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Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Drug resistance mainly drives GBM patients to poor prognoses because drug-resistant glioblastoma cells highly defend against apoptotic insults. This study was designed to evaluate the effects of cobalt chloride (CoCl2) on hypoxic stress, autophagy, and resulting apoptosis of human and mouse drug-resistant glioblastoma cells. Treatment of drug-resistant glioblastoma cells with CoCl2 increased levels of hypoxia-inducible factor- (HIF-) 1α and triggered hypoxic stress. In parallel, the CoCl2-induced hypoxia decreased mitochondrial ATP synthesis, cell proliferation, and survival in chemoresistant glioblastoma cells. Interestingly, CoCl2 elevated the ratio of light chain (LC)3-II over LC3-I in TMZ-resistant glioblastoma cells and subsequently induced cell autophagy. Analyses by loss- and gain-of-function strategies further confirmed the effects of the CoCl2-induced hypoxia on autophagy of drug-resistant glioblastoma cells. Furthermore, knocking down HIF-1α concurrently lessened CoCl2-induced cell autophagy. As to the mechanisms, the CoCl2-induced hypoxia decreased levels of phosphoinositide 3-kinase (PI3K) and successive phosphorylations of AKT and mammalian target of rapamycin (mTOR) in TMZ-resistant glioblastoma cells. Interestingly, long-term exposure of human chemoresistant glioblastoma cells to CoCl2 sequentially triggered activation of caspases-3 and -6, DNA fragmentation, and cell apoptosis. However, pretreatment with 3-methyladenine, an inhibitor of autophagy, significantly attenuated the CoCl2-induced autophagy and subsequent apoptotic insults. Taken together, this study showed that long-term treatment with CoCl2 can induce hypoxia and subsequent autophagic apoptosis of drug-resistant glioblastoma cells via targeting the PI3K-AKT-mTOR pathway. Thus, combined with traditional prescriptions, CoCl2-induced autophagic apoptosis can be clinically applied as a de novo strategy for therapy of drug-resistant GBM patients.

OBJECTIVEA high level of vascular endothelial growth factor (VEGF) has been implicated in brain arteriovenous malformation (bAVM) bleeding and rupture. However, direct evidence is missing. In this study the authors used a mouse bAVM model to test the hypothesis that elevation of focal VEGF levels in bAVMs exacerbates the severity of bAVM hemorrhage.METHODSBrain AVMs were induced in adult mice in which activin receptor–like kinase 1 (Alk1, a gene that causes AVM) gene exons 4–6 were floxed by intrabasal ganglia injection of an adenoviral vector expressing Cre recombinase to induce Alk1 mutation and an adeno-associated viral vector expressing human VEGF (AAV-VEGF) to induce angiogenesis. Two doses of AAV-VEGF (5 × 109 [high] or 2 × 109 [low]) viral genomes were used. In addition, the common carotid artery and external jugular vein were anastomosed in a group of mice treated with low-dose AAV-VEGF 6 weeks after the model induction to induce cerebral venous hypertension (VH), because VH increases the VEGF level in the brain. Brain samples were collected 8 weeks after the model induction. Hemorrhages in the bAVM lesions were quantified on brain sections stained with Prussian blue, which detects iron deposition. VEGF levels were quantified in bAVM tissue by enzyme-linked immunosorbent assay.RESULTSCompared to mice injected with a low dose of AAV-VEGF, the mice injected with a high dose had higher levels of VEGF (p = 0.003) and larger Prussian blue–positive areas in the bAVM lesion at 8 or 9 weeks after model induction (p = 0.002). VH increased bAVM hemorrhage in the low-dose AAV-VEGF group. The overall mortality in the high-dose AAV-VEGF group was 26.7%, whereas no mouse died in the low-dose AAV-VEGF group without VH. In contrast, VH caused a mortality of 50% in the low-dose AAV-VEGF group.CONCLUSIONSUsing mouse bAVM models, the authors provided direct evidence that elevation of the VEGF level increases bAVM hemorrhage and mouse mortality.

