B A Chandramouli

National Institute of Mental Health and Neuro Sciences, Bengalūru, Karnātaka, India

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Publications (96)176.98 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma (GBM) is the most aggressive type of brain tumor and shows very poor prognosis. Here, using genome-wide methylation analysis, we show that G-CIMP+ and G-CIMP- subtypes enrich distinct classes of biological processes. One of the hypermethylated genes in GBM, ULK2, an upstream autophagy inducer, was found to be downregulated in GBM. Promoter hypermethylation of ULK2 was confirmed by bisulphite sequencing. GBM and glioma cell lines had low levels of ULK2 transcripts which could be reversed upon methylation inhibitor treatment. ULK2 promoter methylation and transcript levels showed significant negative correlation. Ectopic overexpression of ULK2 induced autophagy which further enhanced upon nutrient starvation or temozolomide chemotherapy. ULK2 also inhibited the growth of glioma cells which required autophagy induction as kinase mutant of ULK2 failed to induce autophagy and inhibit growth. Furthermore, ULK2 induced autophagy and inhibited growth in Ras transformed immortalised Baby Mouse Kidney (iBMK) ATG5+/+ but not in autophagy deficient ATG5-/- cells. Growth inhibition due to ULK2 induced high levels of autophagy under starvation or chemotherapy utilized apoptotic cell death. Growth inhibition by ULK2 also appears to involve catalase degradation and reactive oxygen species generation. ULK2 overexpression inhibited anchorage independent growth, inhibited astrocyte transformation in vitro and tumor growth in vivo. Of all autophagy genes, we found ULK2 and its homologue ULK1 were only downregulated in all grades of glioma. Thus these results put together suggest that inhibition of autophagy by ULK1/2 down regulation is essential for glioma development.
    The Journal of biological chemistry. 06/2014;
  • Neurology India 05/2014; 62(3):343. · 1.04 Impact Factor
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    ABSTRACT: Background Mesial temporal sclerosis (MTS) is the most common cause of drug resistant epilepsy amenable for surgical treatment and seizure control. Methods This study analyzed the outcome of patients with MTS following anterior temporal lobectomy and amygdalohippocampectomy (ATL-AH) over ten years and correlated theelectrophysiological and radiological factorswith the post operative seizure outcome. Results Eighty seven patients were included in the study. Sixty seven(77.2%) patients had an Engel Class 1 outcome, 9 (11.4%) had Class 2 outcome. Engel's class 1 outcome was achieved in 89.9% at 1 year, while it reduced slightly to 81.9% at 2 yr and 76.2% at 5 year follow up. Seventy seven (88.5%) patients had evidence of hippocampal sclerosis on histopathology. Dual pathology was observed in 19 of 77 specimens with hippocampal sclerosis, but did not influence the outcome. Factors associated with an unfavorable outcome included male gender (p = 0.04), and a higher frequency of pre-operative seizures (p = 0.005), whereas presence of febrile seizures (p = 0.048) and loss of hippocampal neurons in CA4 region on histopathology (p = 0.040) were associated with favorable outcome.The effect of CA4 loss on outcome is probably influenced by neuronal loss in other subfields as well since isolated CA4 loss was rare.. Abnormal post operative EEG at the end of one week was found to be a significant factor predicting unfavorable outcome (p = 0.005). On multivariate analysis, the pre-operative seizure frequency was the only significant factor affecting outcome. Conclusions The present study observed excellent seizure free outcome in a carefully selected cohort of patients with MTS with refractory epilepsy. Presence of dual pathology did not influence the outcome.
