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Purpose: Patient-derived glioma-propagating cells (GPC) contain karyotypic and gene expression profiles that are found in the primary tumor. However, their clinical relevance is unclear. We ask whether GPCs contribute to disease progression and survival outcome in patients with glioma by analyzing gene expression profiles.Experimental Design: We tapped into public sources of GPC gene expression data and derived a gene signature distinguishing oligodendroglial from glioblastoma multiforme (GBM) GPCs. By adapting a method in glioma biology, the Connectivity Map, we interrogated its strength of association in public clinical databases. We validated the top-ranking signaling pathways Wnt, Notch, and TGFβ, in GPCs and primary tumor specimens.Results: We observed that patients with better prognosis correlated with oligodendroglial GPC features and lower tumor grade, and this was independent of the current clinical indicator, 1p/19q status. Patients with better prognosis had proneural tumors whereas the poorly surviving cohort had mesenchymal tumors. In addition, oligodendroglial GPCs were more sensitive to Wnt and Notch inhibition whereas GBM GPCs responded to TGFβR1 inhibition.Conclusions: We provide evidence that GPCs are clinically relevant. In addition, the more favorable prognosis of oligodendroglial tumors over GBM could be recapitulated transcriptomically at the GPC level, underscoring the relevance of this cellular model. Our gene signature detects molecular heterogeneity in oligodendroglial tumors that cannot be accounted for by the 1p/19q status alone, indicating that stem-like traits contribute to clinical status. Collectively, these data highlight the limitation of morphology-based histologic analyses in tumor classification, consequently impacting on treatment decisions. Clin Cancer Res; 18(15); 4122–35. ©2012 AACR.

Insults to religion have the potential to stoke tensions and result in physical violence. To protect religious sensitivities, speech which insults religion may be criminalised, even in countries where freedom of speech is enshrined as a constitutional right. The purpose of this article is to look at the role played by the state in dealing with speech which insults religion, through an examination of three Southeast Asian case studies. This article attempts to provide a comparison of the constitutional provisions and specific legislation relating to the insulting of religion in the three countries, as well as consider how the laws have worked in practice. It finds that while the ‘law on the books’ across the three countries may have broad similarities in the way they are drafted, they differ vastly in the ways they are applied and enforced, due to differences in the state-religion relationship, religious demographics and the influence of religious nationalism. At the same time, despite the social, political and cultural heterogeneity of the three countries, the prioritisation of communitarian interests in the three countries over the freedom of speech suggests the continued salience of “Asian values” in Southeast Asia.

Constructing a complex functional gene circuit composed of different modular biological parts to achieve the desired performance remains challenging without a proper understanding of how the individual module behaves. To address this, mathematical models serve as an important tool toward better interpretation by quantifying the performance of the overall gene circuit, providing insights, and guiding the experimental designs. As different gene circuits might require exclusively different mathematical representations in the form of ordinary differential equations to capture their transient dynamic behaviors, a recurring challenge in model development is the selection of the appropriate model. Here, we developed an automated biomodel selection system (BMSS) which includes a library of pre-established models with intuitive or unintuitive features derived from a vast array of expression profiles. Selection of models is built upon the Akaike information criteria (AIC). We tested the automated platform using characterization data of routinely used inducible systems, constitutive expression systems, and several different logic gate systems (NOT, AND, and OR gates). The BMSS achieved a good agreement for all the different characterization data sets and managed to select the most appropriate model accordingly. To enable exchange and reproducibility of gene circuit design models, the BMSS platform also generates Synthetic Biology Open Language (SBOL)-compliant gene circuit diagrams and Systems Biology Markup Language (SBML) output files. All aspects of the algorithm were programmed in a modular manner to ease the efforts on model extensions or customizations by users. Taken together, the BMSS which is implemented in Python supports users in deriving the best mathematical model candidate in a fast, efficient, and automated way using part/circuit characterization data.

The Zika virus (ZIKV) epidemic in the Americas was alarming because of its link with microcephaly in neonates and Guillain-Barre syndrome in adults. The unusual pathologies induced by ZIKV infection and the knowledge that the flaviviral nonstructural protein 5 (NS5), the most conserved protein in the flavivirus proteome, can modulate the host immune response during ZIKV infection prompted us to investigate the subcellular localization of NS5 during ZIKV infection and explore its functional significance. A monopartite nuclear localization signal (NLS) sequence within ZIKV NS5 was predicted by the cNLS Mapper program, and we observed localization of ZIKV NS5 in the nucleus of infected cells by immunostaining with specific antibodies. Strikingly, ZIKV NS5 forms spherical shell-like nuclear bodies that exclude DNA. The putative monopartite NLS 390KRPR393 is necessary to direct FLAG-tagged NS5 to the nucleus as the NS5 390ARPA393 mutant protein accumulates in the cytoplasm. Furthermore, coimmunostaining experiments reveal that NS5 localizes with and sequesters importin-α, but not importin-β, in the observed nuclear bodies during virus infection. Structural and biochemical data demonstrate binding of ZIKV NS5 with importin-α and reveal important binding determinants required for their interaction and formation of complexes that give rise to the supramolecular nuclear bodies. Significantly, we demonstrate a neuronal-specific activation of the host immune response to ZIKV infection and a possible role of ZIKV NS5's nuclear localization toward this activation. This suggests that ZIKV pathogenesis may arise from a tissue-specific host response to ZIKV infection.

Oligomerization of transcription factors controls their translocation into the nucleus and DNA-binding activity. Here we present a fluorescence microscopy analysis termed pCOMB (pair correlation of molecular brightness) that tracks the mobility of different oligomeric species within live cell nuclear architecture. pCOMB amplifies the signal from the brightest species present and filters the dynamics of the extracted oligomeric population based on arrival time between two locations. We use this method to demonstrate a dependence of signal transducer and activator of transcription 3 (STAT3) mobility on oligomeric state. We find that on entering the nucleus STAT3 dimers must first bind DNA to form STAT3 tetramers, which are also DNA-bound but exhibit a different mobility signature. Examining the dimer-to-tetramer transition by a cross-pair correlation analysis (cpCOMB) reveals that chromatin accessibility modulates STAT3 tetramer formation. Thus, the pCOMB approach is suitable for mapping the impact oligomerization on transcription factor dynamics., Oligomerisation of transcription factors regulates their translocation into the nucleus, DNA binding affinity and sequence specificity. Here, Hinde et al. present a microscopy analysis, pair correlation of molecular brightness, that tracks the molecular mobility of different oligomeric species in the same cell.

