Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and upregulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inf lammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-D-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A 2 (PLA 2 ) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA 2 inhibitors preserved the wave propagation. NBQX, an ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid͞kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COXinhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, N G -nitro-L-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptors and PLA 2 , most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.

which has the only neurological emergency room with 24/7 service in a catchment area of 1.5 million inhabitants. We retrospectively analyzed all consecutive primary Background and Purpose-Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients.

No abstract

Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods:We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype.Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency ,0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D1R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients.Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully. TLR3 is one of the most highly conserved TLRs in humans that have evolved under the strongest purifying selection.1 TLR3 recognizes double-stranded RNA (dsRNA), a by-product produced during the viral replication of most viruses, including herpes simplex virus 1 (HSV-1).2 The most common known clinical consequence of human TLR3 deficiency is childhood herpes simplex encephalitis (HSE). Childhood HSE is a rare life-threatening complication of primary infection with HSV-1, a common neurotropic dsDNA virus that is innocuous in most children.3 HSE is the most common form of sporadic viral encephalitis in Western countries. 4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or

Background and Purpose-More effective imaging methods are needed to overcome the limitations of CT in the investigation of treatments for acute ischemic stroke. Diffusion-weighted MRI (DWI) is sensitive in detecting infarcted brain tissue, whereas perfusion-weighted MRI (PWI) can detect brain perfusion in the same imaging session. Combining these methods may help in identifying the ischemic penumbra, which is an important concept in the hemodynamics of acute stroke. The purpose of this study was to determine whether combined DWI and PWI in acute (Ͻ24 hours) ischemic stroke can predict infarct growth and final size. Methods-Forty-six patients with acute ischemic stroke underwent DWI and PWI on days 1, 2, and 8. No patient received thrombolysis. Twenty-three patients underwent single-photon emission CT in the acute phase. Lesion volumes were measured from DWI, SPECT, and maps of relative cerebral blood flow calculated from PWI. Results-The mean volume of infarcted tissue detected by DWI increased from 46.1 to 75.6 cm 3 between days 1 and 2 (PϽ0.001; nϭ46) and to 78.5 cm 3 after 1 week (PϽ0.001; nϭ42). The perfusion-diffusion mismatch correlated with infarct growth (rϭ0.699, PϽ0.001).

Nineteen patients with acute ischemic stroke (<24 hours) underwent diffusion-weighted and perfusion-weighted (PWI) magnetic resonance imaging at the acute stage and 1 week later. Eleven patients also underwent technetium-99m ethyl cysteinate dimer single-photon emission computed tomography (SPECT) at the acute stage. Relative (ischemic vs. contralateral control) cerebral blood flow (relCBF), relative cerebral blood volume, and relative mean transit time were measured in the ischemic core, in the area of infarct growth, and in the eventually viable ischemic tissue on PWI maps. The relCBF was also measured from SPECT. There was a curvilinear relationship between the relCBF measured from PWI and SPECT (r = 0.854; P < 0.001). The tissue proceeding to infarction during the follow-up had significantly lower initial CBF and cerebral blood volume values on PWI maps (P < 0.001) than the eventually viable ischemic tissue had. The best value for discriminating the area of infarct growth from the eventually viable ischemic tissue was 48% for PWI relCBF and 87% for PWI relative cerebral blood volume. Combined diffusion and perfusion-weighted imaging enables one to detect hemodynamically different subregions inside the initial perfusion abnormality. Tissue survival may be different in these subregions and may be predicted.

Excessive alcohol consumption alters neuronal growth and causes striking elongation of axons and dendrites in several brain regions. This could result from increased sensitivity to neurotrophic factors, since ethanol markedly enhances nerve growth factor (NGF)-and basic fibroblast growth factor (bFGF)-stimulated neurite outgrowth in the neural cell line PC12. The mechanism by which ethanol enhances growth factor responses was investigated by examining activation of mitogen-activated protein kinases (MAP kinases), a key event in growth factor signaling. Ethanol (100 mM) increased NGF-and bFGF-induced activation of MAP kinases. This increase, like ethanol-induced increases in neurite outgrowth, was prevented by down regulation of .3, 6, and E protein kinase C (PKC) isozymes. Since chronic ethanol exposure specifically upregulates 6 and E PKC, these findings suggest that ethanol promotes neurite growth by enhancing growth factor signal transduction through a a or E PKC-regulated pathway.Medical complications of alcohol abuse contribute to more than 20% of hospital admissions in the United States (1). Several neurological disorders are associated with alcoholism and many appear to result from a direct neurotoxic effect of alcohol (2). One mechanism by which alcohol injures the nervous system is by altering the growth of axons and dendrites (neurites). Although early studies showed that ethanol inhibited neurite growth in some neurons (3, 4), several reports (5-10) indicate that ethanol markedly enhances neurite growth in several brain regions. For example, in adult rats, chronic ethanol exposure increases the length of dendrites in cerebellar Purkinje cells and hippocampal dentate granule cells and the number of dendritic spines on dentate granule cells and somatosensory cortical neurons (5-8). Prenatal ethanol exposure increases dendritic arborization in layer Vb somatosensory corticospinal neurons and causes hyperdevelopment of hippocampal dentate granule cell axons (9, 10). Ethanol also enhances neurite outgrowth in cultured cerebellar neurons (11) and in PC12 cells treated with nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) (12, 13). Increases in neurite length could disturb neuronal function by delaying nerve conduction and by interfering with remodeling of neurites and synapses during development and learning.We have used PC12 cells as a model system to study mechanisms by which ethanol alters neurite outgrowth. We previously reported that enhancement of NGF-induced neurite outgrowth by ethanol was inhibited by downregulation of ,B, 6, and s isoforms of protein kinase C (PKC) (14). We also found that exposure to 25-100 mM ethanol for 2-6 days increased levels of mRNA (15) and protein (16) for 8 and s PKC and activated PKC in PC12 cells (16). Taken together, these findings suggest that ethanol enhances neurite formation by activating specific isozymes of PKC.One mechanism by which ethanol and PKC could modulate NGF-induced neurite outgrowth is by altering NGF signal transduction. A k...