    Journal of the neurological sciences 01/2014; · 2.32 Impact Factor
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    ABSTRACT: Stereotactic biopsy of brainstem lesions have been performed with varying indications, with most of the literature reporting on children. The present study retrospectively analyzed all cases that underwent stereotactic biopsy for brainstem lesion in both adult and pediatric population between 1994 and 2009 in a single tertiary neurosurgical center. The clinical and radiological features, technique of the procedure, morbidity, diagnostic accuracy, spectrum of diagnosis, and variations in adult and pediatric population were analyzed. Eighty-two patients were included in the study. Computed tomography (CT) was used as guidance in 73 (38 children and 35 adults) patients and magnetic resonance imaging (MRI) in 9 (3 children and 6 adults). The biopsy was performed in a procedure room under local anesthesia in most adults, while children required sedation. Glioblastoma comprised 29.3% of all pathologies in children, compared with only 4.9% of the pathologies in adult population (P = 0.007). Tuberculosis was the next major diagnosis (9.8%). In 12 patients, initial biopsy was inconclusive. Following a repeat biopsy in 5 of these patients, a diagnosis was possible for 75/82 (91.5%) patients by STB. The location of the target, the choice of entry, the radiological characteristic of the lesion, enhancement pattern, and age group did not significantly correlate with the occurrence of inconclusive biopsy. Permanent complications occurred in two patients (2.4%). There was no mortality in this series. Stereotactic biopsy has an important role in brainstem lesions, more significantly in adults, due to wider pathological spectrum. It can be performed safely under local anesthesia through a twist drill craniostomy in most of the adults.
    Journal of neurosciences in rural practice. 01/2014; 5(1):32-9.
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    ABSTRACT: Anaplastic astrocytoma (AA; Grade III) and glioblastoma (GBM; Grade IV) are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a more robust molecular classifier, we analysed RT-qPCR expression data of 175 differentially regulated genes across astrocytoma using Prediction Analysis of Microarrays (PAM) and found the most discriminatory 16-gene expression signature for the classification of anaplastic astrocytoma and glioblastoma. The 16-gene signature obtained in the training set was validated in the test set with diagnostic accuracy of 89%. Additionally, validation of the 16-gene signature in multiple independent cohorts revealed that the signature predicted anaplastic astrocytoma and glioblastoma samples with accuracy rates of 99%, 88%, and 92% in TCGA, GSE1993 and GSE4422 datasets, respectively. The protein-protein interaction network and pathway analysis suggested that the 16-genes of the signature identified epithelial-mesenchymal transition (EMT) pathway as the most differentially regulated pathway in glioblastoma compared to anaplastic astrocytoma. In addition to identifying 16 gene classification signature, we also demonstrated that genes involved in epithelial-mesenchymal transition may play an important role in distinguishing glioblastoma from anaplastic astrocytoma.
    PLoS ONE 01/2014; 9(1):e85200. · 3.73 Impact Factor
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    ABSTRACT: We studied the MRI findings in 16 patients with Rasmussen's encephalitis (RE), further analysed serial MRI changes in 11 of them and correlated it with clinical features. The diagnosis of RE was based on the European consensus statement (Brain, 128, 2005, 454). Details related to demographical, clinical, MRI observations were analysed. Forty MRIs of brain of 16 patients were reviewed. Eleven patients had undergone serial brain MRIs ranging from two to five occasions. All the patients had unihemispheric focal cortical atrophy, predominantly in the perisylvian region (n = 13). Other features were white matter signal changes (n = 14), and ipsilateral caudate (n = 6) and putamen (n = 4) atrophy. Signal alterations in putamen and caudate were noted in four each. In all the 11 patients with serial MRI, there was progression of cerebral atrophy and a trend towards increase in MRI staging. The MRI signal changes remained same in five patients, resolved in three patients, differential change in two patients and increased in one patient. Diffusion-weighted imaging showed facilitated diffusion (n = 5), and MR spectroscopy showed reduced N-acetyl-aspartate and elevated lactate (n = 2). Pattern recognition of MRI findings and the changes in serial MRI might serve as a surrogate marker of disease viz. unihemispheric progressive focal cortical atrophy and signal changes predominantly in the perisylvian distribution and caudate followed by putamen involvement. This might assist in understanding and monitoring of the disease progression.
    Acta Neurologica Scandinavica 12/2013; · 2.47 Impact Factor
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    ABSTRACT: Glioblastoma is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n=44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in glioblastoma patients. A risk-score derived from methylation signature, predicted survival in univariate analysis in our and TCGA cohort. Multivariate analysis identified methylation risk-score as an independent survival predictor in TCGA cohort. Methylation risk-score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NFkB pathway association with high-risk group. NFkB inhibition reversed glioma chemoresistance and RNA interference studies identified IL6 and ICAM1 as key NFkB targets in imparting chemoresistance. Promoter hypermethylation of NPTX2, a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth and rendered glioma cells chemosensitive. Further, NPTX2 repressed NFkB activity by inhibiting AKT through a p53-PTEN dependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NFkB activated high-risk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Pro-survival NFkB pathway activation characterized high-risk patients with poor prognosis indicating it to be a therapeutic target.