Posterior circulation aneurysms account for approximately 10% of all aneurysms, which affect 1–6% of the population [1, 2]. Aneurysms of the posterior inferior cerebellar artery (PICA) are very rare, only 0.5–3% of all aneurysms [3]. Patients with PICA aneurysms usually present with subarachnoid hemorrhage, or they might have symptoms due to compression of the brainstem or lower cranial nerves. Microsurgical clipping of PICA aneurysms is difficult and very challenging due to the limited working space and its surrounding neurovascular structure, the brainstem and lower cranial nerves IX, X, XI, and XII, and very often the aneurysm is located very deep and far from the surgeon’s view. Surgical maneuvers require moving around and sometimes in between cranial nerves. PICA aneurysms may vary widely within a range in terms of their complex anatomy, as a result either of their origin, branching out of the vertebral artery (VA), or their course along the lower cranial nerve. The PICA itself is usually of a small caliber, and aneurysms on it with a wide neck create a difficult situation with respect to clipping the aneurysm and preserving the PICA.

The Zika virus (ZIKV) non-structural protein 5 (NS5) plays multiple viral and cellular roles during infection, with its primary role in virus RNA replication taking place in the cytoplasm. However, immunofluorescence assay studies have detected the presence of ZIKV NS5 in unique spherical shell-like structures in the nuclei of infected cells, suggesting potentially important cellular roles of ZIKV NS5 in the nucleus. Hence ZIKV NS5′s subcellular distribution and localization must be tightly regulated during ZIKV infection. Both ZIKV NS5 expression or ZIKV infection antagonizes type I interferon signaling, and induces a pro-inflammatory transcriptional response in a cell type-specific manner, but the mechanisms involved and the role of nuclear ZIKV NS5 in these cellular functions has not been elucidated. Intriguingly, these cells originate from the brain and placenta, which are also organs that exhibit a pro-inflammatory signature and are known sites of pathogenesis during ZIKV infection in animal models and humans. Here, we discuss the regulation of the subcellular localization of the ZIKV NS5 protein, and its putative role in the induction of an inflammatory response and the occurrence of pathology in specific organs during ZIKV infection.

We explore the role of an elevated O2(-):H2O2 ratio as a prosurvival signal in glioma-propagating cells (GPCs). We hypothesize that depleting this ratio sensitizes GPCs to apoptotic triggers.We observed that an elevated O2(-):H2O2 ratio conferred enhanced resistance in GPCs, and depletion of this ratio by pharmacological and genetic methods sensitized cells to apoptotic triggers. We established the reactive oxygen species (ROS) Index as a quantitative measure of a normalized O2(-):H2O2 ratio and determined its utility in predicting chemosensitivity. Importantly, mice implanted with GPCs of a reduced ROS Index demonstrated extended survival. Analysis of tumor sections revealed effective targeting of complementarity determinant 133 (CD133)- and nestin-expressing neural precursors. Further, we established the Connectivity Map to interrogate a gene signature derived from a varied ROS Index for the patterns of association with individual patient gene expression in four clinical databases. We showed that patients with a reduced ROS Index demonstrate better survival. These data provide clinical evidence for the viability of our O2(-):H2O2-mediated chemosensitivity profiles.Gliomas are notoriously recurrent and highly infiltrative, and have been shown to arise from stem-like cells. We implicate an elevated O2(-):H2O2 ratio as a prosurvival signal in GPC self-renewal and proliferation. The ROS Index provides quantification of O2(-):H2O2-mediated chemosensitivity, an advancement in a previously qualitative field. Intriguingly, glioma patients with a reduced ROS Index correlate with longer survival and the Proneural molecular classification, a feature frequently associated with tumors of better prognosis. These data emphasize the feasibility of manipulating the O2(-):H2O2 ratio as a therapeutic strategy.

Dengue virus NS5 is the most highly conserved amongst the viral non-structural proteins and is responsible for capping, methylation and replication of the flavivirus RNA genome. Interactions of NS5 with host proteins also modulate host immune responses. Although replication occurs in the cytoplasm, an unusual characteristic of DENV2 NS5 is that it localizes to the nucleus during infection with no clear role in replication or pathogenesis. We examined NS5 of DENV1 and 2, which exhibit the most prominent difference in nuclear localization, employing a combination of functional and structural analyses. Extensive gene swapping between DENV1 and 2 NS5 identified that the C-terminal 18 residues (Cter18) alone was sufficient to direct the protein to the cytoplasm or nucleus, respectively. The low micromolar binding affinity between NS5 Cter18 and the nuclear import receptor importin-alpha (Impα), allowed their molecular complex to be purified, crystallised and visualized at 2.2 Å resolution using x-ray crystallography. Structure-guided mutational analysis of this region in GFP-NS5 clones of DENV1 or 2 and in a DENV2 infectious clone reveal residues important for NS5 subcellular localization. Notably, the trans conformation adopted by Pro-884 allows proper presentation for binding Impα and mutating this proline to Thr, as present in DENV1 NS5, results in mislocalizaion of NS5 to the cytoplasm without compromising virus fitness. In contrast, a single mutation to alanine at NS5 position R888, a residue conserved in all flaviviruses, resulted in a completely non-viable virus, and the R888K mutation led to a severely attenuated phentoype, even though NS5 was located in the nucleus. R888 forms a hydrogen bond with Y838 that is also conserved in all flaviviruses. Our data suggests an evolutionarily conserved function for NS5 Cter18, possibly in RNA interactions that are critical for replication, that is independent of its role in subcellular localization., Author Summary DENV NS5 is critical for virus RNA replication and an important drug target based on its high sequence conservation across serotypes, and the successful development of potent drugs that target the homologous NS5B of hepatitis C virus. NS5 also mediates other functions that are important for innate and adaptive immune responses by the infected host. Extensive gene swapping and functional analyses between NS5 of DENV serotypes 1 and 2, that are the two most disparate in terms of nuclear vs cytoplasmic localization of NS5 identified the last 18 amino acid residues of the ~900 amino-acid residues long protein to be responsible for subcellular localization. Because this region is very flexible and not easily seen in crystal structures of DENV NS5, co-crystals of the newly discovered peptide region with importin α were obtained. Structure-based mutations introduced into a DENV2 infectious clone showed that the proline to threonine at position 884 resulted in NS5 being mostly cytoplasmic without affecting virus replication. However mutation of arginine 888, which is conserved in all flaviviruses, to alanine resulted in a completely non-viable virus, suggesting that the C-terminal region is essential for NS5 function irrespective of its role in subcellular location.

