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Funding Information: The research in the M.P. laboratory was supported by the Max Planck Society, the European Research Council (ERC) Consolidator Grant EMERGE (no. 773047), the Deutsche Forschungsgemeinschaft (DFG, Project-ID 75732319 – SFB 834), the Leducq Foundation, the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action (no. 814316), the Excellence Cluster Cardio-Pulmonary Institute (EXC 2026, Project-ID 390649896), the DZHK (German Centre for Cardiovascular Research), the Stiftung Charité and the European Molecular Biology Organization (EMBO) Young Investigator Programme. Work in the H.G. laboratory was supported by the DFG, Project-ID 427826188 – SFB 1444 and Project-ID 437531118 – SFB1470. Research in the Carmeliet laboratory is supported by Methusalem funding by the Flemish government and by an ERC Advanced Research grant (no. EU-ERC269073). This work was performed with assistance from the CSHL Mass Spectrometry Shared Resource, which is supported by a Cancer Centre Support grant (no. 5P30CA045508). Publisher Copyright: © 2022, The Author(s). Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs-elicited by the loss of Rag GTPases-inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature. publishersversion published

© 2021 Springer Nature Limited. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium., Research in the M.P. laboratory was supported by the Max Planck Society, the European Research Council (ERC) Consolidator Grant EMERGE (773047), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 75732319 – SFB 834, the Leducq Foundation, the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action (814316), the Excellence Cluster Cardio-Pulmonary Institute (EXC 2026, project ID 390649896), the DZHK (German Centre for Cardiovascular Research), the Stiftung Charité, and the European Molecular Biology Organization (EMBO) Young Investigator Programme. Work in the T.B. laboratory was supported by the DFG – Project-ID 268555672 – SFB 1213. Work in the C.F. laboratory was supported by the Medical Research Council (MRC_MC_UU_12022/6). This work was performed with assistance from the CSHL Mass Spectrometry Shared Resource, which is supported by the Cancer Center Support Grant 5P30CA045508.

To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover,APELINexpression is regulated by Notch signaling in human ECs, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown zebrafish embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.

Background One of the important aims of surgery for moyamoya disease is to establish indirect revascularization. The purpose of this study was to assess the progress of the middle meningeal artery (MMA) after our novel preservation method and to evaluate the relation between direct and indirect bypass in the chronic stage. Methods A total of 24 hemispheric sides of 19 patients with moyamoya disease were included in this study. Craniotomy was performed with preservation of the MMA during the procedure, then direct bypass was carried out. The relationship between anatomic variations of the MMA and success rate of preserving the MMA during craniotomy was noted. The alteration of the MMA and superficial temporal artery (STA) diameters was then evaluated using magnetic resonance imaging, and the correlation between the MMA and the STA in the chronic stage was examined. Results In total, the MMA was preserved during craniotomy in 20 hemispheric sides (83.3%). During the 3-year follow-up period, the MMA and STA diameters were significantly increased. At 3 years after surgery, the alteration of the MMA diameter was significantly more marked in pediatric cases than in adult cases, and MMA diameter was moderately but significantly negatively correlated with STA diameter. Conclusions In moyamoya disease, the MMA could be developed as a pathway for indirect revascularization even after simple preservation, especially in pediatric patients. The progress of the MMA and the STA occurs through their synergistic interaction, and the balance might be decided based on their complementary relations in the chronic stage.

Objective A 3-dimensional temporal bone model for skull base surgical training was reconstructed via the use of a selective laser sintering technique, which is one of the 3-dimensional printing technologies. Methods The temporal bone model was created in 2 pieces to remove powder material in the mastoid air cells and to place dye into the semicircular canal and the Fallopian canal. Results The powder material was minimal, and the decisive structures were identified in color. Conclusions This artificial model will pave the way to a “new era” in surgical training and medical education.

