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Background Radiotherapy is an important treatment option for central nervous system malignancies. However, cranial radiation induces hippocampal dysfunction and white matter injury; this leads to cognitive dysfunction, and results in a reduced quality of life in patients. Excitatory glutamate signaling through N-methyl-d-aspartate receptors (NMDARs) plays a central role both in hippocampal neurogenesis and in the myelination of oligodendrocytes in the cerebrum. Methods We provide a method for quantifying neurogenesis in human subjects in live brain during cancer therapy. Neuroimaging using originally created behavioral tasks was employed to examine human hippocampal memory pathway in patients with brain disorders. Results Treatment with memantine, a non-competitive NMDAR antagonist, reversed impairment in hippocampal pattern separation networks as detected by functional magnetic resonance imaging. Hyperbaric preconditioning of the patients just before radiotherapy with memantine mostly reversed white matter injury as detected by whole brain analysis with Tract-Based Spatial Statics. Neuromodulation combined with the administration of hyperbaric oxygen therapy and memantine during radiotherapy facilitated the restoration of hippocampal function and white matter integrity, and improved higher cognitive function in patients receiving cranial radiation. Conclusions The method described herein, for diagnosis of hippocampal dysfunction, and therapeutic intervention can be utilized to restore some of the cognitive decline experienced by patients who have received cranial radiation. The underlying mechanism of restoration is the production of new neurons, which enhances functionality in pattern separation networks in the hippocampi, resulting in an increase in cognitive score, and restoration of microstructural integrity of white matter tracts revealed by Tract-Based Spatial Statics Analysis.

Purpose Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. Methods At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. Results PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Symptom was headache in 50% (14/28). Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.02) and GTR (p < 0.01) were found to be independent prognostic factors. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. Conclusions Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

Evidence has accumulated that higher consumption of high-fat diets (HFDs) during the juvenile/adolescent period induces altered hippocampal function and morphology; however, the mechanism behind this phenomenon remains elusive. Using high-resolution structural imaging combined with molecular and functional interrogation, a murine model of obesity treated with HFDs for 12 weeks after weaning mice was shown to change in the glutamate-mediated intracellular calcium signaling and activity, including further selective reduction of gray matter volume in the hippocampus associated with memory recall disturbance. Dysregulation of intracellular calcium concentrations was restored by a non-competitive α-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonist, followed by normalization of hippocampal volume and memory recall ability, indicating that AMPARs may serve as an attractive therapeutic target for obesity-associated cognitive decline.

We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3–46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

The epidemiology of patients with traumatic brain injury (TBI) has changed dramatically over recent decades as a result of rapid advances in aging societies. We assessed the influence of age on outcomes of patients with TBI and sought to identify prognostic factors for in-hospital mortality of TBI among elderly patients.Using a nationwide database, we analyzed data from 5651 patients with TBI. Univariate analysis was conducted to compare patient demographics, neurologic status on admission, radiologic findings, systemic complication rates, length of hospital stay, in-hospital mortality, and home discharge rates between elderly and nonelderly groups. Multivariable analysis was conducted to determine prognostic factors for in-hospital mortality among elderly patients.Overall in-hospital mortality was significantly higher in elderly patients (12.8% vs. 19.3%; P0.001). In-hospital mortality of elderly patients with mild TBI increased significantly at7 days after admission, whereas that of elderly patients with moderate or severe TBI was significantly higher immediately after admission. Age (odds ratio [OR], 1.62; P = 0.024), male sex (OR, 1.30; P = 0.004), Japan Coma Scale score on admission (OR, 5.95, P0.001), and incidence of acute subdural hematoma (OR, 1.89; P0.001) were associated with in-hospital mortality in elderly patients with TBI.Elderly patients with TBI showed significantly higher in-hospital mortality. Delayed increases in in-hospital mortality were observed among elderly patients with mild TBI. Level of consciousness on admission was the strongest predictor of in-hospital mortality among elderly patients.

