intravenously) induced a 31% reduction in infarct volume (compared with saline control) assessed 24 hours after permanent MCA occlusion. To determine whether LPS induces true tolerance to ischemia, or merely attenuates initial ischemic severity by augmenting collateral blood flow, local CBF was measured autoradiographically 15 minutes after MCA occlusion. Local CBF did not differ significantly between LPS- and saline-pretreated rats (e.g., 34 ± 10 and 29 ± 15 mL·100 g−1·min−1 for saline and LPS pretreatment in a representative region of ischemic cortex), indicating that the neuroprotective action of LPS is not attributable to an immediate reduction in the degree of ischemia induced by MCA occlusion, and that LPS does indeed induce a state of ischemic tolerance. In contrast to the similarity of the initial ischemic insult between tolerant (LPS-pretreated) and nontolerant (saline-pretreated) rats, microvascular perfusion assessed either 4 hours or 24 hours after MCA occlusion was preserved at significantly higher levels in the LPS-pretreated rats than in controls. Furthermore, the regions of preserved perfusion in tolerant animals were associated with regions of tissue sparing. These results suggest that LPS-induced tolerance to focal ischemia is at least partly dependent on the active maintenance of microvascular patency and hence the prevention of secondary ischemic injury.

A Model of Global Cerebral Ischemia in C57 BL/6 Mice

A reproducible model of global cerebral ischemia in mice is essential for elucidating the molecular mechanism of ischemic neuronal injury. Such a model is particularly important in the mouse because many genetically engineered mutant animals are available. In C57BL/6 and SV129/EMS mice, we evaluated a three-vessel occlusion model. Occlusion of the basilar artery with a miniature clip was followed by bilateral carotid occlusion. The mean cortical cerebral blood flow was reduced to less than 10% of the preischemic value, and the mean anoxic depolarization was attained within 1 minute. In C57BL/6 mice, there was CA1 hippocampal neuronal degeneration 4 days after ischemia. Neuronal damage depended upon ischemic duration: the surviving neuronal count was 78.5 ± 8.5% after 8-minute ischemia and 8.4 ± 12.7% after 14-minute ischemia. In SV129/EMS mice, similar neuronal degeneration was not observed after 14-minute ischemia. The global ischemia model in C57BL/6 mice showed high reproducibility and consistent neuronal injury in the CA1 sector, indicating that comparison of ischemic outcome between wild-type and mutant mice could provide meaningful data using the C57BL/6 genetic background. Strain differences in this study highlight the need for consideration of genetic background when evaluating ischemia experiments in mice.

Intramedullary Angiographically Occult Vascular Malformations of the Spinal Cord

OBJECTIVE This study was performed to elucidate the differences between angiographically occult vascular malformations of the spinal cord and the histological subtypes. METHODS The cases of six patients with spinal intramedullary angiographically occult vascular malformations encountered during the past 10 years were examined regarding clinical course, neuroradiological manifestations, and surgical consideration. RESULTS There were four cavernous malformations and two arteriovenous malformations. The cervical section of the spinal cord was involved in four cases, and the thoracic section of the spinal cord was involved in two. All of the patients had presented with motor weakness and sensory disturbance below the level of the lesion. Two distinct clinical courses were observed; they were neurological decline with repeated episodes of relapse and remission (four patients) and continuing neurological decline (two patients). Although a mixed-intensity core surrounded by a low-intensity rim is thought to be characteristic of cavernous malformations, we were not able to differentiate the histological types on the basis of magnetic resonance imaging findings alone. CONCLUSION In cases of spinal intramedullary angiographically occult vascular malformations, even if clinical course and magnetic resonance imaging findings are consistent with cavernous malformation, other histological subtypes need to be considered. Surgery should be considered for symptomatic patients, because symptoms and signs that are probably caused by bleeding tend to worsen rather than stabilize.

Primary cavernous sinus malignant lymphoma treated by gamma knife radiosurgery: case report and review of the literature.

BACKGROUND Malignant lymphomas originating primarily in the cavernous sinus have not been histologically verified by any authors. The first reported case to our knowledge of primary cavernous sinus malignant lymphoma, initially diagnosed as benign meningioma and treated by gamma knife radiosurgery, is presented. CASE DESCRIPTION The patient was a 77-year-old man whose initial symptoms were left facial hypesthesia and diplopia on left gaze. During the 21-month follow-up period after gamma knife radiosurgery, no evidence of tumor regrowth was seen in the irradiated area, but an unirradiated mass expanded with invasion of the brain stem. Subsequent surgery provided histologic verification of the diagnosis. Despite successful local tumor control, the patient died due to sepsis 31 months after the onset of symptoms. Autopsy failed to disclose any remaining lymphoma cells either in the primary lesion or anywhere throughout the entire body. CONCLUSION Primary cavernous sinus malignant lymphoma is an extremely rare brain tumor, but it must be considered in the differential diagnosis of an enhanced mass in the cavernous sinus. Stereotactic radiosurgery using the gamma knife technique for intracranial brain tumors, especially in the cavernous sinus, is associated with risk, as was seen in our patient. Our experience points out the pitfalls of gamma knife radiosurgery; it should be performed only after histologic confirmation has been obtained.