Compared to nonaggressive cranial dural arteriovenous fistulae (cDAVF), aggressive cDAVF carries leptomeningeal venous drainage (LVD) and has approximately 15% annual risk of hemorrhagic and non-hemorrhagic aggressive neurological presentations. In terms of aggressive clinical presentations, the previous classification does not adequately differentiate the higher risk group from the lower risk group. Herein, we retrospectively collected a series of patients with aggressive cDAVF and explored the risk factors for differentiating the higher-risk group from the lower-risk group with aggressive clinical presentations. We retrospectively collected patients with aggressive cDAVF from March 2011 to March 2019. The risk of aggressive clinical presentation was recorded. Risk factors were included in the analysis for aggressive clinical presentations. From March 2011 to March 2019, 37 patients had aggressive cDAVF. Among them, 24 presented with aggressive clinical presentation (20, hemorrhagic presentation; four, non-hemorrhagic presentation). In patients presenting with hemorrhage, four patients experienced early rebleeding after diagnosis. In the univariate analysis, risk location, directness of LVD, exclusiveness of LVD, and venous strain were significantly different in patients with aggressive clinical presentation. In the multivariate analysis, exclusiveness of LVD and venous strain were observed, with a significant difference between patients with aggressive clinical presentation and those with benign clinical presentation. Among patients with angiographically aggressive cDAVFs, approximately 65% presented with aggressive clinical presentations in our series. Among all potential risk factors, patients with exclusiveness of LVD and venous strain have even higher risk and should be treated aggressively and urgently.

Vertebro–venous fistula (VVF) refers to an abnormal arteriovenous shunt connecting the extracranial vertebral artery and the paraspinal venous structures. Coil embolization is the mainstay treatment of choice for VVF, and accurate definition of the endovascular target is mandatory. Traditionally, catheter-based angiograms are used for treatment planning, but those images lack bony information to delineate the precise relationship of the drainage veins to the spinal structure. Herein, we presented two VVF cases and demonstrated how we used intra-arterial cone-beam computed tomography angiography (IA-CBCTA) to determine the safe embolization zone for dense coil packing. We propose that IA-CBCTA is a useful adjunct in the endovascular planning of VVF by offering an image consisting of bony and vascular information.

Aims The estrogen-ERα axis participates in osteoblast maturation. This study was designed to further evaluated the roles of the estrogen-ERα axis in bone healing and the possible mechanisms. Main methods Female ICR mice were created a metaphyseal bone defect in the left femurs and administered with methylpiperidinopyrazole (MPP), an inhibitor of ERα. Bone healing was evaluated using micro-computed tomography. Colocalization of ERα with alkaline phosphatase (ALP) and ERα translocation to mitochondria were determined. Levels of ERα, ERβ, PECAM-1, VEGF, and β-actin were immunodetected. Expression of chromosomal Runx2, ALP, and osteocalcin mRNAs and mitochondrial cytochrome c oxidase (COX) I and COXII mRNAs were quantified. Angiogenesis was measured with immunohistochemistry. Key findings Following surgery, the bone mass was time-dependently augmented in the bone-defect area. Simultaneously, levels of ERα were specifically upregulated and positively correlated with bone healing. Administration of MPP to mice consistently decreased levels of ERα and bone healing. As to the mechanisms, osteogenesis was enhanced in bone healing, but MPP attenuated osteoblast maturation. In parallel, expressions of osteogenesis-related ALP, Runx2, and osteocalcin mRNAs were induced in the injured zone. Treatment with MPP led to significant inhibition of the alp, runx2, and osteocalcin gene expressions. Remarkably, administration of MPP lessened translocation of ERα to mitochondria and expressions of mitochondrial energy production-related coxI and coxII genes. Furthermore, exposure to MPP decreased levels of PECAM-1 and VEGF in the bone-defect area. Significance The present study showed the contributions of the estrogen-ERα axis to bone healing through stimulation of energy production, osteoblast maturation, and angiogenesis.