Notch signaling is a core patterning module for vascular morphogenesis that codetermines the sprouting behavior of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in ECs. In mice, the loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase that fine-tunes endothelial Notch responses during angiogenic sprouting. This work is supported by the Max Planck Society, European Research Council (ERC) starting grant ANGIOMET (311546), ERC consolidator grant EMERGE (773047), the Deutsche Forschungsgemeinschaft (SFB 834), the Excellence Cluster Cardiopulmonary System (EXC 147/1), LOEWE grant Ub-Net, the DZHK (German Center for Cardiovascular Research), the Stiftung Charité, the Cardio-Pulmonary Institute (EXC 2026 project ID 390649896), and the European Molecular Biology Organization (EMBO) Young Investigator Programme Sí

We report a case of an optic nerve mass lesion associated with IgG4-related disease. A 39-year-old man presented with right blurred vision and proptosis 8 years before admission. Magnetic resonance imaging showed a mass lesion in the center of the right orbit, which was diagnosed as optic nerve sheath meningioma by neuroradiologists and neurosurgeons. Irradiation was selected for treatment of the lesion on the basis of the radiological diagnosis; subsequently, the lesion gradually reduced in size. However, regrowth of an optic nerve mass lesion observed during the previous 2 years caused remarkable exophthalmos, and removal of the orbital mass lesion was performed via a transcranial orbital approach. Pathological examinations resulted in a diagnosis of IgG4-related disease, and hematological tests revealed an elevated level of serum IgG4. Additional radiological examinations showed mass lesions in the left maxillary nerve, bilateral inferior alveolar nerves, paravertebral tissue, and left kidney. Treatment with oral steroids has produced a reduction in the size of these lesions.

Background Meningiomas or solitary fibrous tumors arising from the cavernous sinus (CS) are usually treated with radiosurgery to control growth. Surgical removal of cavernous tumors is indicated only for tumors extending outside the CS. However, even after adequate treatment, the tumor may exhibit recurrence or malignant transformation. We report a treatment option for recurrent meningeal tumors of the CS. Methods In 4 patients with CS tumors that exhibited regrowth after multiple operations and radiosurgery, radical removal in combination with high-flow bypass was performed, and a vascularized muscle flap was used for reconstruction. One patient had a radiation-induced atypical meningioma, 2 patients had transformed atypical meningiomas, and 1 patient had a frequently recurring solitary fibrous tumor. Results No local recurrence was observed in any patients during a follow-up period of 13–41 months. In all patients, a Karnofsky performance scale score of >80 on admission was maintained at >70 at the final follow-up evaluation. Conclusions Radical removal in combination with high-flow bypass provides favorable results and maintains quality of life in patients with recurrent CS meningeal tumors.

Background Preoperative evaluation of malignancy in gliomas is important for surgical planning, particularly to determine whether a 1,3-bis-2-chloroethyl-1-nitrosourea wafer should be placed into the tumor cavity. In some cases, the intraoperative pathologic diagnosis of World Health Organization grade differs from the final diagnosis. Supplemental methods in addition to the routine contrast tomography or magnetic resonance imaging sequences may provide a more accurate preoperative diagnosis. Because tumor vascularity has been useful in distinguishing between low- and high-grade gliomas, we evaluated the accuracy of the arterial spin labeling (ASL) method, which could measure the cerebral blood flow (CBF) without using contrast medium, to determine the malignancy of gliomas. Methods This study included 102 patients with glioma (grade II, n = 40; grade III, n = 18; grade IV, n = 44). All patients underwent ASL to determine the tumor blood flow (TBF) and CBF in the middle cerebral region. The relative tumor vascular index (tVI), which is calculated as TBF divided by CBF in the contralateral middle cerebral region, was used to avoid dispersion of the absolute TBF value. Results tVI was significantly greater (1.46 ± 0.751) in high-grade gliomas than in low-grade gliomas (1.05 ± 0.343) (P = 0.003). As for each grade, tVI was statistically higher in grade IV than in grade II (P = 0.03) gliomas. Conclusions The noninvasive ASL method provides additional information to distinguish high-grade glioma from low-grade gliomas without using contrast medium.

