Anil Nanda

Mechanisms of Erythropoietin-induced Brain Protection in Neonatal Hypoxia-Ischemia Rat Model:

Erythropoietin, a hemotopoietic growth factor, has brain protective actions. This study investigated the mechanisms of Recombinant Human EPO (rhEPO)-induced brain protection in neonates. An established rat hypoxia-ischemia model was used by ligation of the right common carotid artery of 7-day-old pups, followed by 90 minute of hypoxia (8% 02 and 92% N2) at 37°C. Animals were divided into three groups: control, hypoxia-ischemia, and hypoxia-ischemia plus rhEPO treatment. In rhEPO treated pups, 300 units rhEPO was administered intraperitoneally 24 hours before hypoxia. rhEPO treatment (300 units) was administered daily for an additional 2 days. ELISA and immunohistochemistry examined the expression of EPO and EPOR. Brain weight, morphology, TUNEL assay, and DNA laddering evaluated brain protection. rhEPO abolished mortality (from 19% to 0%) during hypoxia insult, increased brain weight from 52% to 88%, reduced DNA fragmentation, and decreased TUNEL-positive cells. Real-time RT-PCR, Western blot, and immunohistochemistry revealed an enhanced expression of heat shock protein 27 (HSP27) in ischemic brain hemisphere. Double labeling of TUNEL with HSP27 showed most HSP27 positive cells were negative to TUNEL staining. rhEPO reduces brain injury, especially apoptotic cell death after neonatal hypoxia-ischemia, partially mediated by the activation of HSP27.

Role of Inflammation and Its Mediators in Acute Ischemic Stroke

Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Increasing evidence suggests that inflammatory response is a double-edged sword, as it not only exacerbates secondary brain injury in the acute stage of stroke but also beneficially contributes to brain recovery after stroke. In this article, we provide an overview on the role of inflammation and its mediators in acute ischemic stroke. We discuss various pro-inflammatory and anti-inflammatory responses in different phases after ischemic stroke and the possible reasons for their failures in clinical trials. Undoubtedly, there is still much to be done in order to translate promising pre-clinical findings into clinical practice. A better understanding of the dynamic balance between pro- and anti-inflammatory responses and identifying the discrepancies between pre-clinical studies and clinical trials may serve as a basis for designing effective therapies.

Vagal nerve stimulation for the treatment of medically refractory epilepsy: a review of the current literature

OBJECT The authors conducted a study to evaluate the published results of vagal nerve stimulation (VNS) for medically refractory seizures according to evidence-based criteria. METHODS The authors performed a review of available literature published between 1980 and 2010. Inclusion criteria for articles included more than 10 patients evaluated, average follow-up of 1 or more years, inclusion of medically refractory epilepsy, and consistent preoperative surgical evaluation. Articles were divided into 4 classes of evidence according to criteria established by the American Academy of Neurology. RESULTS A total of 70 publications were reviewed, of which 20 were selected for review based on inclusion and exclusion criteria. There were 2 articles that provided Class I evidence, 7 that met criteria for Class II evidence, and 11 that provided Class III evidence. The majority of evidence supports VNS usage in partial epilepsy with a seizure reduction of 50% or more in the majority of cases and freedom from seizure in 6%-27% of patients who responded to stimulation. High stimulation with a gradual increase in VNS stimulation over the first 6 weeks to 3 months postoperatively is well supported by Class I and II data. Predictors of positive response included absence of bilateral interictal epileptiform activity and cortical malformations. CONCLUSIONS Vagal nerve stimulation is a safe and effective alternative for adult and pediatric populations with epilepsy refractory to medical and other surgical management.

Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1α and apoptotic genes in a middle cerebral artery occlusion-induced focal ischemia rat model

