TGF-ß-induced hCG-ß regulates redox homeostasis in glioma cells.

Transforming growth factor (TGF-ß) is associated with the progression of glioblastoma multiforme (GBM)-the most malignant of brain tumors. Since there is a structural homology between TGF-ß and human chorionic gonadotropin (hCG) and as both TGF-ß and hCG-ß are known regulators of oxidative stress and survival responses in a variety of tumors, the role of TGF-ß in the regulation of hCG-ß and its consequences on redox modulation of glioblastoma cells was investigated. A heightened hCG-ß level was observed in GBM tumors. TGF-ß treatment increased hCG-ß expression in glioma cell lines, and this heightened hCG-ß was found to regulate redox homeostasis in TGF-ß-treated glioma cells, as siRNA-mediated knockdown of hCG-ß (i) elevated reactive oxygen species (ROS) generation, (ii) decreased thioredoxin Trx1 expression and thioredoxin reductase (TrxR) activity, and (iii) abrogated expression of TP53-induced glycolysis and apoptosis regulator (TIGAR). Silencing of hCG-ß abrogated Smad2/3 levels, suggesting the existence of TGF-ß-hCG-ß cross-talk in glioma cells. siRNA-mediated inhibition of elevated TIGAR levels in TGF-ß-treated glioma cells was accompanied by an increase in ROS levels. As a farnesyltransferase inhibitor, Manumycin is known to induce glioma cell apoptosis in a ROS-dependent manner, and we investigated whether Manumycin could induce apoptosis in TGF-ß-treated cells with elevated hCG-ß exhibiting ROS-scavenging property. Manumycin-induced apoptosis in TGF-ß-treated cells was accompanied by elevated ROS levels and decreased expression of hCG-ß, Trx1, Smad2/3, and TIGAR. These findings indicate the existence of a previously unknown TGF-ß-hCG-ß link that regulates redox homeostasis in glioma cells.

Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

TNFα regulates the localization of CD40 in lipid rafts of glioma cells.

Resistance of glioblastoma multiforme (GBM) to TNFα induced apoptosis is attributed to NFκB activation. As TNF-receptor family member CD40 regulates NFκB activation, we investigated the role of CD40 in NFκB activation in GBM. We observed elevated CD40 levels in human glioma samples as compared to the surrounding normal tissue. Treatment with TNFα elevated CD40 levels in glioma cells and inhibition of CD40 signaling failed to abrogate TNFα induced NFκΒ activity. While TNFα increased the interaction between TRAF2/6, IκBα, IKKα/ß in the CD40 signalosome, the level of CD40 in the signalosome remained unaffected upon TNFα treatment. Interestingly, TNFα decreased the spatial localization of CD40 and increased TRAF2/6 co-localization with lipid raft marker Caveolin. As localization of CD40 signalosome in lipid raft is crucial for NFκB activation, TNFα mediated decreased clustering of CD40 in lipid rafts could have possibly contributed to its non-involvement in NFκB activation.

Factors affecting the development of hypothalamus and pituitary lesions in fatal closed head injury: a prospective study.