    Cancer Research 09/2013; · 9.28 Impact Factor
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    ABSTRACT: To analyze the seizure outcome of lesionectomy for refractory epilepsy secondary to non-mesial temporal sclerosis (non-MTS) lesions. Sixty-eight patients with non-MTS lesions (M:F=42:26; age at onset: 11.7±9.6 years; age at surgery: 21.1±9.4 years), who underwent lesionectomy for refractory epilepsy were analyzed. The age at onset, frequency/type of seizure, MRI findings, video-EEG, histopathology and Engel's grading at 1 year/last follow up were recorded. The duration of epilepsy at surgery was 9.9±6.9 years. The location of lesions were: temporal: 41 (60.3%); frontal: 21 (30.9%); parietal: 6 (8.8%). The type of lesionectomies performed were temporal 41 (60.3%), extra-temporal: 25 (36.8%), temporo-frontal and temporo-parietal: 1 (1.5%) patient each. The histopathological diagnosis were neoplastic: 32 (47.1%), cortical dysplasia: 19 (27.9%), other focal lesions: 17 (25%). At mean follow up of 2.9±2.1 years (median: 2.6 years), outcome was - Engel's class I: 43 (63.2%), IIa: 14 (20.6%), III: 7 (10.3%), IV: 4 (5.9%). Good seizure control (Engel's class I/IIa) was achieved in 57 (83.8%) patients. The good prognostic markers included temporal seizures, extended lesionectomy and AEDs after surgery while poor prognostic marker was gliotic lesion on histopathology. Following lesionectomy due to non-MTS lesions, seizure freedom (Engel I) was noted in about 63.2% of patients, which is comparable to other series and reiterates the effectiveness of lesionectomy for seizure control.
    Clinical neurology and neurosurgery 09/2013; · 1.30 Impact Factor
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    ABSTRACT: A brain abscess which is caused by Streptococcus pneumoniae is a rare entity. Here, we have described a gentle man who presented with the signs and symptoms of a mass lesion which was localized to the temporal lobe. The clinical examination and computerized tomography revealed the diagnosis of a temporal abscess. The loculated mass was tapped and it was sent for histopathology, which confirmed the presence of an organizing abscess. A laboratory investigation of the pus revealed Streptococcus pneumoniae. The treatment included total excision and the administration of prolonged antibiotics, which led to a good outcome in the patient.
    Journal of clinical and diagnostic research : JCDR. 08/2013; 7(8):1694-1695.
  • Sanjay Kumar, Shobini L Rao, Bangalore A Chandramouli, Shibu Pillai
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    ABSTRACT: AIM: Mild traumatic brain injury (MTBI) is associated with often selective impairment of both working memory (WM) and the executive functions (EFs). Research indicates that one of the commonest deficits present in MTBI patients falls in the domain of WM. We aimed to investigate the role of EFs in WM impairment following MTBI. METHODS: Performance on the tests of EFs and the verbal and visuo-spatial WM of 30 consecutive MTBI patients were compared with age/education/IQ matched 30 normal healthy control participants. Correlation between EFs and WM was studied separately for the MTBI and the control group. RESULTS: The MTBI and control group were tested on a range of EF tests and WM. The MTBI group was demonstrated impairment on verbal and visuo-spatial WM and category fluency tests only. Furthermore, the MTBI group had fewer significant correlations between the WM and EFs (5 out of 54 possible correlations) than in the control group (13 out of 54 possible correlations). CONCLUSIONS: We suggest that MTBI may lead to WM deficits as the contribution of executive processes to support the WM is diminished following MTBI. Such an understanding of the poor WM performance in MTBI patients will be helpful when planning appropriate strategies for cognitive rehabilitation.