To assess the utility of pre-operative 3-dimension (3D) visualisation and surgical planning with the Dextroscope in combination with the use of DEX-Ray-a novel augmented reality surgical navigation platform for resection of meningiomas in the falcine, convexity and parasagittal regions.Magnetic resonance imaging (MRI) and magnetic resonance venogram (MRV) images of the patients were reconstructed in 3D using the Dextroscope workstation. Using a variety of available tools, we were able to view the tumour in various surgical angles and appreciate the intricate relationship of the tumour with respect to the surrounding structures and venous anatomy. Critical draining veins both superficial and deep to the tumour were well visualised. By varying the transparency of the overlying scalp and bone we were able to preoperatively determine the ideal size of our scalp flap and bone window for surgical approach. The Dextroscope enabled us to simulate surgical opening and various trajectories of approach while the DexRay virtual reality navigation system enabled the transfer of the Dextroscope 3D planning data into the operating by displaying it in real-time video-augmented mode which further enhanced the appreciation of the tumour's location in 3D space. Four patients underwent total excision of their meningioma while one patient had near total excision with a small residual remnant left behind at the medial third of the superior sagittal sinus. All 5 patients had good neurological recovery post-operatively.The use of the Dextroscope for pre-operative surgical planning allows for appreciation of complex anatomical relationships in 3D. This appreciation is further translated for use during surgical navigation utilizing the DEX-Ray platform that provided us with the superior advantage of allowing fast and accurate surgical resection confidently.

Objective To assess the feasibility and potential utility of intraoperative computed tomographic angiography (iCTA) in identifying unexpected residual aneurysms and major cerebral artery occlusion after cerebral aneurysm surgery. Methods We prospectively studied 6 consecutive patients with ruptured anterior circulation aneurysms who underwent craniotomy and clipping. iCTA was performed in all cases after the surgeon was satisfied that the aneurysm was completely obliterated and the clip did not occlude a major artery. We analyzed the iCTA images with regard to residual aneurysm and major arterial occlusion and compared them with the postoperatively acquired angiographic images, which served as a control. Patient age and sex, aneurysm location and size, clinical presentation after rupture, and postoperative course, as well as postoperative modified Rankin Scale scores, were also recorded. Results One of the 6 patients had a residual aneurysm detected on the iCTA images, and it was confirmed on the immediate postoperative digital subtraction angiography. There were no cases of major arterial occlusion on iCTA imaging or postoperatively acquired angiographic imaging. Conclusion iCTA is both feasible and potentially useful in identifying unexpected residual aneurysms and major arterial occlusion after surgical clipping of aneurysms.

Background We describe the development of a prototype neurosurgical robotic system called NISS . The aim is to implement a robotic system capable of achieving accurate registration of robotic coordinate systems based on CT images, so that it can be used in clinical application. This system has been refined with a better level of predictability, reliability, and robustness sufficient for animal trial evaluation in stereotactic biopsy of brain lesions. Methods Point accuracy evaluation of NISS began with an in vitro study. The in vitro robotic application accuracy result was 0.1 ± 0.05 mm and absolute needle-to-target deviation was 0.3 ± 0.2 mm. An in vivo experiment approach of using steel balls of 1.56-mm-diameter as targets inside the brain of an anaesthetized dog was used to evaluate the performance accuracy of NISS stereotactic probe placement. Five dogs underwent surgical insertion of steel balls into the brain, and the steel balls were served as targets to be reached by a core needle (1.56-mm-diameter). The experiment was carried out by precise manipulation of the needle to reach the steel ball using frameless stereotactic localization principles. Results A total of 9 needle results were collected from procedures involving 5 dogs. In the first 5 procedures on 3 dogs, the results were less than 1.9 mm, with an average of 1.3 ± 0.5 mm. The remaining 4 procedures on 2 dogs yielded results of less than 0.7 mm, with an average of 0.3 ± 0.2 mm. Conclusion The in vitro and in vivo studies represent the first approach toward evaluating targeting accuracy of a robotic surgery system by using stereotactics biopsy application in a living subject.

Surgery for parasagittal and falcine meningiomas requires meticulous preservation of the cortical veins that surround the tumour; thus, knowledge of the relevant venous anatomy would be extremely helpful during surgery. This study utilises virtual reality technology to determine the number, size and disposition of the veins in relation to the tumour in 8 patients with parasagittal and falcine meningiomas. The same data were also collected from the scans of 8 normal subjects and compared with the data from the meningioma patients. Our results show that the average number of veins is comparable in the tumour and control groups, and that the number of veins on either side does not differ significantly for both groups. On measurement, the size of the veins is approximately the same on either side of the superior sagittal sinus for both the control and the tumour groups. It was also observed that regardless of size, most of the parasagittal and falcine meningiomas demonstrated no significant anatomical distortion effects on the adjacent venous structures, with the exception of one parasagittal meningioma with invasion of the superior sagittal sinus and concomitant engulfment of the draining veins. Data from a larger population would have to be collected in order to determine the effect of the growth of these tumours on the surrounding venous anatomy. With virtual reality technology, the parasagittal veins are clearly discerned, and knowing their location and relationship to the tumour would contribute towards safe and effective surgery.