An estrogen deficiency is the main cause of osteoporosis in postmenopausal women. In bone remodeling, estrogen receptors (ERs) can mediate estrogen-transducing signals. Methylpiperidinopyrazole (MPP) is a highly specific antagonist of ER-alpha (ER&alpha, ). This study was designed to evaluate the effects of MPP on estrogen-induced energy production, subsequent osteoblast maturation, and the possible mechanisms. Exposure of primary osteoblasts isolated from neonatal rat calvarias to MPP did not affect cell morphology or survival. Estradiol can induce translocation of ER&alpha, into mitochondria from the cytoplasm. Interestingly, pretreatment of rat calvarial osteoblasts with MPP lowered estrogen-induced ER&alpha, translocation. Sequentially, estrogen-triggered expressions of mitochondrial energy production-linked cytochrome c oxidase (COX) I and COX II messenger (m)RNAs were inhibited following pretreatment with MPP. Consequently, MPP caused decreases in estrogen-triggered augmentation of the activities of mitochondrial respiratory complex enzymes and levels of cellular adenosine phosphate (ATP). During progression of osteoblast maturation, estrogen induced bone morphogenetic protein (BMP)-6 and type I collagen mRNA expressions, but MPP treatment inhibited such induction. Consequently, estrogen-induced osteoblast activation and mineralization were attenuated after exposure to MPP. Taken together, MPP suppressed estrogen-induced osteoblast maturation through decreasing chromosomal osteogenesis-related BMP-6 and type I collagen mRNA expressions and mitochondrial ATP synthesis due to inhibiting energy production-linked COX I and II mRNA expressions. MPP can appropriately be applied to evaluate estrogen-involved bioenergetics and osteoblast maturation.

Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups&mdash, group A (n = 13, stereotactically injected pure PLGA microparticles), group B (n = 12, stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13, stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG.

Background Temozolomide (TMZ) is a first-line chemotherapeutic drug for malignant gliomas. Nonetheless, TMZ-induced side effects and drug resistance remain challenges. Our previous study showed the suppressive effects of honokiol on growth of gliomas. Purpose This study was further aimed to evaluate if honokiol could enhance TMZ-induced insults toward malignant glioma cells and its possible mechanisms. Methods Human U87 MG glioma cells were exposed to TMZ, honokiol, and a combination of TMZ and honokiol. Cell survival, apoptosis, necrosis, and proliferation were successively assayed. Fluorometric substrate assays were conducted to determine activities of caspase-3, -6, -8, and -9. Levels of Fas ligand, Bax, and cytochrome c were immunodetected. Translocation of Bax to mitochondria were examined using confocal microscopy. Mitochondrial function was evaluated by assaying the mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and complex I enzyme activity. Caspase-6 activity was suppressed using specific peptide inhibitors. The honokiol-induced effects were further confirmed using human U373 MG and murine GL261 cells. Results Exposure of human U87 MG glioma cells to honokiol significantly increased TMZ-induced DNA fragmentation and cell apoptosis. Interestingly, honokiol enhanced intrinsic caspase-9 activity without affecting extrinsic Fas ligand levels and caspase-8 activity. Sequentially, TMZ-induced changes in Bax translocation, the MMP, mitochondrial complex I enzyme activity, intracellular ROS levels, and cytochrome c release were enhanced by honokiol. Consequently, honokiol amplified TMZ-induced activation of caspases-3 and -6 in human U87 MG cells. Fascinatingly, suppressing caspase-6 activity concurrently decreased honokiol-induced DNA fragmentation and cell apoptosis. The honokiol-involved improvement in TMZ-induced intrinsic apoptosis was also confirmed in human U373 MG and murine GL261 glioma cells. Conclusions This study showed that honokiol can enhance TMZ-induced apoptotic insults to glioma cells via an intrinsic mitochondrion-dependent mechanism. Our results suggest the therapeutic potential of honokiol to attenuate TMZ-induced side effects.

Background Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors. Intracranial GBM metastases to the spine are rarely detected clinically. Secondary gliosarcomas after treatment of primary GBM are rarely described. Case presentation Herein, we report the case of a 53-year-old woman who presented to our emergency room with progressive headache and weakness on the left side. Plain computed tomography and contrast magnetic resonance imaging of the brain revealed an approximately 6.8 cm × 4.5 cm right temporoparietooccipital intraaxial cystic tumor with surrounding diffuse perifocal edema that caused midline shift toward the left. Emergency craniotomy was performed to remove the tumor, and pathological examination revealed GBM. The patient received proton beam therapy, Gliadel implantation, and oral temozolomide chemotherapy as well as targeted therapy with bevacizumab. Approximately 15 months after diagnosis, she underwent surgical resection of the right temporal recurrent tumor and was newly diagnosed as having a metastatic spinal tumor. Pathologically, the right temporal and metastatic spinal tumors were gliosarcoma and GBM, respectively. Conclusions Concurrent spinal metastasis and gliosarcomatous transformation, which are two types of GBM complications, are rare. To our knowledge, this is the first report of a case of recurrent GBM with gliosarcoma after proton bean therapy.