    Clinical neurology and neurosurgery 01/2013; · 1.30 Impact Factor
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    ABSTRACT: Glioblastoma is one of the common types of primary brain tumors with a median survival of 12-15 months. The receptor tyrosine kinase (RTK) pathway is known to be deregulated in 88% of the patients with glioblastoma. 45% of GBM patients show amplifications and activating mutations in EGFR gene leading to the upregulation of the pathway. In the present study, we demonstrate that a brain specific miRNA, miR-219-5p, repressed EGFR by directly binding to its 3'-UTR. The expression of miR-219-5p was downregulated in glioblastoma and the overexpression of miR-219-5p in glioma cell lines inhibited the proliferation, anchorage independent growth and migration. In addition, miR-219-5p inhibited MAPK and PI3K pathways in glioma cell lines in concordance with its ability to target EGFR. The inhibitory effect of miR-219-5p on MAPK and PI3K pathways and glioma cell migration could be rescued by the overexpression of wild type EGFR and vIII mutant of EGFR (both lacking 3'-UTR and thus being insensitive to miR-219-5p) suggesting that the inhibitory effects of miR-219-5p were indeed because of its ability to target EGFR. We also found significant negative correlation between miR-219-5p levels and total as well as phosphorylated forms of EGFR in glioblastoma patient samples. This indicated that the downregulation of miR-219-5p in glioblastoma patients contribute to the increased activity of the RTK pathway by the upregulation of EGFR. Thus, we have identified and characterized miR-219-5p as the RTK regulating novel tumor suppressor miRNA in glioblastoma.
    PLoS ONE 01/2013; 8(5):e63164. · 3.73 Impact Factor
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    ABSTRACT: Recent research on glioblastoma (GBM) has focused on deducing gene signatures predicting prognosis. The present study evaluated the mRNA expression of selected genes and correlated with outcome to arrive at a prognostic gene signature. Patients with GBM (n = 123) were prospectively recruited, treated with a uniform protocol and followed up. Expression of 175 genes in GBM tissue was determined using qRT-PCR. A supervised principal component analysis followed by derivation of gene signature was performed. Independent validation of the signature was done using TCGA data. Gene Ontology and KEGG pathway analysis was carried out among patients from TCGA cohort. A 14 gene signature was identified that predicted outcome in GBM. A weighted gene (WG) score was found to be an independent predictor of survival in multivariate analysis in the present cohort (HR = 2(.)507; B = 0(.)919; p<0(.)001) and in TCGA cohort. Risk stratification by standardized WG score classified patients into low and high risk predicting survival both in our cohort (p = <0(.)001) and TCGA cohort (p = 0(.)001). Pathway analysis using the most differentially regulated genes (n = 76) between the low and high risk groups revealed association of activated inflammatory/immune response pathways and mesenchymal subtype in the high risk group. We have identified a 14 gene expression signature that can predict survival in GBM patients. A network analysis revealed activation of inflammatory response pathway specifically in high risk group. These findings may have implications in understanding of gliomagenesis, development of targeted therapies and selection of high risk cancer patients for alternate adjuvant therapies.
    PLoS ONE 01/2013; 8(4):e62042. · 3.73 Impact Factor
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    ABSTRACT: We report a rare case of a patient with a pial arteriovenous malformation (AVM) who presented in altered sensorium. He was found to have large epidural and subdural hematomas overlying a pial AVM. He underwent evacuation of these hematomas and postop computed tomography showed infarcts deep to the site of hematoma evacuation. These infarcts were postulated to be due to a steal phenomenon combined with raised intracranial pressure. The management and possible mechanisms for this rare combination are discussed.
    Asian journal of neurosurgery. 10/2012; 7(4):210-3.