To evaluate the feasibility of surgical planning using a virtual reality platform workstation in the treatment of cerebral arterio-venous malformations (AVMs)Patient-specific data of multiple imaging modalities were co-registered, fused and displayed as a 3D stereoscopic object on the Dextroscope, a virtual reality surgical planning platform. This system allows for manipulation of 3D data and for the user to evaluate and appreciate the angio-architecture of the nidus with regards to position and spatial relationships of critical feeders and draining veins. We evaluated the ability of the Dextroscope to influence surgical planning by providing a better understanding of the angio-architecture as well as its impact on the surgeon's pre- and intra-operative confidence and ability to tackle these lesions.Twenty four patients were studied. The mean age was 29.65 years. Following pre-surgical planning on the Dextroscope, 23 patients underwent microsurgical resection after pre-surgical virtual reality planning, during which all had documented complete resection of the AVM. Planning on the virtual reality platform allowed for identification of critical feeders and draining vessels in all patients. The appreciation of the complex patient specific angio-architecture to establish a surgical plan was found to be invaluable in the conduct of the procedure and was found to enhance the surgeon's confidence significantly.Surgical planning of resection of an AVM with a virtual reality system allowed detailed and comprehensive analysis of 3D multi-modality imaging data and, in our experience, proved very helpful in establishing a good surgical strategy, enhancing intra-operative spatial orientation and increasing surgeon's confidence.

Cancer stem cells have been shown to initiate and sustain tumor growth. In many instances, clinical material is limited, compounded by a lack of methods to preserve such cells at convenient time points. Although brain tumor-initiating cells grown in a spheroid manner have been shown to maintain their integrity through serial transplantation in immune-compromised animals, practically, it is not always possible to have access to animals of suitable ages to continuously maintain these cells. We therefore explored vitrification as a cryopreservation technique for brain tumor-initiating cells. Tumor neurospheres were derived from five patients with glioblastoma multiforme (GBM). Cryopreservation in 90% serum and 10% dimethyl sulfoxide yielded greatest viability and could be explored in future studies. Vitrification yielded cells that maintained self-renewal and multipotentiality properties. Karyotypic analyses confirmed the presence of GBM hallmarks. Upon implantation into NOD/SCID mice, our vitrified cells reformed glioma masses that could be serially transplanted. Transcriptome analysis showed that the vitrified and nonvitrified samples in either the stem-like or differentiated states clustered together, providing evidence that vitrification does not change the genotype of frozen cells. Upon induction of differentiation, the transcriptomes of vitrified cells associated with the original primary tumors, indicating that tumor stem-like cells are a genetically distinct population from the differentiated mass, underscoring the importance of working with the relevant tumor-initiating population. Our results demonstrate that vitrification of brain tumor-initiating cells preserves the biological phenotype and genetic profiles of the cells. This should facilitate the establishment of a repository of tumor-initiating cells for subsequent experimental designs.

Background This study aimed to evaluate 2 commonly used posterior approach entry points for ventricular cannulation and the ideal trajectories using 3-dimensional virtual reality technology. Methods Magnetic resonance imaging data of 10 patients without gross ventricular dilatation or distortion were retrieved and reconstructed. A stereoscopic 3-dimensional preoperative planning system was used to designate the entry points. Various trajectories were simulated. The ideal trajectory was determined as the one that provided direct entry into the atrium or body of the lateral ventricle en route to the ipsilateral frontal horn. Results Magnetic resonance imaging data sets from 10 patients were used. For the entry point 6 cm above and 4 cm lateral to the inion (Frazier's point), ideal cannulation was achieved for all 10 patients when the selected target was 4 cm above the contralateral medial canthus. When the contralateral medial canthus was targeted, 5 patients had successful outcomes. There were only 3 satisfactory outcomes each when the ipsilateral medial canthus and glabella were targeted. The target 2 cm above the glabella yielded 2 satisfactory outcomes. The entry point 3 cm above and 2 cm lateral to the inion (Dandy's point) had 10 satisfactory outcomes when the target point was 2 cm above the glabella. All the other target points, namely, ipsilateral medial canthus, contralateral medial canthus, 4 cm above the contralateral medial canthus and glabella yielded poor results. Conclusions For satisfactory placement when entering via Frazier's point, the best trajectory target would be 4 cm above the contralateral medial canthus. When entering via Dandy's point, the best target would be 2 cm above the glabella.

There have been fewer than 60 cases of malignant teratocarcinosarcoma (TCS) described in the literature, usually arising in the nose and paranasal sinuses. The authors report on a patient who presented with neurological symptoms caused by a frontal lobe TCS, and in whom widespread spinal tumor dissemination developed. In rare cases, TCSs can occur with a predominantly cranial and neurological presentation and spread to the spinal canal.

Introduction: Resection or even biopsy of an intra-axial mass lesion in close relationship to eloquent cortex carries a major risk of neurological deficit. We review the safety and effectiveness of craniotomy under local anaesthesia and monitored conscious sedation for resection of mass lesions involving eloquent cortex. Materials and Methods: We performed a 3-year retrospective review of patients who underwent awake craniotomy under local anaesthesia at the National Neuroscience Institute, Singapore. All patients had tumours in close proximity to eloquent cortex, including speech areas in the dominant hemisphere as well as primary sensory and motor cortex in either hemisphere. Brain mapping was performed by direct cortical stimulation using the Ojemann stimulator to identify a safe corridor for surgical approach to the tumour. Intraoperative physiological monitoring was carried out by assesment of speech, motor and sensory functions during the process of surgical resection. All resections were evaluated and verified by postoperative imaging and reviewed by an independent assessor. Postoperative complications and neurological deficits, as well as extent of tumour resection, were evaluated. Results: A total of 20 patients underwent stereotactic resection over a period of 3 years from July 2003 to August 2006. There were 7 male patients and 13 female patients, with a mean age of 39.8 years. The average length of stay was 5.5 days. There were no major anaesthetic complications and no perioperative deaths. Postoperative neurological deficits were seen in 6 patients (30%) and this was permanent in only 1 patient (5%). The degree of cytoreduction achieved was greater than 90% in 58% of patients and a further 21% had greater than 80% cytoreduction. Conclusion: Tumour surgery with conscious sedation in combination with frameless computer stereotactic guidance is a safe technique that allows maximal resection of lesions in close relationship to eloquent cortex and has a low risk of neurological deficit. Key words: Awake craniotomy, Brain tumour, Cortical mapping, Cytoreduction, Tumour resection

OBJECTIVE We have developed a highly interactive virtual environment that enables collaborative examination of stereoscopic three-dimensional (3-D) medical imaging data for planning, discussing, or teaching neurosurgical approaches and strategies. MATERIALS AND METHODS The system consists of an interactive console with which the user manipulates 3-D data using hand-held and tracked devices within a 3-D virtual workspace and a stereoscopic projection system. The projection system displays the 3-D data on a large screen while the user is working with it. This setup allows users to interact intuitively with complex 3-D data while sharing this information with a larger audience. RESULTS We have been using this system on a routine clinical basis and during neurosurgical training courses to collaboratively plan and discuss neurosurgical procedures with 3-D reconstructions of patient-specific magnetic resonance and computed tomographic imaging data or with a virtual model of the temporal bone. Working collaboratively with the 3-D information of a large, interactive, stereoscopic projection provides an unambiguous way to analyze and understand the anatomic spatial relationships of different surgical corridors. In our experience, the system creates a unique forum for open and precise discussion of neurosurgical approaches. CONCLUSION We believe the system provides a highly effective way to work with 3-D data in a group, and it significantly enhances teaching of neurosurgical anatomy and operative strategies.