A 76-year-old man presented with progressive dementia, gait disturbance, and urinary incontinence for 1 year. Computed tomography scan revealed nonobstructive hydrocephalus, but abnormal papillary structures at the ventricular wall were noted. Before cerebrospinal fluid (CSF) diversion surgery for hydrocephalus, we performed magnetic resonance angiography and magnetic resonance venography, which revealed multiple engorged vessels over the ventricular wall and bilateral hemispheres. Digital subtraction angiography revealed 2 dural arteriovenous fistulas (DAVFs) at the left transverse-sigmoid sinus and superior sagittal sinus. Signs of angioarchitecture characteristic of cerebral venous hypertension (CVH) were noted, including cortical vein regurgitation and severe pseudophlebitic pattern. DAVFs with CVH might be a factor contributing to acquired hydrocephalus. DAVFs should be considered when patients with hydrocephalus exhibit abnormal papillary structures at the ventricular wall. Performing CSF diversion surgery for hydrocephalus before downgrading or curing such aggressive DAVFs may lead to major complications.

Background and purpose: High level of VEGF has been implicated in bAVM bleeding and rupture through analyzing the VEGF levels in patients’ blood and in surgically resected bAVM specimens. However, the direct evidence is missing. Using a mouse bAVM model, we tested the hypothesis that elevation of focal VEGF level exacerbates the severity of bAVM hemorrhage. Methods: Brain AVMs were induced in adult mice that have Alk1 (an AVM causal gene) exons 4-6 floxed by injection of an adenoviral vector expressing Cre-recombinase (Ad-Cre) and an adeno-associated viral vector expressing human VEGF (AAV-VEGF) into the basal ganglia. Two doses of AAV-VEGF, 5x10 9 (high) or 2x10 9 (low) viral genomes were used. In addition, the common carotid artery and jugular vein were anastomosis in a group of mice treated with low dose AAV-VEGF 6 weeks after the model induction to induce venous hypertension (VH), because VH increases VEGF level in the brain. Hemorrhages in the bAVM lesions were quantified on brain sections stained with Prussian blue, which detect iron deposition 8 or 9 weeks after model induction. VEGF levels were quantified by ELISA. Results: Compared to mice injected with low dose AAV-VEGF, mice injected with high dose of AAV-VEGF had a higher level of VEGF, larger Prussian blue positive areas in the bAVM lesion at 8 and 9-weeks after model induction (P Conclusion: Using mouse bAVM models, we demonstrated that the evaluation of VEGF level through viral vector mediated overexpression of VEGF or create VH increases bAVM hemorrhage and mouse mortality.

Additional file 5: Figure S5. The assays of tumor-initiating cell (TIC) properties. (A) Tumor formation analysis with limiting dilution (50~1000 cells per injection) of U87-parental and TMZ-resistant (r#10) cells in subcutaneous flank area of NOD-SCID mice was performed and recorded. Tumor formation was defined as the measurement to reach 0.1â cm3 or larger. The number of tumor formation in total implanted mice was shown in the brackets. (B) The frequency of the TIC-featured population of GBM#2 (derived from another recurrent GBM patient) with or without TMZ treatment was estimated using the in vitro extreme limiting dilution assay.

Glioblastoma multiforme (GBM) is a highly malignant type of brain tumor found in humans. GBM cells reproduce quickly, and the median survival time for patients after therapy is approximately 1 year with a high relapse rate. Current therapies and diagnostic tools for GBM are limited; therefore, we searched for a more favorable therapeutic target or marker protein for both therapy and diagnosis. We used mass spectrometry (MS) analysis to identify GBM-associated marker proteins from human plasma and GBM cell cultures. Additional plasma and 52 brain tissues obtained from patients with gliomas were used to validate the association rate of serum amyloid A1 (SAA1) in different grades of gliomas and its distribution in tumors. Microarray database analysis further validated the coefficient of SAA1 levels in gliomas. The cellular mechanisms of SAA1 in GBM proliferation and infiltration were investigated in vitro. We analyzed the correlation between SAA1 and patients' medication requirement to demonstrate the clinical effects of SAA1 in GBM. SAA1 was identified from MS analysis, and its level was revealed to be correlated with the disease grade, clinical severity, and survival rate of patients with gliomas. In vitro cultures, including GBM cells and normal astrocytes, revealed that SAA1 promotes cell migration and invasion through integrin αVβ3 to activate the Erk signaling pathway. Magnetic resonance imaging and tumor region-specific microarray analysis identified a correlation between SAA1 and GBM cell infiltration in patients. In summary, our results demonstrate that SAA1 in combination with integrin αV and β3 can serve as an indicator of high glioblastoma risk. We also identified the cellular mechanisms of SAA1 contributing to GBM progression, which can serve as the basis for future GBM therapy.