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    ABSTRACT: IDH1 mutations are frequent genetic alterations in low-grade diffuse gliomas and secondary glioblastoma (GBM). To validate mutation frequency, IDH1 gene at codon 132 was sequenced in 74 diffusely infiltrating astrocytomas: diffuse astrocytoma (DA; World Health Organization [WHO] grade II), anaplastic astrocytoma (AA; WHO grade III), and GBM (WHO grade IV). All cases were immunostained with IDH1-R132H monoclonal antibody. Mutational status was correlated with mutant protein expression, patient age, duration of symptoms, and prognosis of patients with GBM. We detected 31 (41.9%) heterozygous IDH1 mutations resulting in arginine-to-histidine substitution (R132H;CGT-CAT). All 12 DAs (100%), 13 of 14 AAs (92.9%), and 6 of 48 GBMs (12.5%) (5/6 [83.3%] secondary, and 1/42 [2.4%] primary) harbored IDH1 mutations. The correlation between mutational status and protein expression was significant (P < . 001). IDH1 mutation status, though not associated with prognosis of patients with GBM, showed significant association with younger age and longer duration of symptoms in the whole cohort (P < .001). Our study validates IDH1 mutant protein expression across various grades of astrocytoma, and demonstrates a high incidence of IDH1 mutations in DA, AA, and secondary GBM.
    American Journal of Clinical Pathology 08/2012; 138(2):177-84. · 2.88 Impact Factor
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    ABSTRACT: The role of insulin- like growth factors and their regulatory proteins (IGFBP isoforms) in gliomas, particularly glioblastoma, has been a subject of active research in recent years. There is paucity of literature on their expression and impact on clinical outcome in anaplastic astrocytomas. To evaluate the expression patterns of IGFBP isoforms in anaplastic astrocytoma and correlate with clinical outcome, a retrospective study of 53 adult patients operated for supratentorial lobar anaplastic astrocytoma was performed. The protein expression of IGFBP isoforms (IGFBP-2, -3, -5 and -7), was studied by immunohistochemistry on all samples. The patients were followed up and outcome was documented. The median age at presentation in the present study was 35 years. The pattern of staining was intra cytoplasmic, homogenous and diffuse for IGFBP-2, -3 and -5 and granular for IGFBP-7. IGFBP-2 expression was significantly low in anaplastic astrocytoma as compared to other isoforms (P < 0.001). IGFBP-3 expression was higher than the other isoforms. However, its' expression correlated with favorable overall survival and demonstrated a trend towards significance on univariate analysis. The present study is the first of its kind to describe comprehensively the pattern of expression of IGFBP isoforms (IGFBP-2, -3, -5 and -7) in anaplastic astrocytomas. IGFBP-2 and IGFBP-3 expression patterns and correlation to prognosis were distinct in anaplastic astrocytoma patients, contradictory to what has been reported in glioblastoma, thus giving further evidence that anaplastic astrocytomas are molecularly distinct from glioblastoma.
    Pathology & Oncology Research 05/2012; 18(4):961-7. · 1.56 Impact Factor
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    ABSTRACT: The search for molecular markers which predict response to chemotherapy is an important aspect of current neuro-oncology research. MGMT promoter methylation is the only proved marker of glioblastoma. The purpose of this study was to assess the effect of topoisomerase expression on glioblastoma survival and study the mechanisms involved. The transcript levels of all isoforms of the topoisomerase family in all grades of diffuse astrocytoma were assessed. A prospective study of patients with glioblastoma treated by a uniform treatment procedure was performed with the objective of correlating outcome with gene expression. The ability of TOP2A enzyme to relax the super coiled plasmid DNA in the presence of temozolomide was evaluated to assess its effect on TOP2A. The temozolomide cyctotoxicity of TOP2A-silenced U251 cells was assessed. The transcript levels of TOP2A, TOP2B, and TOP3A are upregulated significantly in GBM in comparison with lower grades of astrocytoma and normal brain samples. mRNA levels of TOP2A correlated significantly with survival of the patients. Higher TOP2A transcript levels in GBM patients predicted better prognosis (P = 0.043; HR = 0.889). Interestingly, we noted that temozolomide inhibited TOP2A activity in in-vitro enzyme assays. We also noted that siRNA knock down of TOP2A rendered a glioma cell line resistant to temozolomide chemotherapy. We demonstrated for the first time that temozolomide is also a TOP2A inhibitor and established that TOP2A transcript levels determine the chemosensitivity of glioblastoma to temozolomide therapy. Very high levels of TOP2A are a good prognostic indicator in GBM patients receiving temozolomide chemotherapy.