Melanoma is highly metastatic, but the mechanism of melanoma cell migration is still unclear. We found that melanoma cells expressed the nicotinamide adenine dinucleotide–dependent protein deacetylase SIRT1 in the cytoplasm. Cell membrane extension and migration of melanoma cells were inhibited by SIRT1 inhibitors or SIRT1 knockdown, whereas SIRT1 activators enhanced elongation of protrusion and cellular motility. In B16F1 cells, growth factor stimulation induced lamellipodium extension, a characteristic feature at the leading edge of migrating cells, and SIRT1 was found in the lamellipodium. SIRT1 inhibitor nicotinamide (NAM) or SIRT1 small interfering RNAs suppressed the lamellipodium extension by serum or platelet-derived growth factor (PDGF). The lamellipodium formation by dominant-active Rac1 was also inhibited by NAM, a SIRT1 inhibitor. NAM inhibited the accumulation of phosphorylated Akt at the submembrane by serum or PDGF. Using fluorescence resonance energy transfer, we found that NAM impaired PDGF-dependent increase in the phosphatidylinositol-3,4,5-trisphosphate level at the leading edge. NAM inhibited the abdominal metastasis of transplanted B16F1 melanoma cells in C57BL6/J mice and improved survival. Finally, SIRT1-knockdown B16F1 cells showed significantly reduced metastasis in transplanted mice compared with that in control B16F1 cells. These results indicate that SIRT1 inhibition is a strategy to suppress metastasis of melanoma cells.

Impalement injury is a rare type of trauma, and the management should be performed carefully. In cases with impalement injuries, the area of injury and crush might be extensive because the penetrating object itself is generally large and long. Herein, we report our experience with a rare case of cervical impalement injury caused by an iron reinforcing bar penetrating the optic canal and thereby causing brain contusion. A 32-year-old man fell while working at a construction site and sustained an injury due to an iron reinforcing bar that penetrated his right neck. On arrival at the hospital, consciousness was clear and the bar was removed by himself. The patient had lost the sight in his right eye, and cerebrospinal fluid (CSF) rhinorrhea was present. Based on the results of computed tomography (CT) of the head and neck, the bar was thought to have passed through the right mandible and the right optic canal and penetrated the frontal lobe. Surgical repair of frontal base was performed using femoral fascia, completely stopping the CSF leak. The patient was discharged on the 31st hospital day walking independently. In our present case, the top of a foreign body was reached an intracranial site. Impalement injuries require detailed assessment of the injury sites because outcomes depend on the severity of injuries at surrounding anatomical structures. Multiple planar reconstruction using recent multidetector row CT scanning was considered to be useful for the assessment of penetrating routes and injury severity.

Flow voids in the basal ganglia cannot always be recognized on magnetic resonance imaging, even in patients with typical moyamoya disease. In this report, flow voids in the basal ganglia and cisternal flow voids of the sylvian valley were evaluated in patients with moyamoya disease, and their diagnostic value was verified. A total of 41 consecutive patients with moyamoya disease were included in this analysis. The number of flow voids in the basal ganglia and the sylvian valley were counted on each side by 3 observers. Then the numbers of flow voids were compared between the patients with moyamoya disease and controls. The patients with moyamoya disease had a significantly higher mean number of flow voids in the basal ganglia and the sylvian valley (P < .0001); however, the number of flow voids in the basal ganglia was 0 or 1 in 69 sides (28.0%) in patients with moyamoya disease. Comparative analysis using the area under the receiver operating curve indicated that the evaluation of flow voids in the sylvian valley was significantly superior method to that in the basal ganglia (P < .0001). The cutoff value for the number of cisternal flow voids in the sylvian valley for the diagnosis of moyamoya disease was 6. Based on these findings, we recommend a definitive diagnosis of moyamoya disease should include assessment for abnormal vessels around the terminal portions of the internal carotid arteries.

The recent introduction of multidetector row computed tomography (MDCT) scanners has enabled high-resolution 3-dimensional reconstruction. The purpose of this study was to establish a method to evaluate moyamoya disease using computed tomography angiography (CTA), specifically MDCT. Twenty-four patients (48 sides total) with moyamoya disease diagnosed by magnetic resonance angiography (MRA) were evaluated by means of CTA using MDCT by 3 independent observers, and the resulting 144 sides were analyzed. CTA and MRA were compared in terms of the steno-occlusive changes exhibited in each vessel. CTA and MRA scores were assigned on the basis of the severity of occlusive changes in the internal carotid artery, middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. CTA scores were significantly correlated with MRA scores (P.0001), and the 2 scores were in complete agreement in 57 sides (39.6%). The mean CTA score was significantly lower than the mean MRA score (P.0001). Compared with CTA, MRA overestimated occlusion in 115 of the 576 vessels assessed. The mean MRA score was significantly higher in the overestimation group than in the good correlation group (P.0001). CTA had a significantly higher rate of detection of moyamoya-affected vessels (P = .0001). Our data indicate that CTA using MDCT is a more reliable technique than MRA for diagnosing moyamoya disease. The ability to perform CTA quickly is a significant benefit for patients with moyamoya disease, particularly in pediatric and emergency cases.