Objective: The use of herbals and health supplements is not without risk. This case report of a 17-year-old girl who presented with acute dural sinus thrombosis following herbal tonic ingestion illustrates the dangers of unsupervised ingestion of "health supplements." Subject and Methods: A 17-year-old girl with normal menses and no prior medical history, procoagulant risk factors, or oral contraceptives use, presented following ingestion of herbal liquid for 2 days, with signs and symptoms of dural sinus thrombosis confirmed by CT scan. MRI and MRV showed bilateral transverse sinuses thrombosis. The patient had an extensive workup, and all procoagulant disorders or factors, including Behcet's disease, were ruled out. The temporal profile of the ingestion of herbal fluid may suggest association with the development of sinus thrombosis. Conclusion: Combinations of herbs in dietary or health supplements could potentiate their subclinical procoagulant effects, and this case highlights the need to report such serious central nervous system adverse effects associated with the ingestion of herbal preparations.

Background Neurosurgical emergencies constitute a significant proportion of workload of a tertiary neurosurgical service. Prompt diagnosis and emergent institution of definitive treatment are critical to reduce neurological mortality and morbidity. Diagnosis is highly dependent on accurate interpretation of scans by experienced clinicians. This expertise may not be readily available especially after office hours because many neurosurgical units are manned by middle-level neurosurgical staff with varying levels of experience in scan interpretation. Multimedia Messaging Service mobile phone technology offers a simple, cheap, quick, and effective solution to the problem of scan interpretation. An MMS takes only a few minutes to send and receive and allows senior doctors to view important images and make important clinical decisions to enhance patient management in an emergency situation. Methods A mobile phone (with VGA camera and MMS capabilities) was provided to the neurosurgery registrar on call. The on-call mobile phone is passed on to the corresponding registrar on-call the next day. All consultants had personal mobile phones that are MMS-enabled. Relevant representative CT/MRI images can be taken directly from the mobile phone from the PACS off the computer screen. When only hard copies are available, the images can be taken off the light box. After a 12-month trial period, a questionnaire was given to all staff involved in the project to ascertain the usefulness of the MMS teleradiology service. Results The survey on the use of the MMS service in a tertiary neurosurgical service demonstrated that the technology significantly improved the level of confidence of the senior-level staff in emergent clinical decision making. Significantly, the MMS images were of sufficient quality and resolution to obviate the need to view the actual scans. The impact of MMS is less pronounced in the middle-level staff, but there was a trend that most of the junior staff found the service more useful. Conclusion The MMS technology is demonstrated to be a useful media for the transmission of high-quality images to assist in the diagnostic process and implementation of emergent clinical therapy. It is already in widespread use and can be seamlessly and rapidly implemented in the clinical arena to improve the quality of patient care.

The 3D volume visualization is to overcome the difficulties of the 2D imaging by using computer technology. A volume visualization approach has been successfully implemented for Surgical Planning System in National Neuroscience Institute (NNI). The system allows surgeons to plan a surgical approach on a set of 2D image slices and process into volume models and visualise them in 3D rapidly and interactively on PC. In our implementation, we have applied it in neurosurgical planning. The surgeon can visualize objects of interest like tumor and surgical path, and verify that the surgical plan avoids the critical features and the planning of the surgical path can thus be optimal.

Background Inhibitory signals, i.e . neurite growth inhibitors (NGIs), presenting on central nervous system (CNS) myelin have been shown to play a crucial role in inhibiting lesioned axonal sprouting and leading to less functional recovery. Vaccines targeting NGIs may provide multifactorial protection against brain insults by overcoming the inhibitory effects of these NGIs and boosting the immune repair mechanisms of body. Objective To evaluate the effect of pre-stroke DNA immunization against NGIs on the rehabilitation for sensorimotor function of rat models of focal cerebral ischemia. Design A completely randomized design, and controlled experiment. Setting Brain Injury Research Laboratory, Department of Neurosurgery, National Neuroscience Institute, Singapore. Materials Sixty adult male Sprague-Dawley rats ranging in age from 45 to 120 days and in body mass from 180 to 250 g were provided by the Animal Center of Department of Anatomy, Faculty of Medicine, National University of Singapore. pcDNA3.1(+)-neurite growth inhibitors (pcDNA-NGIs) a gift was provided by Dr. Xiao from the Department of Clinical Research, Singapore General Hospital, Singapore. Methods The experiment was carried out at Brain Injury Research Laboratory, Department of Neurosurgery, National Neuroscience Institute, Singapore from August 2003 to April 2005. The involved rats were randomized into 3 groups: model group (group A), pcDNA3.1(+) group (group B) and pcDNA-NGIs group (group C), with 20 rats in each group. Left focal cerebral ischemia was permanently induced through middle cerebral artery occlusion with the assistance of an operating microscope. Successful middle cerebral artery occlusion was determined by a 20% decrease to baseline in the ipsilateral cerebral blood flow. 100 μg of pcDNA-NGIs eluted in phosphate-buffered saline (PBS) was intramuscularly injected into the tibial muscle once a week before middle cerebral artery occlusion for 6 weeks in group C. As control, pcDNA3.1 (+) was also administrated in the same way in group B and nothing was administrated in group A. The modified neurological severity score (mNSS), a composite of motor, sensory, reflex and balance tests, was used to test the sensorimotor deficit. The mNSS was graded on 0–18, i.e . normal score was 0, maximal deficit score was 18, and 1 point was warded for the inability to perform the tasks or the lack of a tested reflex. The newly generated axons of corticorubral projection were traced by stereotaxic guided injection of 100 g/L biotinylated dextran amine (BDA). Rats were sacrificed two weeks after tracing, and cryostat coronal sections of midbrains (30 μm) were reacted to BDA according to the manufacturer's instruction by the free-floating method. Images were captured on a DM RXA2 LEICA Microscope with a Spot Digital Camera system (Germany), and the numbers of labeled axons on the denervated side in four standard coronal sections including the red nucleus were manually quantified. Main outcome measures The number of newly generated axons of corticorubral projection; The improvement of the sensorimotor deficit. Results All the involved 60 rats entered the final analysis. The number of newly generated axons of corticorubral projection of rats: Only ipsilateral axons of corticorubral projiction were noted with little evidence of fibers crossing to the contralateral red nucleus in rats of groups A and B. More BDA-positive fibers crossing the midline and terminating in the contralateral red nucleus in appropriate target areas mirroring the non-differentiated red nucleus were found in rats of group C. Quantitative analysis showed that BDA-labelled axons in the denervated side of rats in group C were more than those in group B ( P The improvement of the sensorimotor deficit: At two weeks after middle cerebral artery occlusion, significant improvement in sensorimotor deficit was found in rats of group C. There was significant difference of improvement in sensorimotor deficit of rats between group C and group B or group A at eight and 10 weeks after middle cerebral artery occlusion ( P Conclusion Pre-stroke DNA immunization against NGIs led to increased sensorimotor recovery following focal cerebral ischemia and compensatory newly growth of axons from corticorubral projection.