Background Cerebral hemangioblastomas are benign tumors with abundant blood flow that occur mainly in the posterior fossa. Tumor removal en bloc is important in surgical treatment because of the risk of bleeding; however, it is actually rather difficult in practice. Therefore, we propose a surgical strategy for visualizing hypervascular tumors of the posterior fossa utilizing indocyanine green (ICG). Case description Case 1 involved a 48-year-old male with a history of von Hippel-Lindau (VHL) disease. Magnetic resonance imaging (MRI) revealed a solid tumor measuring 3.0 cm in diameter in the right cerebellopontine angle. We performed surgery because the tumor was pressing against the brainstem. Surgery was performed via the posterior subtemporal transtentorial approach in order to visualize the feeding artery and draining vein intraoperatively. The vessels were confirmed by ICG and the tumor was removed en bloc. Case 2 involved a 30-year-old woman. Signs of increased intracranial pressure were noted, and an MRI revealed a solid tumor 3.5 cm in diameter in the left cerebellar hemisphere. Surgery was performed via the midline suboccipital approach. Similarly, we confirmed the vessels using ICG and the tumor was removed en bloc. Conclusions For hypervascular tumors of the posterior fossa, preoperative image assessment is important. Furthermore, the use of ICG during surgery is advantageous for surgical strategies where the feeding arteries and draining veins exist superficially in the operative field and are therefore easier to remove en bloc.

The factors that lead to the improvement of gait function in patients with diseases of the central nervous system (CNS) who use a hybrid assistive limb (HAL) are not yet fully understood. The purpose of the present study was to analyze these factors to determine the prognosis of the patients’ gait function. Patients whose CNS disease was within 180 days since onset were designated as the subacute-phase patients, and patients whose disease onset had occurred more than 180 days previously were designated as chronic-phase patients. Fifteen subacute-phase patients and 15 chronic-phase patients were given HAL training. The study analyzed how post-training walking independence in these patients was affected by the following factors: age, disease, lesion area, lower limb function, balance, period until the start of training, number of training sessions, additional rehabilitation, higher-order cognitive dysfunction, HAL model, and the use of a non-weight-bearing walking-aid. In subacute-phase patients, walking independence was related to lower limb function (r_s = 0.35). In chronic-phase patients, there was a statistically significant correlation between post-training walking independence and balance (r_s = 0.78). In addition, in patients with a severe motor dysfunction that was accompanied by inattention and global cognitive dysfunction, little improvement occurred, even with double-leg model training, because they had difficulty wearing the device. The results demonstrated that the factors that improved walking independence post HAL training differed between patients with subacute- and chronic-stage CNS diseases. The findings may serve as valuable information for future HAL training of patients with CNS diseases., 論文

The cerebellum is a crucial structure for cognitive function as well as motor control. Benign brain tumors such as schwannomas, meningiomas, and epidermoids tend to occur in the cerebellopontine angle cisterns and may cause compression of the posterior lateral cerebellum near the superior posterior fissure, where the eloquent area for cognitive function was recently identified. The present study examined cognitive impairment in patients with benign cerebellar tumors before and after surgical intervention in order to clarify the functional implications of this region in humans. Patients with cerebellar tumors showed deficits in psychomotor speed and working memory compared with healthy controls. Moreover, these impairments were more pronounced in patients with right cerebellar tumors. Functional magnetic resonance imaging during performance of a lure task also demonstrated that cerebellar tumors affected pattern separation or the ability to distinguish similar experiences of episodic memory or events with discrete, non-overlapping representations, which is one of the important cognitive functions related to the hippocampus. The present findings indicate that compression of the human posterior lateral cerebellum affects hippocampal memory function., 論文

Background and Purpose γ-Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby γ-oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine D2 receptor signalling locally attenuates insulin secretion in pancreatic islets, presumably via decreased levels of intracellular cAMP. We therefore hypothesized that γ-oryzanol would improve high-fat diet (HFD)-induced dysfunction of islets through the suppression of local D2 receptor signalling. Experimental Approach Glucose metabolism and regulation of molecules involved in D2 receptor signalling in pancreatic islets were investigated in male C57BL/6J mice, fed HFD and treated with γ-oryzanol . In isolated murine islets and the beta cell line, MIN6 , the effects of γ-oryzanol on glucose-stimulated insulin secretion (GSIS) was analysed using siRNA for D2 receptors and a variety of compounds which alter D2 receptor signalling. Key Results In islets, γ-oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in D2 receptor signalling was increased in islets from HFD-fed mice, which were reciprocally decreased by γ-oryzanol. Experiments with siRNA for D2 receptors and D2 receptor ligands in vitro suggest that γ-oryzanol suppressed D2 receptor signalling and augmented GSIS. Conclusions and Implications γ-Oryzanol exhibited unique anti-diabetic properties. The unexpected effects of γ-oryzanol on D2 receptor signalling in islets may provide a novel; natural food-based, approach to anti-diabetic therapy.

Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

Recent epidemiological studies have demonstrated that coffee drinking is associated with reduced mortality of cardiovascular disease. However, its precise mechanisms remain to be clarified. In this study, we examined whether single ingestion of caffeine contained in a cup of coffee improves microvascular function in healthy subjects.A double-blind, placebo-controlled, crossover study was performed in 27 healthy volunteers. A cup of either caffeinated or decaffeinated coffee was drunk by the subjects, and reactive hyperemia of finger blood flow was assessed by laser Doppler flowmetry. In an interval of more than 2 days, the same experimental protocol was repeated with another coffee in a crossover manner. Caffeinated coffee intake slightly but significantly elevated blood pressure and decreased finger blood flow as compared with decaffeinated coffee intake. There was no significant difference in heart rate between caffeinated and decaffeinated coffee intake. Importantly, caffeinated coffee intake significantly enhanced post-occlusive reactive hyperemia of finger blood flow, an index of microvascular endothelial function, compared with decaffeinated coffee intake.These results provide the first evidence that caffeine contained in a cup of coffee enhances microvascular function in healthy individuals.

Object Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo. Methods The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans. Results Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans. Conclusions These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

Object Blockade of Ca++-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) inhibits the proliferation of human glioblastoma by inhibiting Akt phosphorylation, which is independent of the phosphatidylinositol 3-kinase pathway. Inhibiting platelet-derived growth factor receptor (PDGFR)–mediated phosphorylation causes growth inhibition in glioblastoma cells. The authors of this study investigated the effects of YM872 and AG1296, singly and in combination and targeting different pathways upstream of Akt, on Akt-mediated tumor growth in glioblastoma cells in vivo and in vitro. Methods The expression of AMPAR, PDGFR, and c-kit in glioblastoma cells was analyzed via immunofluorescence. Glioblastoma cells, both in culture and in xenografts grown in mice, were treated with YM872 and AG1296, singly or in combination. Inhibition of tumor growth was observed after treatment in the xenograft model. Cell proliferation assays were performed using anti–Ki 67 antibody in vivo and in vitro. The CD34-positive tumor vessel counts within the vascular hot spots of tumor specimens were evaluated. Phosphorylation of Akt was studied using Western blot analysis. Results Combined administration of YM872 and AG1296 had a significant enhanced effect on the inhibition of cell proliferation and reduction of tumor vascularity in the xenograft model. These agents singly and in combination demonstrated a significant reduction of Akt phosphorylation at Ser473 and inhibition of tumor proliferation in vitro, although combined administration had no enhanced antitumor effects. Conclusions The strongly enhanced antitumor effect of this combination therapy in vivo rather than in vitro may be attributable to disruption of the aberrant vascular niche. This combination therapy might provide substantial benefits to patients with glioblastoma.

Background Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san'o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model. Methods and results Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes. Myocardial inducible nitric oxide synthase (iNOS) expression and peroxynitrite levels were significantly higher in ovariectomized rats compared with sham-operated rats, and long-term TJ-113 treatment significantly reduced these oxidative changes. Furthermore, myocardial manganese superoxide dismutase (Mn-SOD) activity was significantly lower in ovariectomized than in sham-operated rats, and long-term TJ-113 treatment significantly restored antioxidant activity. Importantly, those beneficial actions of TJ-113 were significantly inhibited by the estrogen receptor antagonist, fulvestrant, and the phytoestrogen, emodin, a TJ-113 ingredient, mimicked the actions of TJ-113, suggesting involvement of emodin in the effects of TJ-113. Conclusions These results provide the first evidence that long-term treatment with a clinical dosage of TJ-113 markedly ameliorates cardiac IR injury in ovariectomized rats via inhibition of iNOS expression, suppression of peroxynitrite formation, and restoration of Mn-SOD activity. TJ-113 may be a novel therapeutic option in the treatment of ischemic heart disease in climacteric women.

An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH2in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH2concentration causes endothelial dysfunction in rats. To increase vascular BH2levels, the BH2precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH2to BH4. MTX/SEP treatment did not significantly affect aortic BH4levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH2levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH4levels but decreased the BH4-to-BH2ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations ( P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD ( P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH2causes eNOS dysfunction in vivo even in the absence of BH4deficiency, demonstrating a novel insight into the regulation of endothelial function.