Microsurgical resection remains an important treatment for cerebral arteriovenous malformations (AVMs). We developed an accurate method for planning AVM resections using multidetector row CT (MDCT). Between January 2007 and January 2011, 21 consecutive patients with AVMs were enrolled in this study. Sixteen patients were symptomatic, and of these, 15 had a hemorrhagic onset. Preoperative CT angiography (CTA) was performed using an MDCT scanner (GE Lightspeed VCT; GE Healthcare, Milwaukee, WI, USA). In total, 1 to 1.2 mL/kg of iopamidol, a low-osmolar iodinated contrast material, was administered intravenously with the bolus tracking method. In all cases, three-dimensional CTA imaging demonstrated critical arterial feeders and their specific geometric associations with the nidus. Accurate visualization of the architecture of AVMs and surgical trajectory was possible with the volume rendering method, especially when using transparency imaging. Additionally, employing feeder extraction imaging with segmentation post-processing, clear preoperative identification of the feeding arteries around the surrounding structures allowed for not only intraoperative orientation but also planning for presurgical embolization. Moreover, the precise anatomical structures of the brain surface were obtained using fusion imaging with MRI. While it is difficult to scientifically assign a value to a technology, we sought to objectively assess the utility of the currently available CTA. The significant benefits of this modality for presurgical planning include enhanced surgeon confidence and optimization of the sequence of surgical procedures.

Primary central nervous system lymphoma (PCNSL) is usually diffuse large B-cell lymphoma. Anaplastic large-cell lymphoma (ALCL) rarely occurs in the central nervous system. PCNSL always presents as single or multiple nodular contrast-enhancing mass lesions within T2-hyperintense areas on magnetic resonance imaging (MRI). Infrequently, diffuse infiltrating change with little contrast enhancement called lymphomatosis cerebri can be seen in PCNSL. In this report, we describe a 75-year-old immunocompetent man who had progressive dementia. On MRI, diffuse white matter lesions with little contrast enhancement were observed to gradually progress, which was clinically consistent with his worsening condition. A biopsy specimen revealed non-destructive, diffusely infiltrating, anaplastic large CD30-positive lymphoma, indicating a diagnosis of ALCL. After the biopsy, he was treated by whole brain irradiation (total 46 Gy) and focal boost irradiation (total 14 Gy). However, his performance status worsened and there was no symptom improvement. The patient died 8 months after symptom onset. The clinical course, diagnostic workup, pathologic correlates, and treatment outcomes are described herein.

甲状腺機能亢進症に併発した類もやもや病4症例を経験したので，文献的考察を加えてその病態や治療指針に関して検討した．2007年1月から2010年12月までに当科で血行再建術を行った，甲状腺機能亢進症に併発した類もやもや病4症例を後ろ向きに検討した．男性2例，女性2例で，平均年齢は27.5歳（14-43歳）であった．全例直接血行再建術と間接血行再建術を行った．神経学的な予後は良好であったが，1例で甲状腺機能の悪化が認められた．周術期の甲状腺機能コントロールは，虚血性合併症を避けるうえでも非常に重要であるが，甲状腺機能亢進症の活動性を評価するのは非常に困難であり，治療指針の検討には内分泌科との連携が重要であると考えられた．

A 68-year-old woman presented with severe headache 9 days after undergoing successful clipping of a right middle cerebral artery aneurysm. Postoperative imaging revealed increased perfusion and diffuse edema in the right frontotemporal cortex. A 57-year-old woman exhibited perseveration soon after undergoing successful clipping of an anterior communicating artery aneurysm. Postoperative imaging studies revealed increased perfusion and diffuse edema in the left frontal and insular cortex. The symptoms and diffuse edema gradually resolved in both patients. These two cases of hyperperfusion syndrome occurred in a series of 190 patients treated by clipping of unruptured cerebral aneurysms. Hyperperfusion syndrome is a rare complication following aneurysm surgery, especially surgery for unruptured cerebral aneurysms without temporary clipping.