Numerous studies addressing different methods of head injury prognostication have been published. Unfortunately, these studies often incorporate different head injury prognostication models and study populations, thus making direct comparison difficult, if not impossible. Furthermore, newer artificial intelligence tools such as machine learning methods have evolved in the field of data analysis, alongside more traditional methods of analysis. This study targets the development of a set of integrated prognostication model combining different classes of outcome and prognostic factors. Methodologies such as discriminant analysis, logistic regression, decision tree, Bayesian network, and neural network were employed in the study. Several prognostication models were developed using prospectively collected data from 513 severe closed head-injured patients admitted to the Neurocritical Unit at National Neuroscience Institute of Singapore, from April 1999 to February 2003. The correlation between prognostic factors at admission and outcome at 6 months following injury was studied. Overfitting error, which may falsely distinguish different outcomes, was compared graphically. Tenfold cross-validation technique, which reduces overfitting error, was used to validate outcome prediction accuracy. The overall prediction accuracy achieved ranged from 49.79% to 81.49%. Consistently high outcome prediction accuracy was seen with logistic regression and decision tree. Combining both logistic regression and decision tree models, a hybrid prediction model was then developed. This hybrid model would more accurately predict the 6-month post-severe head injury outcome using baseline admission parameters. © Mary Ann Liebert, Inc.

Analysis of slow waves in arterial blood pressure (ABP) and intracranial pressure (ICP) has been used as an index to describe cerebrovascular pressure-reactivity. It has been previously demonstrated that the pressure-reactivity index (PRx) can be used to reflect global cerebrovascular reactivity with changes in ABP. A positive PRx signifies a positive association between ABP and ICP, indicating a non-reactive vascular bed, while a negative PRx is reflective of intact cerebral autoregulation, where ABP waves provoke inversely correlated waves in ICP. To date, there has been no characterization of pressure-reactivity following decompressive craniectomy. In this prospective observational study, 33 patients who underwent surgery for acute brain injury with mass lesions for which the bone flap was left out were studied. The PRx was calculated as a moving correlation coefficient between 30 consecutive samples of values of ICP and ABP averaged for a period of 10 s. The time profiles of mean PRx values at 6-hourly intervals were analysed and compared with that in seven patients treated by medical therapy alone. The initial mean PRx 6 h after surgery was positive, indicative of disturbed pressure-reactivity. With time, PRx trended towards a more negative value, suggestive of an improving cerebrovascular autoregulatory reserve. The mean PRx 24 h after surgery was 0.28 (+/-0.26), while the mean PRx 72 h after surgery was 0.15 (+/-0.25) (p = 0.012). In contrast, the mean PRx in patients that were not decompressed did not change significantly with time (p = 0.357). Surgery in acute brain injury for which the bone flap is left out in anticipation of raised intracranial pressure in the postoperative period leads to an improved PRx as compared with controls. Craniectomy in this situation may have a contribution to the restoration of disturbed cerebrovascular pressure-reactivity.

The publication of the ISAT trial in 2002 has resulted in increasing numbers of patients with aneurysmal subarachnoid haemorrhage undergoing endovascular coiling, as first line treatment for aneurysm occlusion. During the first 2-year period post-ISAT, in which all suitable intracranial aneurysms were coiled first, we had to perform surgery in seven patients out of 54 who underwent initial coiling. The reasons for subsequent surgery were failed coiling, residual or recurrent aneurysm necks and delayed aneurysmal rebleeding despite coiling. We reviewed our surgical experience with the repair of these previously coiled aneurysms to identify unique technical difficulties. In particular, we found that an aneurysm height to neck ratio of less than 2:1 after coiling, and the use of stent-assisted coiling presented formidable challenges to direct clipping.

Cell surface sialylation has been associated with tumor cell invasiveness in several cancers. Patients with grade IV glioblastoma multiforme (GBM) often show a median survival period of fifteen months, even with the current standard-of-care treatment. Among the reasons for this poor prognosis lies in the cellular and molecular heterogeneity of tumor cells. The Cancer Genome Atlas efforts have shown that histologically identical GBM tumors can be divided into four molecular subtypes based on gene expression, with each subtype corresponding to unique genomic aberrations and clinical outcome. These findings highlight the limitation of relying solely on morphological approaches to diagnose and subsequently treat patients. We conducted a lectin screen with the goal of identifying candidates that stained normal and tumor cells differentially. We identified a sialyltransferase, ST3Gal1 as a mediator of the binding pattern of one such lectin, Peanut Agglutinin. We demonstrate that ST3Gal1 promotes tumor cell invasiveness and enriches for self-renewal potential in the mesenchymal tumor subclass of patients, typified by highly aggressive and recurrent profiles. Depletion of ST3Gal1 extends tumor latency and prolongs survival in mice. Importantly, an enrichment of the ST3GAL1 transcriptomic program portends poor prognosis in glioma patients. Moving forward, since there are no mutations or changes in copy number of ST3GAL1, we explored epigenetic regulation as a possible mechanism. By tapping into data from the NIH Roadmap Epigenome, and transcriptomic analysis of our patient tumor-derived cells, we identified a histone clustering signature that correlates with survival outcome and disease progression. We are currently investigating one such histone modifier, lysine (K)-specific demethylase 1A (LSD1) and its role at modifying ST3GAL1 transcription and activity. Citation Format: Yuk Kien Chong, Edwin Sandanaraj, Lynnette Koh, Moogaambikai Thangaveloo, Melanie SY Tan, Geraldene Koh, Tan Boon Toh, Grace GY Lim, Joanna Holbrook, Oi Lian Kon, Mahendran Nadarajah, Ivan Ng, Wai Hoe Ng, Nguan Soon Tan, Kah Leong Lim, Carol S. Tang, Beng Ti Ang. ST3GAL1-associated transcriptomic program portends poor prognosis in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4470.