Percutaneous transluminal angioplasty (PTA) and stent placement are effective in patients with stenosis of the cavernous or petrous portion of the internal carotid artery (ICA), but the long-term outcomes remain unclear. The present study evaluated long-term outcomes in 54 patients treated by PTA or stent placement for stenotic lesions involving more than 50% of the cavernous or petrous portion of the ICA with ischemic symptoms or without ischemic symptoms if cerebral blood flow on single photon emission computed tomography images was decreased by 20% compared with the contralateral side. Follow-up magnetic resonance, three-dimensional computed tomography, and conventional angiography were performed. Patient condition in the follow-up period was investigated using telephone interviews or questionnaires. PTA was used to treat 13 lesions and stent placement for 41 lesions. Permanent and transient complications occurred in 2 and 5 patients, respectively. The morbidity rate was 13% (7 of 54 patients). The follow-up period ranged from 3 to 80 months (mean 29.9 months), and restenosis and occlusion were recognized in 4 patients (7.4%). Five patients died (2 of malignancy and 3 of myocardial infarction) during the follow-up period. PTA and stent placement are safe and effective in patients with stenosis of the cavernous or petrous portion of the ICA, and result in low long-term rates of restenosis.

To assess the clinical significance of 201Tl-SPECT after postoperative radiotherapy in patients with glioblastoma multiforme (GM). Eighteen patients with macroscopically residual GM who underwent 201Tl-SPECT just after postoperative radiotherapy were analyzed. Fifteen patients (83%) received radiotherapy with a total dose of 60 Gy in conventional fractionation, and the remaining three patients were treated with 72 Gy with hyperfractionation schedules. Sixteen patients (89%) were treated with chemotherapy that consisted of procarbazine, nimustine (ACNU) and vincristine. Concerning 201Tl-SPECT, we calculated the radioactivity ratio of the tumors to contralateral normal brain (T/N ratio) on early and delayed images after 111 MBq 201Tl chloride injections. The median follow-up of all 18 patients was 14.7 months (range, 2.7-38.0 months). At the time of this analysis, 15 patients (83%) had died, and the 1-year overall survival and the median survival time were 67% and 16.2 months, respectively. Fifteen patients (83%) had disease recurrence, and the 1-year progression-free survival (PFS) rate and the median time to progression in all 18 patients were 29% and 7.6 months, respectively. Patients with a high early T/N ratio had a significantly poorer PFS than those with a low T/N ratio (P = 0.0131). On univariate analysis, early T/N ratio alone had a significant impact on PFS, and on mutivariate analysis, early T/N ratio alone was a significant prognostic factor for PFS. 201Tl-SPECT after postoperative radiotherapy was predictive of PFS in patients with macroscopically residual GM.

World Health Organization (WHO) grade 3 glioma is one of the common brain tumors and has three main histological subtypes, including anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO). However, most previous studies have considered AOA and AO as one group because of the difficult differential diagnosis between AOA and AO. Therefore the prognostic difference among patients with these histological subtypes has been unclear. In this study, 68 patients with histologically proven WHO grade 3 glioma, consecutively received postoperative radiotherapy at the Gunma University Hospital, Japan, between 1983 and 2005, were investigated to assess the impact of histological subtype on the survival. The number of AA, AOA and AO patients was 41, 16 and 11, respectively. The mean and median follow-up periods were 72 and 48 months, respectively. The number of patients treated with gross total resection, partial resection and biopsy was 14, 38 and 16, respectively. The mean and median radiation doses were 58 ± 5 Gy and 60 Gy, respectively. The 5-year overall survival rates of AA, AOA and AO were 21%, 38% and 80%, and median survival period were 16 months, 58 months and not reached, respectively. Univariate analysis showed that the histological subtype (P < 0.01) and extent of surgery (P < 0.01) were significant prognostic factors for survival. Selective comparison showed that overall survival of patients with AA was significantly worse than for those with AOA (P = 0.01) and AO (P < 0.01). The overall survival of patients with AO was better than for those with AOA; however, the difference was not statistically significant (P = 0.14). Multivariate analysis demonstrated that histological subtype, age and extent of surgery were the significant independent variable for survival (P < 0.01, P < 0.01 and P = 0.04). In our study, histological subtype was one of the most important prognostic factors of WHO grade 3 glioma.