    Journal of Neuro-Oncology 11/2011; 107(2):289-97. · 3.12 Impact Factor
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    ABSTRACT: Focal intradural infections of the brain include empyema and abscess in the supratentorial and infratentorial spaces. These are amenable to surgical management. Various other issues may complicate the course of management, e.g. hydrocephalus with infratentorial lesions or cortical venous thrombosis with supratentorial lesions. Here, we review the management and identify factors affecting outcome in these patients. This is a retrospective analysis of all children (aged <18 years) treated at the National Institute of Mental Health and Neurosciences, Bangalore, India, between 1988 and 2004. Case records were analyzed to obtain clinical, radiological, bacteriological and follow-up data. There were 231 children who underwent treatment for focal intradural abscess/empyema at our institute. These included 57 children with cerebral abscess, 65 with supratentorial empyema, 82 with cerebellar abscess and 27 with infratentorial empyema. All patients underwent emergency surgery (which was either burr hole and aspiration of the lesion or craniotomy/craniectomy and excision/evacuation), along with antibiotic therapy, typically 2 weeks of intravenous and 4 weeks of oral therapy. The antibiotic regimen was empiric to begin with and was altered if any sensitivity pattern of the causative organism(s) could be established by culture. Hydrocephalus was managed with external ventricular drainage initially and with ventriculoperitoneal shunt if warranted. Mortality rates were 4.8% for cerebral abscess, 9.6% for cerebellar abscess, 10.8% for supratentorial subdural empyema and 3.7% for posterior fossa subdural empyema. The choice of surgery was found to have a strong bearing on the recurrence rates and outcome in most groups, with aggressive surgery with craniotomy leading to excellent outcomes with a low incidence of residual/recurrent lesions. Antibiotic therapy, emergency surgery and management of associated complications are the mainstays of treatment of these lesions. We strongly advocate early, aggressive surgery with antibiotic therapy in children with focal intradural infections.
    Pediatric Neurosurgery 09/2011; 47(2):113-24. · 0.42 Impact Factor
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    ABSTRACT: Models for prediction of outcome of intensive care patients greatly help the physician to make decisions and are also important for risk stratification in clinical research and quality improvement. At present, there are no major predictive models for neurosurgical intensive care unit (NSICU) patients. This study aimed to develop a predictive model for survival in NSICU patients. This is a prospective observational study in the NSICU at a tertiary-care university hospital. The data were collected within 24 hours of admission in all patients admitted to the NSICU. The parameters collected were demographic variables, systolic blood pressure, arterial oxygen tension after resuscitation (PaO2), Glasgow coma score (GCS) and pupillary signs, blood urea, creatinine, albumin, glucose, sodium, potassium, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, hemoglobin concentration, leukocyte count, platelet count, temperature, and evidence of infection. Mortality or discharge from NSICU was the primary outcome variable. All patients were provided full care until death or discharge from the ICU. Life support was not withdrawn in any of the patient based on the perception of outcome by the treating physician. All variables were compared between survivors and nonsurvivors. Significant variables were analyzed by multivariate logistic regression and a prediction model was developed. Four hundred six patients were included in the study. Three hundred two patients survived and 104 died (mortality of 25.6%). Significant variables on univariate analysis include primary reason for admission, GCS, pupillary reaction, systolic blood pressure, serum albumin, glucose, serum sodium concentration, hypothermia, and infection at the time of admission. Multivariate analysis showed that the significant independent factors for predicting outcome in NSICU patients are age, diagnosis, GCS, pupillary status, albumin, and serum sodium concentration. The predictive model has good discrimination (receiver operating characteristic curve=0.796) and good calibration (P=0.937). The overall accuracy of the model was 81%. In the current model of prediction of survival in a neurosurgical ICU, age, diagnosis, GCS, pupillary status, serum albumin, and serum sodium are independent predictors of survival in NSICU patients.