Summary Background Vascular endothelial growth factor (VEGF) and its tyrosine kinase family of receptors (VEGFR) (Flt-1, Flk-1, Flt-4) have been implicated in vascular angiogenesis and remodelling in cerebral arteriovenous malformations (CAVM). In this study, we investigate the role of hypoxia inducible factor-1 (HIF-1α) in CAVM and its relationship to VEGF and VEGFR. Methods Surgical specimens from 26 patients undergoing CAVM resection were studied for HIF-1α , VEGF, Flt-1, Flk-1 and Flt-4. The mean age was 34.08+/−14.18 years. Twenty-one patients presented with intracerebral haemorrhage. Results VEGF, Flt-1 and Flt-4 were expressed in all specimens. Flk-1 was expressed in 15 of 26 patients. HIF-1α was expressed in 15 of 26 patients. HIF-1α expression was significantly associated with VEGF, Flt-1 and Flk-1 expression ( p Conclusions HIF-1α is expressed in human CAVM. The expression of HIF-1α is significantly related to VEGF and VEGFR expression, suggesting a possible role for its induction and role in maintaining angiogenesis and vascular remodelling.

The hypothalamus, a vital regulator of multiple physiologic functions, is the principal source of the neuropeptide orexin, which is thought to regulate the sleep-wake cycle. As hypothalamic damage may result from aneurysmal subarachnoid haemorrhage (SAH) and be associated with a depressed conscious level, we sought to investigate whether orexin levels reflected the severity of the ictus and were of any prognostic value in SAH. CSF orexin levels from 15 patients with aneurysmal SAH were analysed for up to 14 days. The correlation between orexin and GCS, WFNS grade, Fisher grade, GOS at 6 months and hydrocephalus were ascertained. Orexin levels in 5 patients with normal pressure hydrocephalus were used as controls. Patients with GCS less than 8 on admission had undetectable orexin whilst those with a GCS of 8 or greater had measurable orexin (p < 0.05). CSF orexin levels appear to correlate with conscious level and might be a valid indicator of hypothalamic injury. As some adverse sequelae of SAH are due to hypothalamic damage, pharmacological manipulation of orexinergic neuronal pathways could lead to exciting therapeutic options in the future.

Traumatic brain injury is a cause of high mortality and morbidity and is an area of intense research. Apoptosis plays a crucial role in the pathogenesis of head injury, and the inhibition of apoptosis can potentially reverse the deleterious effects and lead to better functional outcome. Elucidation of the apoptotic pathway and its role in traumatic brain injury will provide potential targets for therapeutic intervention. This article aims to review the current wealth of literature on apoptosis and traumatic head injury and explores the current status of therapeutic strategies available.

The Biomolecular Interaction Network Database (BIND) (http://bind.ca) archives biomolecular interaction, reaction, complex and pathway information. Our aim is to curate the details about molecular interactions that arise from published experimental research and to provide this information, as well as tools to enable data analysis, freely to researchers worldwide. BIND data are curated into a comprehensive machine-readable archive of computable information and provides users with methods to discover interactions and molecular mechanisms. BIND has worked to develop new methods for visualization that amplify the underlying annotation of genes and proteins to facilitate the study of molecular interaction networks. BIND has maintained an open database policy since its inception in 1999. Data growth has proceeded at a tremendous rate, approaching over 100 000 records. New services provided include a new BIND Query and Submission interface, a Standard Object Access Protocol service and the Small Molecule Interaction Database (http://smid.blueprint.org) that allows users to determine probable small molecule binding sites of new sequences and examine conserved binding residues.

This retrospective study analyses the outcome of posterior inferior cerebellar artery aneurysms treated surgically. Thirteen consecutive ruptured and unruptured PICA aneurysm patients from January 1998 to January 2004 were reviewed retrospectively. The mean age was 49.1 +/- 7.4 years. Three were unruptured aneurysms and ten presented with acute subarachnoid haemorrahge. Surgery was performed immediately after completed 4 vessel angiograms using the far lateral approach. Eight were fusiform while five were saccular aneurysms. The saccular aneurysms were clipped. Treatment of the fusiform aneurysms included 3 trappings and three proximal clippings. One patient refused surgery and had endovascular occlusion of a giant PICA aneurysm. Eight out of ten (80%) operated patients needed CSF shunting for hydrocephalus. All check angiograms during follow up demonstrated adequate exclusion of the aneurysms from the circulation. None developed the PICA syndrome clinically or showed infarction on brain scans. All good grade patients recovered without neurological deficits. Our experience showed that early surgery for ruptured PICA aneurysm carries a good prognosis with low morbidity. In aneurysms that cannot be clipped, sacrifice of the PICA without revascularisation procedures in proximally located PICA aneurysms may still be feasible if the occlusion is done distal to the perforators.