// Kao-Hui Liu 1 , Shun-Tai Yang 2 , Yen-Kuang Lin 3 , Jia-Wei Lin 2 , Yi-Hsuan Lee 4 , Jia-Yi Wang 1,5 , Chaur-Jong Hu 6 , En-Yuan Lin 7 , Shu-Mei Chen 8 , Chee-Kin Then 9 and Shing-Chuan Shen 1 1 Taipei Medical University, College of Medicine, Graduate Institute of Medical Sciences, Taipei, Taiwan 2 Taipei Medical University-Shuang Ho Hospital, Department of Neurosurgery, Taipei, Taiwan 3 Taipei Medical University, Biostatistics Center, Taipei, Taiwan 4 National Yang-Ming University, Department and Institute of Physiology, Taipei, Taiwan 5 Taipei Medical University, College of Medicine, School of Medicine, Department of Physiology, Taipei, Taiwan 6 Taipei Medical University-Shuang Ho Hospital, School of Medicine, Department of Neurology, Taipei, Taiwan 7 Taipei Medical University Hospital, Department of Neurosurgery, Taipei, Taiwan 8 Taipei Medical University-Wan Fang Hospital, Department of Neurosurgery, Taipei, Taiwan 9 Taipei Medical University, College of Medicine, School of Medicine, Taipei, Taiwan Correspondence: Shing-Chuan Shen, email: // Keywords : glioblastoma, antidepressant, AMPA receptor, excitotoxicity Received : November 24, 2014 Accepted : December 26, 2014 Published : December 31, 2014 Abstract The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients’ quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca 2+ influx. The rise in the intracellular calcium concentration ([Ca 2+ ] i ) causes mitochondrial Ca 2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease.

Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxia-induced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxia- and 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.

Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan- and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026) and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P

Radiosurgery serves an important function in the treatment of patients with intraocular tumors and preserves visual function via organ conservation. Therefore, it is important to ensure the safety and precision of GK-SRS as a primary treatment for intraocular tumors. The present case study described a 57-year-old female with uveal melanoma treated with GK-SRS. Retrobulbar anesthesia following fixation of the treated eye, via the suture of two of the extraocular muscles to the stereotactic frame, was performed to immobilize the eye during treatment. Computed tomography (CT) scans were performed following eye fixation, immediately prior to and following GK-SRS, to validate the accuracy of the tumor localization. The eye movement analysis revealed that the gravity center point deviations of the tumor and lens during treatment were

A 34-year-old male who had a hemangiopericytoma (HPC) within the trigone of right lateral ventricle presented with headache, disorientated consciousness and blurred vision. Computed tomography and magnetic resonance images revealed with homogenous contrast enhancement a 5 cm × 4.5 cm × 4.2 cm lesion within the trigone of right lateral ventricle. Angiographic study revealed a highly vascularized lesion fed from right anterior choroid artery anteriorly and right medial posterior choroid artery posteriorly. The tumor was grossly totally removed via right temporal gyrus. The immunohistochemical study was consistent with HPC. Differential diagnosis of HPC from meningioma and solitary fibrous tumor is crucial because of the high tendency of local recurrence and mestatasis of HPCs. Immunohistochemical study is a very valuable method to confirm the diagnosis of HPCs. Complete surgical resection and/or postoperative radiotherapy and/or radiosurgery were beneficial to long-term tumor control. Due to a prolonged time interval between surgery and local recurrence or metastasis, extensive follow-up to rule out local recurrences and delayed extracranial metastases is warranted.