Cardiac arrest cerebral ischemia model in mice failed to cause delayed neuronal death in the hippocampus

Global cerebral ischemia models for genetically engineered mice are of particular importance for the study of delayed neuronal death, but have been complicated by variability of vascular anatomy. Here we developed a 5-min cardiac arrest model that was not affected by vascular anatomy, and evaluated the hippocampal neuronal injury in BL/6 and SV129 mice. Despite prolonged anoxic depolarization for approximately 7 min, however, no consistent ischemic neuronal injury was noted in the CA1 sector of the hippocampus in both strains. Thus, our observations suggested that murine hippocampal neurons are relatively resistant to ischemia compared with those in other rodents.

Primary large choroid plexus papillomas in the cerebellopontine angle: radiological manifestations and surgical management.

SummaryTwo cases of primary choroid plexus papilloma originating in the cerebellopontine angle (CPA) are reported. Both papillomas were encapsulated and strongly adhering to a choroid plexus tuft protruding from the foramen of Luschka. Successful removal of the tumour was achieved in each case. Surgical strategy, neuroradiological manifestations, and the differential diagnosis are discussed.

Intracerebroventricular delivery of dominant negative prion protein in a mouse model of iatrogenic Creutzfeldt-Jakob disease after dura graft transplantation

We have developed a novel procedure in which a small collagen sheet (3 mm x 3 mm) absorbing prion-infected brain homogenates was transplanted onto the brain surface of highly prion-susceptible transgenic mice (Tg(MoPrP)4053/FVB), as an animal model of iatrogenic Creutzfeldt-Jakob disease (iCJD) caused by prion-contaminated cadaveric dura graft transplantation. Using the iCJD model, we further investigated the in vivo efficacy of dominant negative recombinant prion protein with lysine substitution at mouse codon 218 (rPrP-Q218K), which is known to inhibit prion replication in vitro (H. Kishida, Y. Sakasegawa, K. Watanabe, Y. Yamakawa, M. Nishijima, Y. Kuroiwa, N.S. Hachiya, K. Kaneko, Non-glycosylphosphatidylinositol (GPI)-anchored recombinant prion protein with dominant-negative mutation inhibits PrPSc replication in vitro, Amyloid, vol. 11, 2004, pp. 14-20.). Following 7-day intracerebroventricular administration of the rPrP-Q218K via an indwelling catheter connected to the implanted osmotic pump, the median incubation period of Tg(MoPrP)4053/FVB was prolonged considerably from 117 days to 131 days (p=0.016, log-rank test) in the rPrP-Q218K-treated group, even after a lengthy latency period of as long as 30 days by starting the rPrP-Q218K injection. Whether wild-type rPrP, other mutant rPrPs, or the combination of rPrP-Q218K with other anti-prion compounds might extend the survival period in that condition must be further investigated.

Preservation of the lesser occipital nerve during microvascular decompression for hemifacial spasm : Technical note

The authors report on their technique for preserving the lesser occipital nerve (LON) during lateral suboccipital craniotomy. In their technique, the LON, which runs along the surface of or just beneath the sternocleidomastoid muscle, is identified and preserved. Lesser occipital nerve preservation using their technique was attempted in 25 patients who underwent microvascular decompression for hemifacial spasm. The LON was successfully preserved in 16 of these patients, was impossible to preserve in two patients, and could not be identified in seven patients. Among the patients in whom LON preservation was successful, 87.5% were free of sensory disturbance 6 months after surgery, whereas both patients in whom the LON could not be preserved complained of sensory disturbances in the occipital area and the posterior part of the auricula. Fifty-seven percent of the patients whose LON could not be identified complained of sensory disturbance. Thus, this technique for preserving the LON reduces the incidence of sensory disturbance in the occipital region after suboccipital craniotomy for microvascular decompression for hemifacial spasm.

High-dose methotrexate monotherapy followed by radiation for CD30-positive, anaplastic lymphoma kinase-1–positive anaplastic large-cell lymphoma in the brain of a child

The authors report the case of an 11-year-old immunocompetent boy with primary CNS CD30-positive anaplastic large-cell lymphoma (ALCL) that was also positive for anaplastic lymphoma kinase-1. His initial clinical manifestation was acute meningitis of unknown etiology. Findings on CT scanning were normal. Although he received empirical treatment against infection, his systemic and neurological status deteriorated. Subsequent MRI revealed newly emerged enhanced lesions and concomitant edema in the left parietal lobe. Diagnosis was confirmed following a brain biopsy and immunohistochemical staining. Three courses of systemic high-dose methotrexate (HD-MTX) treatment with 2-week intervals was started, followed by whole-brain radiation. His clinical course improved, and he has remained disease-free for more than 8 years without any additional treatment. Because ALCL originating in the brain is extremely rare and difficult to diagnose, no standard treatment has been established. This report suggests that systemic HD-MTX monotherapy can be an effective and worthwhile tailored therapeutic option for pediatric primary CNS ALCL.