Positron emission tomography with fluorine-18 fluorodeoxyglucose ([18F]FDG-PET) usually shows ganglioglioma as hypometabolic, in the absence of malignant transformation or high grade. We report a case of benign ganglioglioma in the left precentral gyrus showing hypermetabolism on [18F]FDG-PET, which was associated with intractable focal motor seizures. An 11-year-old girl started having simple partial seizures refractory to anti-epileptogenic medication since 4 years of age. Magnetic resonance imaging revealed a tumorous lesion in the left precentral gyrus. Interictal [18F]FDG-PET showed high [18F]FDG uptake in the lesion. Gross total resection was carried out. The histological diagnosis was low-grade ganglioglioma. The hypermetabolism on [18F]FDG-PET may be associated with epileptogenic activity of the ganglioglioma.

Survivin is a member of the inhibitor of apoptosis family, and is expressed in various malignant tumors. Survivin overexpression has been reported to be a poorer prognostic factor in various malignancies. However, the prognostic value of survivin expression in patients with glioblastoma is still controversial. Therefore, in this study the role of survivin as a predictor for survival was investigated in patients with glioblastoma. Tissue specimens were obtained from 66 patients with glioblastoma treated with radiotherapy. Survivin expression was detected by an immunohistochemical method. Nuclear and cytoplasm survivin scores were defined by using the cell positivity and staining intensity. The scores were defined as follows, 0 (no staining), 1 (less than 50% of cell positivity and any staining), 2 (more than 50% of cell positivity and weak to moderate intensity) and 3 (more than 50% of cell positivity and strong intensity). The correlation between survivin scores and the overall survival rate was evaluated. Nuclear and cytoplasm survivin staining were noted in 47 and 58 patients, respectively. The number of patients with nuclear survivin score of 0, 1, 2 and 3, were 19 (28.8%), 26 (39.4%), 9 (13.6%) and 12 (18.2%), respectively. The 3-year overall survival rate of the nuclear survivin score 3 was 0%, significantly lower than the 11.6% of the nuclear survivin score/=2 (P = 0.0003). Cytoplasm survivin score did not correlate with the prognosis. Nuclear survivin expression may be a useful biomarker for predicting prognosis in patients with glioblastoma.

Sphingosine 1-phosphate (S1P) induced the inhibition of glioma cell migration. Here, we characterized the signaling mechanisms involved in the inhibitory action by S1P. In human GNS-3314 glioblastoma cells, the S1P-induced inhibition of cell migration was associated with activation of RhoA and suppression of Rac1. The inhibitory action of S1P was recovered by a small interference RNA specific to S1P(2) receptor, a carboxyl-terminal region of Galpha12 or Galpha13, an RGS domain of p115RhoGEF, and a dominant-negative mutant of RhoA. The inhibitory action of S1P through S1P(2) receptors was also observed in both U87MG glioblastoma and 1321N1 astrocytoma cells, which have no protein expression of a phosphatase and tensin homolog deleted on chromosome 10 (PTEN). These results suggest that S1P(2) receptors/G(12/13)-proteins/Rho signaling pathways mediate S1P-induced inhibition of glioma cell migration. However, PTEN, recently postulated as an indispensable molecule for the inhibition of cell migration, may not be critical for the S1P(2) receptor-mediated action in glioma cells.

γ-Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby γ-oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine DGlucose metabolism and regulation of molecules involved in DIn islets, γ-oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in Dγ-Oryzanol exhibited unique anti-diabetic properties. The unexpected effects of γ-oryzanol on D

We investigated the fused protein of solute carrier family 44 choline transporter member 1 (SLC44A1) and protein kinase C alpha (PRKCA) in three patients with papillary glioneuronal tumors (PGNT). PGNT and rosette-forming glioneuronal tumors (RGNT) are recently identified, unusual glioneuronal tumor variants which were categorized as novel tumor entities in the 2007 World Health Organization classification system. The molecular background of these tumors remains poorly understood due to the paucity of studies. The SLC44A1-PRKCA fusion was recently detected in three cases of PGNT. We invesitgated for the SLC44A1-PRKCA fusion protein in the three PGNT patients and a further two with RGNT using fluorescence in situ hybridization. Two out of the three PGNT patients had a fused signal (paired red-green signal) representing a rearrangement on chromosomes 9 and 17. A normal signal pattern was observed in the third PGNT patient. Neither of the two RGNT patients demonstrated a fused signal. This suggests that the SLC44A1-PRKCA fusion is a characteristic alteration in PGNT but not RGNT. Therefore, it is a potential biomarker of PGNT. The paired red-green signal that was observed in the PGNT patients implies the presence of a different breakpoint than that previously reported in the 9q31 and 17q24 genes.

