Summary: Ruc~ltgroiintl:The purpose of ncuroiniaging of a patient with new onset of seizures is to demonstrate cause and explore thc prognosis. It was recently recommended that eincrgcncy brain coinputcd tomography (CT) be performed only in adult seizure patients with an increased likelihood of lifethreatening lesions, i.c., those with new focal deficits, persistent altcred mental status, lever, recent trauma, persistent headaches, history of cancer, history of anticoagulation, or suspicion of acquired immunodcl'iciency syndrome. The objective of this study was to determine the diagnostic utility of emergency brain CT in children who present to (he emergency deparlment with new onset of seizures.Methods: A I -year retrospective chart review of all children who presented lo thc emergency department of the Schneidcr Children's Hospital with a new onset of seizures and who underwent CT of the brain, excluding children with simple febrile scimrcs.Kesiilts: Sixty-six patients, 34 boys and 32 girls with a mean age of 4.9 years, qualified for inclusion in the study. Fifty-two patients (78.8%) had normal C T results and 14 patients (21.2%) had abnormal CT results. Seizure cause was considered cryplogenic i n 33 patients, of whoin 2 (6%) had abnormal CT results; ncither patient required intervention. Seizure cause was considered symptomatic in 20 patients, of' whom I2 (60%~) had abnormal CT results (p < 0.0001). In two patients with abnormal CT scans (both acutc symptomatic), the imaging findings were of immediate therapeutic significance and were predictable from the clinical history and the physcial examination. None of the 13 patienls with complex febrile seizure ciiusc had an abnormal CT scan. Patients with partial convulsive seizures were more likely to have abnormal CT scans than paticnts with generalized convulsive seizures, but the difference was not statistically significant.Conclusions: The routine practice in many pediatric emcrgency departments of obtaining brain CT scans for all patients with ncw onset of nonfebrile seizures is un.justified. History and physical examination are sufficient to identify those patients for whom such studies arc likely to be appropriate. Emergent CT is not indicated for patients with no known seizure risk factors, normal neurological examinations, no acutc symptomatic cause other than fever, and reliable neurological follow-up. For these patients, referral to a pediatric neurologist I'or further workup, including electroencephalography and the more diagnostically valuable magnetic resonance iinaging, would be more appropriate. Key Words: Seizure diagnosis-CT scanEmergency department.Adults and children presenting to emergency departments (EDs) with a new onset of seizures are often evaluated with computed tomography (CT) ( 1-4). Previous neuroradiological studies have demonstrated that approximately one-third of children with epilepsy have CT abnormalities (5-7); however, fewer than 3% of these

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Abstract.Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin ( 2 p~) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32%, respectively: this was not significantly different. Lovastatin (10 p~) reduced [methyl 'HI-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 p~) but cholesterol (10-40 pgml-l) had no effect. Isopentenyl adenine (25-50 p~) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 p~) , but farnesol (20 p~) , another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia. dentate gyrus | spine | glutamatergic transmission | AMPA receptors | schizophrenia S chizophrenia is a disabling psychiatric disorder that affects 1% of the general population. It is thought to be a neurodevelopment disorder, as many symptoms appear or worsen during adolescence, a time of great transition and refinements in brain structure and function (1, 2). Consequently, patients display characteristic positive symptoms including delusions and hallucinations, negative symptoms including abnormal emotional reactivity and anhedonia and cognitive deficits. Underlying pathophysiological mechanisms have been explored extensively. The medial temporal lobe, including hippocampal dentate gyrus (DG), is thought to be involved in mediating aspects of psychosis and memory deficits in schizophrenia (3, 4). Impaired glutamatergic transmission in DG causes deficits in spatial coding, learning, and memory and emotion processing (5-7). However, detailed molecular mechanisms of DG dysfunction in schizophrenia remain unclear.Identification of risk genes in recent genetic studies has contributed to a better understanding of pathophysiological mechanisms of schizophrenia. Transmembrane protein 108 (TMEM108) has recently been linked with schizophrenia and alcoholism in genome-wide association studies (8, 9). In human, TMEM108 is located on chromosome 3q21-q22, a risk locus for bipolar disorder, schizophrenia and other psychosis (10, 11). In particular, an intronic single nucleotide polymorphism (SNP) (rs7624858) is associated with schizophrenia (8). These findings raise an important question regarding the physiological function of TMEM108 a...