OBJECTIVES: To determine the factors affecting the development of pituitary and hypothalamic lesions after fatal closed head injury. MATERIALS: Thirty-four patients with severe closed head injury succumbing to the effects of brain trauma before or during admission, whether managed conservatively or surgically, formed the study group. Clinical parameters, injury to death interval, radiologic data, and management details were taken into consideration. Autopsy was performed within 48 hours of death; hypothalamus and pituitary were carefully removed and evaluated for the presence of lesions on hematoxylin and eosin and immunohistochemical staining. RESULTS: Patients were categorized into early death group (n = 11, those succumbing before/on admission) and late death group (n = 23, those succumbing after admission). Histopathologic evaluation of pituitary revealed capsular hemorrhages in 50%, posterior pituitary hemorrhage in 25%, anterior pituitary infarct in 21.8%, and anterior pituitary hemorrhage in 6.2% patients. Hypothalamic hemorrhage was observed in 65.2% patients and infarcts in 17.3%. Lesions in hypothalamus and pituitary were significantly related to the presence of ventricular compression on computed tomography scan and survival of >24 hours after injury (p < 0.05). Capsular hemorrhage, anterior pituitary hemorrhage, and posterior pituitary hemorrhage were present in 40%, 10%, and 30% of the patients in the early death group when compared with 54.5%, 4.5%, and 22.7% of the patients in the late death group. Anterior pituitary infarcts were present in 10% of the patients with early deaths and 27.3% patients in the late death group. Hypothalamic hemorrhages were present in 44.4% of patients in early death and 78.6% in late death groups. Hypothalamic infarcts (40%) were present in the late death group only. Two patients (25%) in the early death group and 11 (84.6%) in the late death group had lesions in pituitary as well as hypothalamus (p < 0.05). CONCLUSIONS: Presence of ventricular compression on computed tomography scan and survival >24 hours after severe head injury has a significant correlation with the development of hypothalamic and pituitary lesions. Secondary insults account for a proportion of pituitary and hypothalamic lesions after trauma, which may be amenable to prevention by early intervention to treat raised intracranial pressure (ICP)/herniation.

A clinicopathological and immunohistochemical study of clinically non-functioning pituitary adenomas: a single institutional experience.

BACKGROUND: Non-functioning pituitary adenomas (NFPA) are characterized by the lack of clinical syndrome as compared to functioning adenomas (FA) but not all functioning adenomas have clinical effects. Their exact incidence varies in different series. MATERIALS AND METHODS: This study was undertaken to analyze the hormonal profile of NFPA at the immunohistochemical level in the Indian population and to see if any differences exist from the earlier studies. Their biological aggressiveness was also studied by MIB-1 labeling index (MIB-! LI) and Epidermal Growth Factor Receptor (EGFR) expression. These parameters along with their clinical behavior were correlated with radiological features of invasiveness and size. RESULTS: Of the 151 pituitary adenomas diagnosed during a period of one and half years, 77 (51%) were NFPA with a male predominance. There was increase in the incidence of NFPA with increase in age. Immunopositivity for various hormones was observed in 64 (83%) cases, either singly or in various combinations. On the basis of immunohistochemistry, NFPA were classified into three subtypes; gonadotroph adenomas, silent adenomas, and null cell adenomas. Gonadotroph adenomas were the commonest subtype. In general, NFPA showed low MIB-1LI but invasive NFPA had LI on the higher side, however, this difference was not significant. We observed EGFR positivity in two cases only; therefore the tumorigenesis mechanism may be different in NFPA. CONCLUSION: Although non-functional at the clinical level immunohistochemistry showed reactivity for various hormones. If a battery of immunostains including seven hormones is studied, a significant number of cases are shifted to the functional group.

Assessment of endocrine abnormalities in severe traumatic brain injury: a prospective study.

OBJECTIVE: The frequency and pattern of endocrine abnormalities among patients with traumatic brain injury have been the subject matter of very few studies. This study was intended to assess the pattern of endocrine dysfunction following severe head injury. METHODS: Severe head injury patients admitted to the Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, from January to December in 1 year formed the study group. Apart from clinical assessment, NCCT of the head was performed on all patients on admission. A complete anterior pituitary hormone analysis was performed within 24 h of injury and was repeated at 2 weeks, 3 months and 6 months amongst patients who survived. RESULTS: A total of 99 patients were included in the study. Forty of our patients succumbed in the hospital. Rest of the patients were followed up for 6 months. Elevations of cortisol followed by prolactin were the most common hormonal derangements at admission. Midline shift on CT scans was inversely related to cortisol elevation and directly related to GH elevation. Infarct on CT scans was inversely related to cortisol and LH elevation. A significant alteration was found in the decreasing trend of the mean T4 values and normalisation or a decreasing trend from initially elevated mean cortisol and GH levels during follow-up (p < 0.05). CONCLUSIONS: This study reveals that abnormalities in hormonal profiles appear to be relatively common in severe traumatic brain injury and fluctuate significantly over at least 6 months; there is a correlation with age and radiological findings. Performance of hormonal analysis evaluation should be considered in patients with severe brain injury so that appropriate hormonal replacement can be done to optimise the clinical outcome.