Background and Purpose: A rat model of jugular venous reflux (JVR) is widely used in studies of cerebral arteriovenous fistula, cerebral venous hypertension and chronic cerebral hypoperfusion. However, methods to validate the effectiveness of the operation are needed. Methods: We performed neck 3-dimensional time-of-flight magnetic resonance angiography (MRA) with a clinical scanner in a rat model of JVR before and after the operation. High-resolution arterial angiography of the rat neck was acquired with maximum intensity projection. Results: In the JVR model, the success of the operation was validated by enhanced venous structures on MRA. The angiogram also provided information on the height of JVR and the status of other neck vessels. Conclusions: In conclusion, neck 3-dimensional time-of-flight MRA is a useful noninvasive method for monitoring the blood flow in multiple cerebral vessels in this animal model. It also revealed the height of JVR, collateral development and changes in vessels over time in longitudinal studies. This information should be considered in the evaluation of the animal model.

monly includes cognitive changes, headache, cranial nerve deficit, motor deficit and seizure. Treatment includes radiotherapy and chemotherapy, which may be administrated either systemically or intrathecally. The patient with solitary intracranial plasmacytoma should undergo systemic evaluation, including bone marrow examination, skeletal survey and bone scan to exclude multiple myeloma. In one study, multiple myeloma was diagnosed in four of eight patients, who initially presented with intracranial plasmacytoma. 3 In this study, the strongest predictor of diagnosis of multiple myeloma from a single known plasmacytoma was cranial base involvement Plasmacytoma can involve either the dura or the parenchyma; or occasionally both.

The understanding of the pathophysiology of brain arteriovenous malformations and arteriovenous fistulas has improved thanks to animal models. A rat model creating an artificial fistula between the common carotid artery (CCA) and the external jugular vein (EJV) has been widely described and proved technically feasible. This construct provokes a consistent cerebral venous hypertension (CVH), and therefore has helped studying the contribution of venous hypertension to formation, clinical symptoms, and prognosis of brain AVMs and dural AVFs. Equivalent mice models have been only scarcely described and have shown trouble with stenosis of the fistula. An established murine model would allow the study of not only pathophysiology but also potential genetic therapies for these cerebrovascular diseases. We present a model of arteriovenous fistula that produces a durable intracranial venous hypertension in the mouse. Microsurgical anastomosis of the murine CCA and EJV can be difficult due to diminutive anatomy and frequently result in a non-patent fistula. In this step-by-step protocol we address all the important challenges encountered during this procedure. Avoiding excessive retraction of the vein during the exposure, using 11-0 sutures instead of 10-0, and making a carefully planned end-to-side anastomosis are some of the critical steps. Although this method requires advanced microsurgical skills and a longer learning curve that the equivalent in the rat, it can be consistently developed. This novel model has been designed to integrate transgenic mouse techniques with a previously well-established experimental system that has proved useful to study brain AVMs and dural AVFs. By opening the possibility of using transgenic mice, a broader spectrum of valid models can be achieved and genetic treatments can also be tested. The experimental construct could also be further adapted to the study of other cerebrovascular diseases related with venous hypertension such as migraine, transient global amnesia, transient monocular blindness, etc.

Degenerative diseases of the lumbar spine, which are common among elderly people, cause back pain and radicular symptoms and lead to a poor quality of life. Lumbar spinal fusion is a standardized and widely accepted surgical procedure used for treating degenerative lumbar diseases; however, the classical posterior approach used in this procedure is recognized to cause vascular and neurologic damage of the lumbar muscles. Various studies have suggested that using the minimally invasive transforaminal interbody fusion (TLIF) technique provides long-term clinical outcomes comparable to those of open TLIF approaches in selected patients. In this study, we compared the perioperative and short-term advantages of miniopen, MI, and open TLIF. Compared with open TLIF, MI-TLIF and miniopen TLIF were associated with less blood loss, shorter hospital stays, and longer operative times; however, following the use of these procedures, no difference in quality of life was measured at 6 months or 1 year. Whether miniopen TLIF or MI-TLIF can replace traditional TLIF as the surgery of choice for treating degenerative lumbar deformity remains unclear, and additional studies are required for validating the safety and efficiency of these procedures.

Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

Ischemic and oxidative damage to the hypothalamus may be associated with decreased heat tolerance as well as heatstroke formation. The present study explores the hypothalamic proteome mechanisms associated with heatstroke-mediated hypothalamic ischemia, and oxidative damage. Heatstroke rats had hypotension, hypothalamic ischemia, and lethality. In addition, they had hyperthermia and hypothalamic blood-brain-barrier disruption, oxidative stress, activated inflammation, and neuronal apoptosis and degeneration. 2DE combined LC-MS/MS revealed that heatstroke-induced ischemic injury and apoptosis were associated with upregulation of L-lactate dehydrogenase but downregulation of both dihydropyriminase-related protein and 14-3-3 Zeta isoform protein. Heat-induced blood-brain-barrier disruption might be related to upregulation of glial fibrillary acidic protein. Oxidative stress caused by heatstroke might be related to upregulation of cytosolic dehydrogenase-1. Also, heat-induced overproduction of proinflammatory cytokines might be associated with downregulation of stathmin 1. Heat-induced hypothalamic ischemia, apoptosis, injury (or upregulation of L-lactate dehydrogenase), blood-brain-barrier disruption (or upregulation of glial fibrillary acidic protein), oxidative stress (or upregulation of cytosolic dehydrogenase-1), and activated inflammation (or downregulation of stathmin 1) were all significantly reversed by whole body cooling. Our data indicate that cooling therapy improves outcomes of heatstroke by modulating hypothalamic proteome mechanisms.

Stroke, or brain attack, is the third leading cause of death and the leading cause of adult disability worldwide. There is a great demand for intervention therapy. Unfortunately, although more than 700 drugs that target neuroprotection showed beneficial effects in preclinical animal studies, none of them proved efficacious in treating stroke patients. There is recent interest in understanding mechanism for post-ischemic angiogenesis in the penumbra area, and correlation of the extent of angiogenesis with survival in stroke patients. It is postulated that besides replenishing oxygen and nutrients to ischemic tissue, angiogenesis may play a crucial role in neural protection and tissue recovery. Consequently, therapeutic agents to promote angiogenesis and formation of new vessels after stroke can offer promising approach. Several large population epidemiological and clinical studies have revealed a reciprocal relationship between intake of phytochemicals and incidence of stroke. However, the detailed cellular and molecular mechanisms leading to these beneficial effects remain to be elucidated. In this article, we review the current knowledge on phytochemicals and post-ischemic angiogenesis, and discuss the possibility of a combinatorial treatment, including neuroprotection, angiogenesis, neurogenesis, and phytochemicals regimen for stroke.

Aging is the most significant non-modifiable risk factor and hypertension is the most significant modifiable risk factor for ischemic stroke. We used magnetic resonance imaging (MRI) to investigate the evidence of ischemic susceptibility after aging and hypertension. Four groups of rat were studied: young normotensive Wistar-Kyoto (WKY) rat, aged normotensive WKY rat, young spontaneously hypertensive rat (SHR) and aged SHR. Brain images were acquired at a 3.0T Tim-Trio MRI system. For diffusion-weighted images, apparent diffusion coefficient (ADC) was measured. Relative cerebral blood flow (CBF) was also calculated. Cerebral ischemic susceptibility was examined by using ischemic model of bilateral common carotid artery occlusion. In the MRI study of non-ischemic rat, aged SHR had significantly higher ADC (P0.01) and significantly lower CBF (P0.01) in the parietal cortex, but aged WKY rat had only significantly lower CBF (P0.01) when compared with young WKY rat. The ADC/CBF ratio in the parietal cortex was significantly higher in aged SHR when compared with young WKY rat, young SHR and aged WKY rat (P0.01, P0.05, P0.05, respectively) suggesting a significant diffusion-perfusion disparity in aged SHR. After bilateral common carotid artery occlusion, there was significantly larger damage in the parietal cortex of aged SHR when compared with young WKY rat, young SHR and aged WKY rat (all P0.05), but not in the hippocampus and thalamus (P0.05). Our study demonstrated a significantly increased ADC value and reduced CBF in the ischemia-vulnerable cortical area. This cerebral diffusion-perfusion disparity is seen mainly in aged rat and can be more evident if associated with hypertension indicating an increased susceptibility of brain tissue to ischemic injury.