    Journal of neurosurgical anesthesiology 07/2011; 23(3):183-7. · 2.41 Impact Factor
  • S Arvind, A Arivazhagan, V Santosh, B A Chandramouli
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    ABSTRACT: Ion channels are subjects of intense research, due to their easy access and potential for being drug targets. Kv1.5 is a voltage gated potassium channel, earlier thought to be cardiac specific. Recent studies have revealed that K(+) channels play an important role in apoptosis, glial cell proliferation and biology of various cancers. No study has so far been performed to assess their expression in astrocytomas and correlate its impact on the clinical behaviour of gliomas. Sixty samples of astrocytoma which included 9 diffuse astrocytoma (DA) grade II, 11 anaplastic astrocytoma (AA) grade III and 40 glioblastoma (GBM), along with normal brain tissue (cerebral cortex; n = 5) were analysed for their Kv1.5 protein expression. Immunohistochemical expression of Kv1.5 in various grades was assessed semi quantitatively. The patients with GBM (n = 40) were treated with uniform protocol and their survival was documented. The mean expression of Kv1.5 in DA, AA and GBM was 22.2 ± 9.71%, 11.81 ± 12.3% and 10.37 ± 11.05%, respectively, the difference being statistically significant (p = 0.004). The mean expression in low grade astrocytoma (WHO II) was significantly higher than higher grades (22.2% and 10.7%; p = 0.005). On analysing the influence of Kv1.5 expression on survival of GBM patients, we noted that increasing Kv1.5 labelling index (LI) correlated with a favourable prognosis, albeit not being significant (p = 0.310; HR = 0.901). Kv1.5 expression occurs more in DA, when compared to high grade astrocytoma. GBM patients with higher Kv1.5 expression had better survival, though not reaching statistical significance.
    British Journal of Neurosurgery 06/2011; 26(1):16-20. · 0.86 Impact Factor
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    ABSTRACT: Glioblastoma is the most common and malignant form of primary astrocytoma with a short median survival time despite advances in our understanding. Upon investigation of the IGF pathway, we found IGF2BP3/IMP3 transcript and protein to be up-regulated in GBMs but not in lower grade astrocytomas (p<0.0001). IMP3 is a RNA binding protein known to bind to the 5-prime untranslated region of IGF-2 mRNA thereby activating its translation. Over-expression and knock-down based studies establish a role for IMP3 in promoting proliferation, anchorage-independent growth, invasion and chemoresistance. IMP3 over-expressing B16F10 cells also showed increased tumor growth, angiogenesis and metastasis resulting in poor survival in a mouse model. Additionally, the infiltrating front, perivascular and subpial regions in a majority of the GBMs stained positive for IMP3. A mouse model of glioma further substantiated these findings. IMP3-positive glioblastoma patients (n=83) in a prospectively studied cohort of patients showed poor survival upon univariate analysis (p=0.0441). In agreement with the translation activation functions of IMP3, we also found increased IGF-2 protein in GBMs without a corresponding increase in its transcript levels. Further, in vitro IMP3 knock-down, lowered the IGF-2 protein levels without altering its transcript levels. Concordantly, PI3-kinase and MAP-kinase, the downstream effectors of IGF-2, are activated by IMP3 and are found to be essential for IMP3-induced cell proliferation. Thus, we have identified IMP3 as a GBM-specific pro-proliferative and pro-invasive marker acting through the PI3-kinase and MAP-kinase pathways with a probable prognostic role in GBM patient survival.
    Journal of Biological Chemistry 05/2011; · 4.65 Impact Factor

Publication Stats

680 Citations
176.98 Total Impact Points

Institutions

  • 2009–2014
    • National Institute of Mental Health and Neuro Sciences
      • Department of Neurosurgery
      Bengalūru, Karnātaka, India
  • 2013
    • Basaveshwara Medical College and Hospital , Chitradurga
      Chitaldurg, Karnātaka, India
  • 2012
    • Jawaharlal Institute of Postgraduate Medical Education & Research
      Pondichéry, Pondicherry, India
  • 1989–2012
    • Dharwad Institute of Mental Health and Neurosciences
      Hubli, Karnātaka, India
  • 2011
    • Vikram Hospital Bangalore
      Bengalūru, Karnātaka, India
  • 2008–2010
    • University of Allahabad
      • Centre of Behavioural and Cognitive Sciences (CBCS)
      Allahābād, Uttar Pradesh, India
  • 2007–2010
    • Indian Institute of Science
      • Department of Microbiology and Cell Biology
      Bengalore, State of Karnataka, India