Five Hundred Patients with Memory Loss in One Clinic in India: Does the Prevalence Vary Between Communities?

This observational study reports on the cause of memory loss in 500 consecutive patients. It confirms the previously reported finding in a smaller sample of 100 patients. There have been several publications suggesting that the prevalence of dementia is lower in certain communities but the reason is not known. This study was conducted to see if it could explain the variation between communities. Also, the observation that dementia with Lewy bodies (24.4%) outnumbers cases of Alzheimer's disease (5.8%) has not been reported by any other investigators and needs to be verified. This finding could open a new topic of research and also help in the management of patients.

Skull Vault Plasmacytoma Mimicking Parasagittal Meningioma: "Mini-Brain Appearance".

Plasmacytomas occur as lesions in soft tissue or bone. Skull vault plasmacytomas are rare lesions comprising 0.7% of all plasmacytomas. Workup for myeloma must be done in such cases to rule out multiple myeloma. Here, we report a case of a 63-year-old female who presented to us with a large skull vault swelling which appeared to mimic a parasagittal meningioma on imaging. Histopathological imaging revealed it to be a plasmacytoma. A retrospective review of the radiology revealed the characteristic "mini-brain appearance" in our case. Literature on the subject is also reviewed.

Glioma Simultaneously Present with Adjacent Meningioma: Case Report and Literature Review.

A 51-year-old male patient presented to us with an episode of generalized tonic-clonic seizure. Magnetic resonance imaging revealed a dural-based contrast-enhancing lesion in the right temporal lobe and another heterogeneously contrast-enhancing intra-axial lesion in the right insula adjacent to it. Histopathology confirmed it as a meningioma adjacent to an anaplastic oligodendroglioma. This is only the second such case reported in literature. Literature on "adjacent site" gliomas and meningioma was also reviewed.

Surgical management of giant intracranial aneurysms.

OBJECTIVES: The natural history of giant intracranial aneurysms is generally morbid. Mortality and morbidity associated with giant aneurysms is also higher than for smaller aneurysms. This study was carried out to assess the demographic profile, presenting features, complications, and outcome after surgical treatment of giant intracranial aneurysms. PATIENTS AND METHODS: A retrospective review of the medical records of all patients with giant intracranial aneurysms treated in the Department of Neurosurgery, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, from January 1995 through June 2007 was performed. The demographic profiles, presenting features, radiological findings, surgical treatments, and outcomes were assessed. RESULTS: A total of 1412 patients harboring 1675 aneurysms were treated. Out of these, 222 patients had 229 (13.7%) giant aneurysms, and of those, 181 aneurysms in 177 patients were managed surgically while 48 were treated with endovascular therapy. In the patients treated with surgery, common clinical presentations included subarachnoid hemorrhage (SAH) in 110 (62%) cases followed by mass effect in 57 (32%) cases. In patients who presented with SAH, the Hunt and Hess SAH grading was: grade I in 43 (39%), grade II in 40 (36%), grade III in 23 (21%), grade IV in two (2%), and grade V in 2 (2%) patients. One hundred and seven aneurysms (in 103 patients) were treated using direct surgical clipping. Forty-six patients with good collateral circulation were treated by gradual occlusion and ligation of the internal carotid artery (ICA) in the neck with a Silverstone clamp. Another nine patients with good collateral circulation, but persisting symptoms after ICA ligation, required trapping for obliteration of the aneurysm. Eleven patients with poor collateral circulation required extracranial-intracranial (EC-IC) bypass before proximal ICA ligation. A post-operative digital subtraction angiography (DSA) was performed in 118 patients and revealed well-obliterated aneurysm in 106 patients. The total treatment mortality rate was 9%. In the last 5 years, 117 patients were operated on with four operative deaths. Overall, the outcome was excellent in 131 (74.0%), good in 22 (12.4%), and poor in eight (4.5%) cases. CONCLUSIONS: It is concluded that 14% of all intracranial aneurysms are giant. The most common clinical presentation is SAH followed by features of an intracranial mass lesion. The cavernous ICA is the most common portion of the ICA affected. Direct surgical clipping is a safe and effective method of treatment and should be considered the first line of treatment whenever possible. With proper case selection, optimal radiological evaluation, and appropriate surgical strategy, it is possible to achieve a favorable outcome in almost 90% of the cases.