Despite 2‐methoxyestradiol (2ME2) and tricyclodecan‐9‐yl‐xanthogenate (D609) having multiple effects on cancer cells, mechanistically, both of them down‐regulate hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF). We hypothesize HIF‐1α plays an essential role in cerebral ischemia as a pro‐apoptosis regulator; 2ME2 and D609 decrease the levels of HIF‐1α and VEGF, that might contribute to protecting brain from ischemia injury. A total of 102 male Sprague–Dawley rats were split into five groups: sham, middle cerebral artery occlusion (MCAO), MCAO + dimethyl sulfoxide, MCAO + 2ME2, and MCAO + D609. 2ME2 and D609 were injected intraperitoneally 1 h after reperfusion. Rats were killed at 24 h and 7 days. At 24 h, 2ME2 and D609 reduce the levels of HIF‐1α and VEGF (enzyme‐linked immunosorbent assay), depress the expression of HIF‐1α, VEGF, BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) and cleaved caspase 3 (western blot and immunohistochemistry) in the brain infarct area. Double fluorescence labeling shows HIF‐1α positive immunoreactive materials are co‐localized with BNIP3 and terminal deoxynucleotidyl transferase biotin‐dUTP nick end labeling inside the nuclei of neurons. At 7 days, 2ME2 and D609 reduce the infarct volume (2,3,7‐triphenyltetrazolium chloride) and blood–brain barrier extravasation, decrease the mortality and improve the neurological deficits. In conclusion, 2ME2 and D609 are powerful agents to protect brain from cerebral ischemic injury by inhibiting HIF‐1α expression, attenuating the superfluous expression of VEGF to avoid blood–brain barrier disruption and suppressing neuronal apoptosis via BNIP3 pathway.

Phosphatidylinositol-3-Kinase Gamma Plays a Central Role in Blood–Brain Barrier Dysfunction in Acute Experimental Stroke

Background and Purpose— Phosphoinositide 3-kinase (PI3K)-&ggr; is linked to inflammation and oxidative stress. This study was conducted to investigate the role of the PI3K&ggr; in the blood–brain barrier dysfunction and brain damage induced by focal cerebral ischemia/reperfusion. Methods— Wild-type and PI3K&ggr; knockout mice were subjected to middle cerebral artery occlusion (60 minutes) followed by reperfusion. Evans blue leakage, brain edema, infarct volumes, and neurological deficits were examined. Oxidative stress, neutrophil infiltration, and matrix metallopeptidase-9 were assessed. Activation of nuclear factor-&kgr;B and expression of proinflammatory and pro-oxidative genes were studied. Results— PI3K&ggr; deficiency significantly reduced blood–brain barrier permeability and brain edema formation, which were time-dependently correlated with preventing the degradation of the tight junction protein, claudin-5, and the basal lamina protein, collagen IV, and the phosphorylation of myosin light chain in brain microvessels. PI3K&ggr; deficiency suppressed ischemia/reperfusion-induced nuclear factor-&kgr;B p65 (Ser536) phosphorylation and the expression of the pro-oxidant enzyme NADPH oxidase (Nox1, Nox2, and Nox4) and proinflammatory adhesion molecules (E- and P-selectin, intercellular adhesion molecule-1) at different time points. These molecular changes were associated with significant inhibition of oxidative stress (superoxide production and malondialdehyde content), neutrophil infiltration, and matrix metallopeptidase-9 expression/activity in PI3K&ggr; knockout mice. Eventually, PI3K&ggr; deficiency significantly reduced infarct volumes and neurological scores at 24 hours after ischemia/reperfusion. Conclusions— Our results provide the first direct demonstration that PI3K&ggr; plays a significant role in ischemia/reperfusion-induced blood–brain barrier disruption and brain damage. Future studies need to explore PI3K&ggr; as a potential target for stroke therapy.

Operative versus nonoperative management of acute odontoid Type II fractures: a meta-analysis