Background and Purpose: Modern management of acute stroke necessitates early diagnosis. To this end, we sought to delineate the radiographic features of focal hemispheric infarction within 5 hours of ictus.Methods: Fifty patients, ages 54-79, with ischemic strokes productive of at least hemiparesis underwent computed tomographic scanning and cerebral angiography (n=38) or carotid ultrasound (n=12). Radiographic lesions were characterized for location, size, and pathophysiology.Results: Acute abnormalities, hypodensity, and mass effect were seen in 56% of scans and confirmed on a second scan 5-7 days later. Intracranial angiographic abnormalities occurred in 61% of patients: arterial occlusions in 45% and delayed arterial filling in 16%. Hemorrhagic infarctions occurred in 26% of second scans and were associated with mass effect (100%) and arterial occlusions (89%). Infarcts with hemorrhagic transformation were larger on both scans than those without (p=0.001). Of four patients with infarctions in watershed territories on the scans, two had middle cerebral artery occlusions on angiography, thereby questioning the specificity of such scan lesions to low-flow states.Conclusions: We conclude that cerebral infarctions are often visible on early scans, but their locations may not be etiologically determinative. The infarcts associated with intracranial arterial occlusions (45%) were of thromboembolic origin, but, given current controversies as to the pathophysiology of lacunar and watershed infarctions, we cannot ascertain the etiology in the remainder. These findings are relevant to the new stroke therapies that require administration in the first hours after infarction. (Stroke 1991^2:1245-1253)

Burkholderia pseudomallei is an emerging bacterial pathogen and category B biothreat. Human infections with B. pseudomallei (called melioidosis) present as a range of manifestations, including acute septicemia and pneumonia. Although melioidosis can be fatal, little is known about the molecular basis of B. pseudomallei pathogenicity, in part because of the lack of simple, genetically tractable eukaryotic models to facilitate en masse identification of virulence determinants or explore host-pathogen interactions. Two assays, one highthroughput and one quantitative, were developed to monitor levels of resistance of B. pseudomallei and the closely related nearly avirulent species Burkholderia thailandensis to predation by the phagocytic amoeba Dictyostelium discoideum. The quantitative assay showed that levels of resistance to, and survival within, amoeba by these bacteria and their known virulence mutants correlate well with their published levels of virulence in animals. Using the high-throughput assay, we screened a 1,500-member B. thailandensis transposon mutant library and identified 13 genes involved in resistance to predation by D. discoideum. Orthologs of these genes were disrupted in B. pseudomallei, and nearly all mutants had similarly decreased resistance to predation by D. discoideum. For some mutants, decreased resistance also correlated with reduced survival in and cytotoxicity toward macrophages, as well as attenuated virulence in mice. These observations suggest that some factors required by B. pseudomallei for resistance to environmental phagocytes also aid in resistance to phagocytic immune cells and contribute to disease in animals. Thus, D. discoideum provides a novel, highthroughput model system for facilitating inquiry into B. pseudomallei virulence.Burkholderia pseudomallei is a betaproteobacterium and causative agent of melioidosis in humans. B. pseudomallei infections are most common in Southeast Asia and Northern Australia, where melioidosis is endemic (13), and typically result from contact with contaminated soil and water after wounding or inhalation (12,13,33,65). Disease onset can be rapid or sometimes after a latency of years (42, 46), with clinical manifestations ranging from localized dermal lesions and soft tissue abscesses to acute septicemia and pneumonia. Due to its prevalence in soils in areas of Thailand, high infectivity, and the fact that melioidosis can be fatal even with antibiotic therapy (13), B. pseudomallei is considered a biothreat agent and as such is designated a category B select agent restricted to biosafety level 3 (BSL-3) by the Centers for Disease Control and Prevention (53).Despite its medical significance and biosecurity implications, relatively few molecular details exist regarding factors contributing to the heightened infectivity and lethality of B. pseudomallei relative to other bacterial pathogens. The majority of validated B. pseudomallei virulence factors are those which are conserved in other pathogens, e.g., exopolysaccharide capsule (3, 16, 51), lip...

Thrombospondin-1 is a large matricellular protein that acts as a pleiotropic growth factor for human vascular smooth muscle cells, and may play a role in the progression of vascular disease. Although we have previously demonstrated the dependence of both thrombospondin-1-stimulated cell chemotaxis and proliferation on tyrosine kinases, the receptor mechanisms involved remain obscure. This investigation aims to determine the nature of the receptor(s) involved in the cellular responses to thrombospondin-1. Cellular signals were identified by western blotting following cell stimulation, while cellular responses were assessed by measuring DNA synthesis and chemotaxis. These data demonstrate that thrombospondin-1-induced cell chemotaxis can be inhibited by a peptide containing the Arg-Gly-Asp motif, a function-blocking αvβ3 antibody, a function-blocking integrin-associated protein (IAP) antibody and pertussis toxin, while thrombospondin-1-stimulated DNA synthesis is inhibited by a function-blocking α3β1 antibody. Similarly the Arg-Gly-Asp-containing peptide inhibits tyrosine phosphorylation of focal adhesion kinase and the p85 regulatory subunit of phosphatidylinositol 3-kinase, but does not significantly affect tyrosine phosphorylation, or activation, of extracellular-regulated kinase. These data suggest that soluble thrombospondin-1 interacts with human vascular smooth muscle cells via two independent and separable receptor-binding sites, to differentially stimulate cell chemotaxis and DNA synthesis.

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