OBJECTIVE Video-assisted endoscopic thoracic sympathectomy is an effective surgical procedure for treating patients with palmar hyperhidrosis. An increase by more than 1 degrees C in palmar temperature has been observed to be predictive of good outcome. In this study, we investigated the use of palmar laser Doppler flowmetry as an intraoperative assessment of the efficacy of the operation. METHODS One hundred sixty-six patients underwent a total of 330 endoscopic thoracic sympathectomy procedures from March 1996 to June 2001. We studied 17 patients (15 men, 2 women) who underwent a total of 33 procedures. The patients' mean age was 27.07 +/- 7.92 years, and the mean hospital stay was 2.23 +/- 0.66 days. RESULTS Mean baseline laser Doppler blood flow was 2.63 +/- 2.56 ml/min/100 g. After the procedure, mean blood flow increased significantly to 7.24 +/- 5.88 ml/min/100 g (r = 0.768, P < 0.000, 95% confidence limit, -6.1060, -3.0946), a 232.18 +/- 219.12% increase. Mean palmar temperature increased to 1.44 +/- 1.44 degrees C. All patients experienced relief after the operation. Compensatory hyperhidrosis occurred in 10 (58.8%) of 17 patients. CONCLUSION Monitoring of palmar laser Doppler blood flow changes is a useful adjunct during endoscopic thoracic sympathectomy surgery, and, when coupled with the established methods of endoscopic visualization and palmar temperature, it can predict the success of the procedure accurately.

Oligomerisation of transcription factors controls their translocation into the nucleus and DNA binding activity. Here we present a fluorescence microscopy method termed pCOMB (pair correlation of molecular brightness) that tracks the mobility of different oligomeric species within live cell nuclear architecture.1 pCOMB amplifies the signal from the brightest species present and filters the dynamics of the extracted oligomeric population based on arrival time between two locations. Here we use this method to demonstrate a dependence of signal transducer and activator of transcription 3 (STAT3) mobility on oligomeric state. We find that upon entering the nucleus STAT3 dimers must first bind DNA to form STAT3 tetramers, which are also DNA-bound but exhibit a different mobility signature. Examining the dimer-to-tetramer transition by a cross pair correlation analysis (cpCOMB) reveals chromatin accessibility to modulate STAT3 tetramer formation. Thus the pCOMB approach is suitable for mapping the impact oligomerisation has on transcription factor dynamics.1. Hinde, E.∗, E. Pandzic, Z. Yang, I. H. W. Ng, D. A. Jans, M. A. Bogoyevitch, E. Gratton and K. Gaus∗. 2016. Quantifying the dynamics of the oligomeric transcription factor STAT3 by pair correlation of molecular brightness. Nature Communications. 7(11047).

Background Calvarial reconstruction of large cranial defects following decompressive surgery is challenging. Autologous bone cannot always be used due to infection, fragmentation, bone resorption, and other causes. Polyetheretherketone (PEEK) is a synthetic material that has many advantages in cranial-repair surgery, including strength, stiffness, durability, and inertness. Objective To describe our experience with custom-made PEEK implants for the repair of large cranial defects in 3 institutions: San Francisco General Hospital, Hadassah-Hebrew University Hospital, and the National Neuroscience Institute, Singapore. Methods A preoperative high-resolution computed tomography scan was obtained for each patient for design of the PEEK implant. Cranioplasty was performed via standard technique with the use of self-tapping titanium screws and miniplates. Results Between 2006 and 2012, 66 cranioplasties with PEEK implants were performed in 65 patients (46 men, 19 women, mean age 35 ± 14 years) for repair of large cranial defects. There were 5 infections of implants and 1 wound breakdown requiring removal of the implant (infection and surgical removal rates of 7.6% and 9.1%, respectively). Two patients required drainage of postoperative hematoma (overall surgical complication rate, 12.7%). Nonsurgical complications in 5 patients included seizures, nonoperative collection, and cerebrospinal fluid rhinorrhea that resolved spontaneously. Overall median patient or family satisfaction with the cranioplasty and aesthetic result was good, 4 on a scale of 5. Temporal wasting was the main aesthetic concern. Conclusion Custom-designed PEEK implants are a good option for patients with large cranial defects. The rate of complications is comparable to other implants or autologous bone. Given the large size of these defects, the aesthetic results are good.

An accurate prognostic model is extremely important in severe traumatic brain injury (TBI) for both patient management and research. Clinical prediction models must be validated both internally and externally before they are considered widely applicable. Our aim is to independently externally validate two prediction models, one developed by the Corticosteroid Randomization After Significant Head injury (CRASH) trial investigators, and the other from the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) group. We used a cohort of 300 patients with severe TBI (Glasgow Coma Score [GCS] ≤8) consecutively admitted to the National Neuroscience Institute (NNI), Singapore, between February 2006 and December 2009. The CRASH models (base and CT) predict 14 day mortality and 6 month unfavorable outcome. The IMPACT models (core, extended, and laboratory) estimate 6 month mortality and unfavorable outcome. Validation was based on measures of discrimination and calibration. Discrimination was assessed using the area under the receiving operating characteristic curve (AUC), and calibration was assessed using the Hosmer-Lemeshow (H-L) goodness-of-fit test and Cox calibration regression analysis. In the NNI database, the overall observed 14 day mortality was 47.7%, and the observed 6 month unfavorable outcome was 71.0%. The CRASH base model and all three IMPACT models gave an underestimate of the observed values in our cohort when used to predict outcome. Using the CRASH CT model, the predicted 14 day mortality of 46.6% approximated the observed outcome, whereas the predicted 6 month unfavorable outcome was an overestimate at 74.8%. Overall, both the CRASH and IMPACT models showed good discrimination, with AUCs ranging from 0.80 to 0.89, and good overall calibration. We conclude that both the CRASH and IMPACT models satisfactorily predicted outcome in our patients with severe TBI.

PURPOSE Image guidance has been used in neurosurgery with great success. The authors illustrate the use of stereotaxy and neuronavigation in the surgical management of a cranio-orbital tumor and for orbital decompresson in thyroid orbitopathy. METHODS Stereotactic image guidance was used in the surgical management of 2 patients, one with a large left sphenoid wing meningioma causing proptosis and visual loss from orbital extension, and the other with disfiguring proptosis due to thyroid eye disease. Virtual reality simulation was used preoperatively in the first patient to visualize surgical corridors of approach to the tumor. RESULTS The patients underwent successful orbital surgery aided by intraoperative neuronavigation. The sphenoidal wing meningioma was removed completely with no damage to adjacent orbital and intracranial tissues, and orbital decompression was successfully performed with good cosmetic improvement. CONCLUSION Image-guided neuronavigation in our cases allowed for safe and precise surgery, with avoidance of complications.