Traumatic vertebral artery (VA) injury has been neglected and mistaken to be innocuous. Herein, we present a rare case with a as subarachnoid hemorrhage (SAH) following blunt suboccipital trauma. Initially, it was mistaken as a saccular aneurysm and was just coincident with traumatic SAH. Surgical clipping was performed by our senior neurosurgeon and looked secure. But massive bleeding occurred before complete closure of the dura wound. Opening the wound again, blood gushed out from the junction of the aneurysm and the parent artery. Because preoperative angiography evaluation had revealed good collateral flow from the contralateral VA, the involved segment of VA was trapped. The patient recovered well with uneventful course. Blunt suboccipital trauma may result in traumatic VA injury which may cause catastrophic complications if neglected. The incidence, risk factors, the pathophysiology of traumatic VA aneurysm, and the treatments are reviewed.

Massive epistaxis following blunt craniofacial trauma should alert clinicians to possible traumatic internal carotid artery (ICA) aneurysm. This article describes a case of a 46-year-old female patient with traumatic ICA pseudoaneurysm presenting similar to a sphenoid sinus mass lesion. Massive bleeding occurred during the endoscopic procedure. Brain angiography revealed two lobulated ICA pseudoaneurysms over a cavernous segment. The patient successfully underwent endovascular stent assisted coil embolization. Timely diagnosis and treatment of the ICA psuedoaneurysm produced a favourable outcome.

Optimally, internal carotid artery (ICA) injury associated with craniofacial trauma should be treated soon after diagnosis. However, diagnosis is difficult and often delayed. The typical symptoms and signs for diagnosis of traumatic ICA injuries are sometimes easily neglected. Clinically, some patients were initially diagnosed by craniofacial fracture nearby the course of ICA. This investigation retrospectively reviews clinical experience in patients with traumatic ICA injury with a focus on the importance of craniofacial fracture nearby the course of ICA observed on brain or facial bone computed tomography. Eighteen patients with traumatic ICA injury were diagnosed at Chang Gung Memorial Hospital, Taiwan, from June 1998 to April 2004, including 10 patients with pseudoaneurysm formation, seven patients with occlusion, and one patient with laceration. Brain or facial bone computed tomography was reviewed retrospectively. The sample included 14 (78%) patients with skull base fractures involving the intracranial course of ICA and three (17%) patients with mandibular and cervical spine fractures near the course of extracranial ICA. Only one (5%) patient did not have evident fracture. Fractures involving the carotid canal were noted in three (17%) patients. Eight patients received interventional treatments. No further interventional treatments for traumatic ICA occlusion were performed as a result of good collateral flow from contralateral ICA or large infarction noted when diagnosed. Three patients with pseudoaneurysm received expectant management. One patient with arterial laceration with extravasation received no further management. Through meticulously evaluating routine brain and facial bone computed tomography, craniofacial fracture involving intracranial or extracranial course of ICA may be an adjuvant indicator of traumatic ICA injury for early diagnosis.

Background: Traumatic aneurysms of the anterior cerebral artery (ACA) were retrospectively reviewed in an effort to identify patients at high risk of ACA aneurysm. Methods: Blunt craniofacial trauma patients featuring vascular injuries over the region of the ACA were studied. Results: Six patients featuring eight ACA aneurysms were diagnosed between June 1992 and December 2005, inclusively. Seven aneurysms were located at nonbranched sites and one was located over the right ACA-anterior communicating artery junction. One patient died immediately of massive intracranial lobar hemorrhage (ICH). The other 5 patients experienced rebleeding during a period of from 1 to 29 days. Brain computed tomography revealed subarachnoid hemorrhage (SAH) in 1 of these 6 patients, ICH over the medial frontal area or cingulated gyrus in 4 patients, intraventricular hemorrhage (IVH) in 3 patients, and an interhemispheric subdural hematoma (SDH) in 2 patients. Conclusion: Delayed-onset deterioration of neurological deficit is the most common clinical presentation of traumatic ACA aneurysms. Midline hemorrhage such as medial frontal hemorrhage or cingulate gyrus hemorrhage, and the presence of an interhemispheric SDH associated with SAH and IVH subsequent to blunt craniofacial trauma should be further evaluated, as they pre-sent a high risk of traumatic ACA aneurysms to patients.