Basal Ganglia Infarct following Trivial Trauma in a Child: Case Report and Review of Literature.

A 2-year-old boy was presented to us with right-side hemiparesis after trivial fall. Diffusion-weighted magnetic resonance imaging showed an infarct in left basal ganglia and thalamic region. Secondary causes of stroke were ruled out. The child was managed conservatively. Basal ganglia infarct secondary to minor trauma is a rare event. Possible mechanisms leading to such an event and its management are discussed.

Distribution of Types of Dementia in the First 100 Patients Seen at a Dementia Clinic in India.

The aim of our study was to determine if the distribution of types of dementia could explain the reported lower prevalence of dementia in India. The study is an observational study of the first 100 cases of dementia. All patients were evaluated clinically and with blood tests and MRI of the brain. The causes of dementia were: Lewy body dementia (22%), depression (20%), Alzheimer's disease (13%), and mild cognitive impairment (18%). Other dementias were less common. The distribution of dementia types in this series is different from that reported globally. The observation of Lewy body dementia being the most common cause of dementia needs to be verified.

Outcome of "unknown" head injury patients at a tertiary care neurosurgical centre.

CONTEXT: A large number of patients are admitted to hospitals in large cities without any identification. These "unknown" patients represent a unique problem in developing countries. There is no systematic study in world literature on this subgroup of patients. AIMS: To elucidate the natural history and outcome of traumatic brain injury patients admitted in the department of neurosurgery as "unknowns". SETTINGS AND DESIGN: Retrospective analysis of all traumatic brain injury patients admitted to the department of neurosurgery as "unknown", between January 2002 and March 2005. RESULTS: Three hundred and twenty five patients were admitted as unknowns over a 3 year and 3 months period. Most of the patients were young males and became known during their hospital stay. Overall, 33 patients stayed for longer than one month, with 4 of them staying for longer than 6 months. Mortality in mild, moderate and severe head injury group was 1%, 6% and 46% respectively. CONCLUSIONS: Unknown patients represent a unique subgroup in metropolitan cities like Delhi. Managing them raises several medico-legal issues. Many of them occupy hospital beds for longer duration than required. There is an acute shortage of rehabilitation homes in Delhi for long term care and rehabilitation of such patients.

Intracranial hemangioblastomas: an institutional experience.

BACKGROUND AND AIMS: We present our Institutional experience with intracranial hemangioblastomas. SETTINGS AND DESIGN: A retrospective study. MATERIALS AND METHODS: This study included all patients of intracranial hemangioblastomas admitted in our institution over a period of 11 years from January 1992 through June 2003. RESULTS: There were a total of 69 patients (45 males and 24 females). The average age at presentation was 34.5 years. The tumor was located in the cerebellar hemispheres, vermian and brainstem regions in 42 (60%) patients, 19 (28%) patients and 8 (12%) patients, respectively. Hydrocephalus was seen in 48 (69%) patients. Thirty-three patients underwent CSF diversion procedures prior to surgery on the tumor. All except one underwent definitive surgery. The mortality was 8 (11%). Sixty eight patients underwent surgery on the tumor. The follow-up ranged from 1 month to 11 years. Fifteen patients developed recurrent lesions. CONCLUSION: Lifelong surveillance is necessary in cases with hemangioblastomas to identify recurrences especially in those patients having VHL syndrome.