Glutamate may cause Ca(2+) entry through Ca(2+)-permeable glutamate receptors, which in turn stimulates the anti-apoptotic signaling cascade in glioma cells. It was found that a human glioma cell line, U-87 MG, expressed subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate acid-type glutamate receptors (AMPAR). Ca(2+) entry through AMPAR was detected in approximately 40% of U-87 MG cells. AMPAR agonists facilitated cell proliferation in low-serum medium containing 0.5% fetal calf serum (FCS). Unexpectedly, cell proliferation by the activation of AMPAR was not detected in serum-rich medium containing 10% FCS. Overexpression of Ca(2+)-permeable AMPAR facilitated proliferation of U-87 MG cells in the low-serum condition, whereas it had again no effect in the serum-rich condition. Cell proliferation of U-87 MG cells is likely to be under the regulation of both growth factors contained in the serum and Ca(2+) entry through AMPAR, and that the latter regulation becomes evident only when serum factors are deprived of culture medium.

Cell-penetrating peptides (CPPs) as a novel biomedical delivery system have been highly anticipated, since they can translocate across biological membranes and are capable of transporting their cargo inside live cells with minimal invasiveness. However, non-selective internalization in various cell types remains a challenge in the clinical application of CPPs, especially in cancer treatment. In this study, we attempted to identify novel cancer-homing CPPs to target glioblastoma multiforme (GBM), which is often refractory and resistant to treatment. We screened for CPPs showing affinity for the human GBM cell line, U87MG, from an mRNA display random peptide library. One of the candidate peptides which amino-acid sequence was obtained from the screening showed selective cell-penetrating activity in U87MG cells. Conjugation of the p16INK4a functional peptide to the GBM-selective CPP induced cellular apoptosis and reduced phosphorylated retinoblastoma protein levels. This indicates that the CPP was capable of delivering a therapeutic molecule into U87MG cells inducing apoptosis. These results suggest that the novel CPP identified in this study permeates with high affinity into GBM cells, revealing it to be a promising imaging and therapeutic tool in the treatment of glioblastoma.

The human Ras association domain family 1A (RASSF1A) gene, recently isolated from the lung and breast tumor suppressor locus 3p21.3, is highly methylated in primary lung, breast, nasopharyngeal and other tumors, and re-expression of RASSF1A suppresses the growth of several types of cancer cells. Epigenetic inactivation of RASSF1A by promoter hypermethylation is also important in the development of several human cancers. The methylation status of the promoter region of RASSF1A was analysed in primary brain tumors and glioma cell lines by methylation-specific polymerase chain reaction. In primary brain tumors, 25 of 46 (54.3%) gliomas and five of five (100%) medulloblastomas showed RASSF1A methylation. In benign tumors, only one of 10 (10%) schwannomas and two of 12 (16.7%) meningiomas showed RASSF1A methylation. The RASSF1A promoter region was methylated in all four glioma cell lines. RASSF1A was re-expressed in all methylated cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine. Methylation of the promoter CpG islands of the RASSF1A may play an important role in the pathogenesis of glioma and medulloblastoma.

【背景・目的】当院での松果体部 germinoma に対する治療は, 約50Gyの放射線療法を主体として行われてきた.その長期予後について検討した.【対象と方法】1980～1998年までに松果体部 germinomaと診断し, 治療後5年以上経過観察しえた10例 (治療時年齢8～24歳, 男性9人, 女性1人, 10例中 double midlineは 2例) を対象とした.【結果】20Gyの時点において全例で腫瘍は著明に縮小した.平均経過観察期間162ヶ月 (期間, 59～268ヶ月) で, 50Gyの放射線療法を主体とした治療により再発はなく, 長期的な予後は良好であった.内分泌学的に補償を要したのはdoublemidlineの1例のみであった.放射線治療後, 新たに内分泌学的補償を要した例は認められなかった.Karnofsky performance scaleは8例が100で生活上問題は認められなかった.2例でKarnofsky performance scaleが80と低下し就労が困難であった.【結語】松果体部 ger-minomaは50Gyの放射線療法で長期にコントロールされた.しかしわずかながら記銘力障害や集中力の低下などの障害を来す可能性が示唆された.従ってquality of lifeを考慮すると, 化学療法の併用等を行う事で照射線量を減らし, かつ治療成績を維持することが今後の課題と考えられた.