OBJECT The purpose of this study was to evaluate the feasibility of the criteria described in the literature as the indications for surgery for acute Type II odontoid fractures. METHODS The authors searched the PubMed database for studies in which the fusion rate of acute Type II odontoid fractures following external immobilization (halo vest or collar) or surgery (posterior C1-2 fusion or anterior screw fixation) was reported. The only studies included reported the fusion rate for either 1) groups of patients whose age was either more or less than a certain age range (45-55 years); or 2) groups of patients with a fracture displacement of either more or less than a certain odontoid fracture displacement (4-6 mm) or the direction of displacement (see Methods section of text for more details). A meta-analysis in which the random effect model was used was conducted to analyze the data. RESULTS There was a statistically significantly higher fusion rate for operative management compared with external immobilization (85 vs 60%, p = 0.01) for the patients > 45-55 years. However, the overall fusion rate was > 80% for the patients whose age was < 45-55 years, regardless of treatment modality, and no significant differences were observed between surgically and nonsurgically treated patients (89 and 81%, respectively; p = 0.29). The result of operation (overall fusion rate 89%) was superior to external immobilization (44%) when the fracture was posteriorly displaced (p < 0.001), but for anteriorly displaced fractures, the results of operative and nonoperative management were identical (p = 0.15). The overall fusion rate of operative management of both anteriorly and posteriorly displaced fractures proved to be > 85%, and no statistically significant difference was observed (p = 0.50). For all degrees of displacement (either > or < 4-6 mm) the operation proved to provide significantly better results than conservative treatment. The fusion rate of conservatively treated fractures with < 4-6 mm displacement was significantly better than in fractures with > 4-6 mm displacement (76 vs 41%, p = 0.002). CONCLUSIONS Operative treatment (posterior C1-2 fixation or anterior screw fixation) provides a better fusion rate than external immobilization for acute odontoid Type II fractures, although in certain situations, such as anterior displacement of the fracture and for younger (< 45-55 years of age) patients, conservative management (halo vest or collar immobilization) can be as effective as surgery. Operative management is recommended in older patients, in cases of posterior displacement of the fracture, and when there is displacement of > 4-6 mm.

Poly (ADP-ribose) polymerase induction is an early signal of apoptosis in human neuroblastoma.

Poly (ADP-ribose) polymerase (PARP) is an abundant chromatin associated protein important in DNA repair, maintenance of chromosomal stability and programmed cell death. Here we report that an increase in caspase 3-activity and cleavage of PARP serves as an early execution phase signal in human neuroblastoma. Human neuroblastoma SK-N-SH cells were exposed to a protein kinase inhibitor, staurosporine, or a topoisomerase II inhibitor, etoposide, at various concentrations and time points. Cells exposed to staurosporine (0.1 microM) for 30 min showed an increase in caspase 3-activity and by 1 h an increase in PARP 116-kDa band and an 85-kDa cleavage product, which further increased in density with time after treatment. Quantitative analysis for condensed chromatin material using bisbenzimide, and DNA fragmentation enzyme immunoassays showed a significant increase in apoptosis 5 h after staurosporine treatment. This was further confirmed with a Klenow fragment of DNA polymerase I assay which primarily detects single-stranded DNA breaks. A significant decrease in mitochondrial metabolism occurred within 8-12 h after treatment. Studies using Trypan Blue exclusion, and lactic dehydrogenase (LDH) release revealed a significant increase in membrane permeability 8 h after staurosporine (0.1 microM) or etoposide (10 microM) treatments. Cleavage of lamin B1, a protein important in maintaining the nuclear envelope integrity was observed 12 h after staurosporine treatment. Our results show that activation of caspase 3 followed by PARP cleavage occur at much earlier time point than any other morphological or biochemical parameters of apoptosis or cytotoxicity.

Use of Dihydroergotamine in Patients with Postconcussion Syndrome

SYNOPSIS

Discharge dispositions, complications, and costs of hospitalization in spinal cord tumor surgery: analysis of data from the United States Nationwide Inpatient Sample, 2003–2010

OBJECT The aim of this study was to analyze the incidence of adverse outcomes and inpatient mortality following resection of intramedullary spinal cord tumors by using the US Nationwide Inpatient Sample (NIS) database. The overall complication rate, length of the hospital stay, and the total cost of hospitalization were also analyzed from the database. METHODS This is a retrospective cohort study conducted using the NIS data from 2003 to 2010. Various patient-related (demographic categories, complications, comorbidities, and median household income) and hospital-related variables (number of beds, high/low case volume, rural/urban location, region, ownership, and teaching status) were analyzed from the database. The adverse discharge disposition, in-hospital mortality, and the higher cost of hospitalization were taken as the dependent variables. RESULTS A total of 15,545 admissions were identified from the NIS database. The mean patient age was 44.84 ± 19.49 years (mean ± SD), and 7938 (52%) of the patients were male. Regarding discharge disposition, 64.1% (n = 9917) of the patients were discharged to home or self-care, and the overall in-hospital mortality rate was 0.46% (n = 71). The mean total charges for hospitalization increased from

Burr-hole versus twist-drill drainage for theevacuation of chronic subdural haematoma:a comparison of clinical results

45,452.24 in 2003 to