Here, we report three cases of moyamoya disease with a history of Kawasaki disease. A 33-year-old man was found to have stenotic lesions of the internal carotid arteries(ICAs)on both sides at a nearby hospital where he visited complaining of headache and lisping. He had received immunoglobulin therapy for Kawasaki disease at the ages of 1, 2, and 6 years. MRI showed only a chronic ischemic lesion in the white matter. Angiography showed occlusion at the terminal portion of the ICAs on both sides. He was diagnosed with moyamoya disease, but as he had no symptoms and preserved cerebral blood flow (CBF), he was kept under observation. An 8-year-old boy was diagnosed with moyamoya disease and underwent right encephaloduroarteriosynangiosis at a nearby hospital. He had received immunoglobulin therapy for Kawasaki disease at the age of 1 year. His ischemic symptoms worsened. Although MRI detected no apparent ischemic lesion, angiography revealed severe stenosis at the terminal portions of the ICAs on both sides, and 123I-IMP SPECT showed CBF impairment. Bilateral direct bypass was performed. His father was subsequently also diagnosed with moyamoya disease. A 4-year-old girl with epilepsy was diagnosed with moyamoya disease at a nearby hospital. She had been treated with aspirin for Kawasaki disease at the age of 1 year. MRI detected no remarkable ischemic lesions, but angiography revealed mild stenosis at the terminal portions of the ICAs on both sides. Five months later, her ischemic symptoms were worsening with progressing stenotic lesions, and she underwent bilateral direct bypass.

Background Damage to the motor division of the lower cranial nerves that run into the jugular foramen leads to hoarseness, dysphagia, and the risk of aspiration pneumonia; therefore, its functional preservation during surgical procedures is important. Intraoperative mapping and monitoring of the motor rootlets at the cerebellomedullary cistern using endotracheal tube electrodes is a safe and effective procedure to prevent its injury. Objective To study the location of the somatic and autonomic motor fibers of the lower cranial nerves related to vocal cord movement. Methods Twenty-four patients with pathologies at the cerebellopontine lesion were studied. General anesthesia was maintained with fentanyl and propofol. A monopolar stimulator was used at amplitudes of 0.05 to 0.1 mA. Both acoustic and visual signals were displayed as vocalis muscle electromyographic activity using endotracheal tube surface electrodes. Results The average number of rootlets was 7.4 (range, 5-10); 75% of patients had 7 or 8 rootlets. As many as 6 rootlets (2-4 in most cases) were responsive in each patient. In 23 of the 24 patients, the responding rootlets congregated on the caudal side. The maximum electromyographic response was predominantly in the most caudal or second most caudal rootlet in 79%. Conclusion The majority of motor fibers of the lower cranial nerves run through the caudal part of the rootlets at the cerebellomedullary cistern, and the maximal electromyographic response was elicited at the most caudal or second most caudal rootlet. Abbreviation EMG, electromyographic.

Mitochondrial autophagy eliminates damaged mitochondria and decreases reactive oxygen species (ROS). The autophagy inhibitor chloroquine (CQ) poten- tiates temozolomide (TMZ) cytotoxicity in glioma cells, but it is not known whether CQ does this by inhibiting mitochondrial autophagy. The effects of CQ and TMZ on MitoSOX Red fluorescence, a mitochondrial ROS indica- tor, and cell death were examined in rat C6 glioma cells. Mitochondrial autophagy was monitored by the colocal- ization of MitoTracker Red fluorescence and EGFP-LC3 dots. Mitochondrial content was measured by MitoTracker Green fluorescence and immunoblotting for a mitochon- drial protein. Finally, CQ's effects on tumor cells derived from a glioblastoma patient and human U87-MG glio- blastoma cells were assessed. TMZ (100-1,000 lM) alone did not affect mitochondrial ROS or cell death in C6 cells, but when administered with CQ (10 lM), it increased mitochondrial ROS and cell death. Antioxidants signifi- cantly suppressed the CQ-augmented cell death in TMZ- treated cells, indicating that mitochondrial ROS were involved in this cell death. TMZ treatment reduced Mito- Tracker Green fluorescence and mitochondrial protein levels, and these effects were inhibited by CQ. TMZ also increased the colocalization of EGFP-LC3 dots with mitochondria, and CQ enhanced this effect. CQ potentiated TMZ-induced cytotoxicity in patient-derived glioblastoma cells as well as human U87-MG glioblastoma cells. These results suggest that CQ increases cellular ROS and aug- ments TMZ cytotoxicity in glioma cells by inhibiting mitochondrial autophagy.