We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs −/− mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs −/− mice as early as 4 months after the surgery. The 2/3NX triple NOSs −/− mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1α (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs −/− mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin–angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs −/− mouse is a new experimentally useful model of AMI. Renin–angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1α-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model.

Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo.The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans.Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans.These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

Glial cells express a variety of neurotransmitter receptors. Notably, Bergmann glial cells in the cerebellum have Ca 2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–type glutamate receptors (AMPARs) assembled without the GluR2 subunit. To elucidate the role of these Ca 2+ -permeable AMPARs, we converted them into Ca 2+ -impermeable receptors by adenoviral-mediated delivery of the GluR2 gene. This conversion retracted the glial processes ensheathing synapses on Purkinje cell dendritic spines and retarded the removal of synaptically released glutamate. Furthermore, it caused multiple innervation of Purkinje cells by the climbing fibers. Thus, the glial Ca 2+ -permeable AMPARs are indispensable for proper structural and functional relations between Bergmann glia and glutamatergic synapses.

AMPA type-glutamate receptor channels (AMPARs) assembled without the GluR2 (GluR-B) subunit are characterized by high Ca 2+ permeability, and are expressed abundantly in cerebellar Bergmann glial cells. Here we show that the morphology of cultured Bergmann glia-like fusiform cells derived from the rat cerebellum was changed by manipulating expression of Ca 2+ -permeable AMPARs using adenoviral vector-mediated gene transfer. Converting endogenous Ca 2+ -permeable AMPARs into Ca 2+ -impermeable channels by viral-mediated transfer of GluR2 gene induced retraction of glial processes. In contrast, overexpression of Ca 2+ -permeable AMPARs markedly elongated glial processes. The process extension was blocked by 2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX), a specific antagonist of AMPAR. These results indicate that glutamate regulates the morphology of glial processes by activating Ca 2+ -permeable AMPARs.

Meningioma consistency is an important factor for surgical treatment. Tumor cellularity and fibrous tissue contribute to the consistency of tumors, and it is proposed that the minimum apparent diffusion coefficient (ADC) value is significantly correlated with meningioma consistency. Twenty-seven consecutive patients with 28 meningiomas were retrospectively enrolled. Minimum ADC values in meningiomas with a hard consistency were significantly lower than those with a soft consistency. The minimum ADC value might have clinical use as a predictor of meningioma consistency.

Type II iodothyronine deiodinase (DII) messenger ribonucleic acid (mRNA) and its activity have been demonstrated in human normal brain. Although DII activity has been demonstrated in brain tumors, expression of DII mRNA has not been studied in these tumors. To investigate the mechanisms involved in the expression of DII activity in brain tumors, we studied DII mRNA and DII activity in astrocytoma (two cases), glioblastoma (three cases), and oligodendroglioma (one case). DII mRNA, the size of which was indistinguishable from that in control cerebral cortical tissue, was demonstrated in all of the brain tumors tested, although the intensity of the hybridization signal showed wide variation among the tumors. DII activity was also detected in all tumors. DII mRNA and DII activity were highest in the tissue from oligodendroglioma. A significantly positive correlation was observed between DII mRNA and DII activity in these tumors (r = 0.94; P < 0.01), suggesting that DII expression in brain tumors is regulated ...

Human central neurocytoma cells were cultured and characterized immunophenotypically and electrophysiologically to clarify their developmental potential. We conducted systematic in vitro studies utilizing fresh tissues from three patients. Initially small homogeneous cell clusters settled down onto the bottom of the culture flasks, and, after 2 weeks from plating, mature neuron-like cells developed from these clusters and expressed neurofilament proteins (NF: specific neuronal markers). On the other hand, approximately 80% of small round cell clusters and flat glial-like cells from which these clusters developed were positively stained for glial fibrillary acidic protein (GFAP: a specific glial marker). Furthermore these neuronal and glial cells showed distinct morphology, and dual-label, indirect immunohistochemistry for GFAP and NF-200 kD disclosed that the two antigens were not found co-localized in the same cells. In single-cell clonal analysis, neuronal, glial, and mixed neuronal and glial clones were generated. Electrophysiologically, the cells of neuronal morphology possessed sodium channels, and also L-type calcium channels in whole-cell voltage clamp. The sodium channels were of a characteristic neuronal phenotype which appears in neurons. These findings suggest that small round human central neurocytoma cells exhibit both neuronal and glial differentiations and have the properties reminiscent of precursor cells derived from subventricular matrix; thus, these cultured cells may be a potential source for investigations of human CNS neuronal and glial development and differentiation.