Maximum tumor extirpation with preservation of the facial and cochlear nerve function is the goal of surgery for vestibular schwannoma. To preserve cochlear nerve function, the surgeon must employ a detailed knowledge of microanatomy, precise microsurgical techniques, and persistence. This paper describes the “pearls” of surgical techniques based on the anatomical study inside the mastoid from the view of the retrosigmoid transmeatal approach. A total of 592 consecutive patients underwent surgical removal of unilateral vestibular schwannoma (VS) between January 1994 and December 2009. The hearing preservation rate was 53.7 % for large vestibular schwannomas (>20 mm in diameter) and 74.1 % for tumors of all sizes. The key procedures for hearing preservation surgery are as follows: bloodless microdissection, sufficient coring-debulking, capsular elevation to locate the facial and cochlear nerves both electrophysiologically and by visual observation, sharp dissection of the facial and cochlear nerves, and avoidance of heat and mechanical injury to the nerves, the internal auditory artery, and the brain stem. Besides these techniques, appropriate instruments are essential to preserve hearing. The function of the facial and cochlear nerves should be the foremost concern. Meticulous techniques and the knowledge of microsurgical anatomy lead to hearing preservation with maximum tumor removal.

Background Various modalities have been used to confirm the blood flow through parent arteries or surrounding perforating arteries during surgical aneurysm clipping, including motor-evoked potentials (MEPs), Doppler ultrasound, and indocyanine green videoangiography. Nonetheless, contralateral hemiparesis due to arterial blood flow insufficiency may arise because of false-positive or false-negative errors. By performing controlled intraoperative awakening during aneurysm clipping, we compared patients' voluntary movements with simultaneous MEP. Methods Four patients with anterior choroidal artery aneurysms and one patient with a dorsal internal carotid artery aneurysm were included in this study. MEP and intraoperative voluntary movements under awake craniotomy were assessed simultaneously during and after the clipping procedure. Results Aneurysms were safely and successfully clipped in all patients, with no evidence of postoperative neurological deficits. Voluntary movements and MEP findings did not differ from the control state in three patients. In the other two patients, we observed a discrepancy between MEP amplitudes and voluntary movements. In one patient, deterioration and subsequent improvement in voluntary movements were preceded by MEP amplitude reduction during clipping. In the other patient, MEP amplitude did not change although voluntary movement deteriorated during temporary occlusion of the internal carotid artery. Conclusions Intraoperative neurological assessment during aneurysmal clipping under awake craniotomy is feasible and safe, and should be valuable for the assessment of ischemia, especially in the anterior choroidal artery. From a neurophysiologic viewpoint, MEP may be insufficiently sensitive for evaluating voluntary movement under ischemia.

In patients with vascular compression syndromes, the preoperative recognition of the cranial nerves and compressed vessels will contribute to improved surgical results. The aim of this study was to clarify the pathophysiology of hemifacial spasm (HFS) associated with the vertebral artery (VA) and to assess the value of preoperative imaging. Fifty-three consecutive patients with HFS underwent microvascular decompression (MVD). Of these, 18 cases of HFS were associated with the VA; this case series was compared with the remaining non-VA-associated HFS. For preoperative assessment, magnetic resonance imaging (MRI) was performed. Since January 2006, fusion imaging has been performed by combining MRI and computed tomography angiography. Of the 18 cases of VA-associated HFS, 17 (94.4 %) were on the left side; this was significantly higher than in the non-VA-associated HFS cases (p

Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a technique for depicting cerebral perfusion without contrast medium. The purpose of this study was to determine whether ASL can be used to detect hyperperfusion after revascularization for moyamoya disease as effectively as N-isopropyl-[123I]β-iodoamphetamine ( 123 I-IMP) single-photon emission computed tomography (SPECT). Fifteen consecutive patients with moyamoya disease were included in the study. All patients underwent surgical revascularization. Postoperatively, regional cerebral blood flow (rCBF) was measured by flow-sensitive alternating inversion recovery (FAIR) ASL and 123 I-IMP SPECT during the acute stage, and rCBF of the operative side was compared with the other side. The asymmetry ratio (AR) was then calculated from the rCBF as measured using each modality. The postoperative AR of ASL was moderately correlated with that of 123 I-IMP SPECT ( y = 0.180 x + 0.819; R = 0.80; P = .0003). In this series, 2 patients (13.3%) suffered symptomatic hyperperfusion after revascularization and accordingly exhibited increased AR of ASL. Our data indicate that early increases in rCBF in patients with hyperperfusion could be detected using FAIR ASL supplemental to 123 I-IMP SPECT after revascularization. Our data indicate that FAIR ASL is a convenient method for evaluating hyperperfusion that can be performed repeatedly without the use of contrast medium or radioisotopes.