To clarify the histogenesis and differentiation potential of central neurocytoma, a pathological investigation of seven tumors from three patients was conducted using immunohistochemistry and ultrastructural analysis in addition to systematic in vitro studies. Six tumors were studied immunohistochemically and five were examined ultrastructurally. All cases that were immunostained were positive for synaptophysin in nuclear-free neuropil islands. In five tumors, a few tumor cells, in addition to reactive astrocytes, were positive for glial fibrillary acidic protein (GFAP). Vimentin staining was also positive in a few tumor cells of five specimens. Neurofilament staining was always negative. All cases for which ultrastructure was examined showed various synaptic abnormalities. Cultured cells were subdivided into three distinct tumor cell types: neuronal cells which stained for neurofilament proteins with neurosecretory granules; small flat undifferentiated cells with a high nuclear-cytoplasmic ratio and scant cytoplasmic organelles; and small round or multipolar astrocytic cells with 10-nm intermediate filaments which stained for GFAP. Our tissue culture studies disclosed that cultured neurocytoma cells form a cellular mosaic similar to subependymal plate layers that are composed of mitotically active cells, neurons and glia.

The clinical and histological characteristics of oligodendroglioma and oligoastrocytoma were investigated in patients, mainly adults with supratentorial tumors, who were treated with surgery and radiotherapy, and with chemotherapy for recurrent, anaplastic tumors, or both. The median survival time was 13.2 years for oligodendroglioma (four patients), 12.7 years for anaplastic oligodendroglioma (five patients), 13.5 years for oligoastrocytoma (seven patients), and 4.8 years for anaplastic oligoastrocytoma (four patients). Two of three recurrent oligodendrogliomas and two of two recurrent oligoastrocytomas showed malignant transformation. Minigemistocytes were sometimes recognized in recurrent tumors and had a sinister prognosis. Oligodendroglioma and oligoastrocytoma may transform into each other at recurrence.

Blockade of Ca(++)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) inhibits the proliferation of human glioblastoma by inhibiting Akt phosphorylation, which is independent of the phosphatidylinositol 3-kinase pathway. Inhibiting platelet-derived growth factor receptor (PDGFR)-mediated phosphorylation causes growth inhibition in glioblastoma cells. The authors of this study investigated the effects of YM872 and AG1296, singly and in combination and targeting different pathways upstream of Akt, on Akt-mediated tumor growth in glioblastoma cells in vivo and in vitro.The expression of AMPAR, PDGFR, and c-kit in glioblastoma cells was analyzed via immunofluorescence. Glioblastoma cells, both in culture and in xenografts grown in mice, were treated with YM872 and AG1296, singly or in combination. Inhibition of tumor growth was observed after treatment in the xenograft model. Cell proliferation assays were performed using anti-Ki 67 antibody in vivo and in vitro. The CD34-positive tumor vessel counts within the vascular hot spots of tumor specimens were evaluated. Phosphorylation of Akt was studied using Western blot analysis.Combined administration of YM872 and AG1296 had a significant enhanced effect on the inhibition of cell proliferation and reduction of tumor vascularity in the xenograft model. These agents singly and in combination demonstrated a significant reduction of Akt phosphorylation at Ser473 and inhibition of tumor proliferation in vitro, although combined administration had no enhanced antitumor effects.The strongly enhanced antitumor effect of this combination therapy in vivo rather than in vitro may be attributable to disruption of the aberrant vascular niche. This combination therapy might provide substantial benefits to patients with glioblastoma.

A 60-year-old woman presented with a rare case of hyperperfusion syndrome after stent placement for subclavian artery stenosis manifesting as dizziness due to vertebrobasilar insufficiency. Three days after undergoing stent placement to treat the severely stenotic (90%) right subclavian artery, she suffered intracranial hemorrhage related to hyperperfusion syndrome. Preoperative single-photon emission computed tomography findings of low cerebral perfusion and poor perfusion reserve might indicate the possibility of hyperperfusion syndrome after stenting in patients with subclavian artery stenosis.