A 68-year-old woman presented with severe headache 9 days after undergoing successful clipping of a right middle cerebral artery aneurysm. Postoperative imaging revealed increased perfusion and diffuse edema in the right frontotemporal cortex. A 57-year-old woman exhibited perseveration soon after undergoing successful clipping of an anterior communicating artery aneurysm. Postoperative imaging studies revealed increased perfusion and diffuse edema in the left frontal and insular cortex. The symptoms and diffuse edema gradually resolved in both patients. These two cases of hyperperfusion syndrome occurred in a series of 190 patients treated by clipping of unruptured cerebral aneurysms. Hyperperfusion syndrome is a rare complication following aneurysm surgery, especially surgery for unruptured cerebral aneurysms without temporary clipping.

SIRT1, a NAD+-dependent protein deacetylase, is known to have neural functions. However, despite its cytoplasmic expression in some neural cells, its cytoplasmic function, if any, is unknown. Here we found that PC12 (pheochromocytoma) cells expressed SIRT1 in the cytoplasm. Nerve growth factor (NGF)-induced neurite outgrowth of these cells was promoted by activators of SIRT1, while inhibitors of SIRT1 or SIRT1-siRNA significantly inhibited it. The overexpression of a mutant SIRT1 that localised to the cytoplasm but not the nucleus enhanced the NGF-dependent neurite outgrowth, and a cytoplasmic dominant-negative SIRT1 suppressed it. Thus, cytoplasmic SIRT1 increases the NGF-induced neurite outgrowth of PC12 cells.

OBJECTIVE: Postcraniotomy subdural empyemas and epidural abscesses are uncommon, potentially lethal, complications of neurosurgery. Patients with these complications may be difficult to manage, and mortality can occur. METHODS: Between 1997 and 2006, the authors treated eight patients with recalcitrant postcraniotomy subdural empyema and epidural abscess with combinations of myocutaneous free flap transfer. The free flap transfer was intended for patients who could not be cured with conventional surgical debridement and bone flap removal. Patient ages ranged from 15 to 67 years (mean, 41.5 yr). There were six men and two women. Treatment was required for cranial base tumors (n = 3), the result of trauma (n = 2), malignant tumors (n = 2), and cerebral hematoma (n = 1). In six patients (75%), an expanded polytetrafluoroethylene sheet was used as a dural substitute at the original surgery. We used three rectus abdominis myocutaneous flaps and five latissimus dorsi myocutaneous flaps. In six patients (75%), surgery was performed in the chronic stage of infection, and the other two patients were in the acute stage of infection. RESULTS: Among all the patients, two failures occurred because of flap ischemia, but these were resolved after an additional procedure. However, one of these two patients, in whom surgery was performed at the acute stage of infection, died 4 weeks after the surgery. The postoperative course of the other six patients was uneventful. Isolated microorganisms were methicillin-resistant Staphylococcus aureus (four patients), Pseudomonas aeruginosa (three patients), and methicillin-sensitive Staphylococcus aureus (one patient). CONCLUSION: Myocutaneous free flap transfer allows sufficient blood circulation and dead space control and is resistant to infection. Therefore, free flap transfer is useful for eliminating intractable empyema and abscess; however, it is important that the procedure be considered in the chronic stage of infection.

An inebriated 86-year-old man impaled himself on a wooden earpick that penetrated through the superior orbital fissure into the prepontine cistern. The patient underwent surgery immediately by a lateral suboccipital approach, and the earpick was pulled out through the wound with control of hemorrhage from the cavernous sinus. He survived this event with no neurologic deficits apart from complete ipsilateral ophthalmoplegia and ptosis. Prompt imaging and surgical intervention allowing direct visualization of the foreign body and prevention of intracranial complications are part of proper management of this problem.