Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The semi-benign nature of diffuse astrocytomas is characterized by an increased risk for tumor recurrence and malignant transformation. In patients with intractable seizures, however, length of history and clinical follow-up studies indicate a better prognosis of this tumor entity. Here, we present a clinico-neuropathological study of 19 patients with chronic seizures and diffuse astrocytomas. In 6 patients, long-term survival and lack of tumor progression after a maximal follow-up time of 13 years appeared to correlate with a histologically isomorphic phenotype. Cytological hallmarks comprise low cellularity, lack of mitotic activity and highly differentiated astroglial elements infiltrating into adjacent brain parenchyma. Compared to "classical" variants of diffuse astrocytomas (WHO grade II), immunohistochemical reactions revealed a cellular proliferation below 1%, absence of nuclear p53 accumulation, and a lack of glial MAP2 and CD34 expression. Histopathologically, the isomorphic astrocytoma subtype can be distinguished from gangliogliomas, pilocytic astrocytomas and dysembryoplastic neuroepithelial tumors as well as from cortical dysplasia or reactive gliosis. Our data support the concept of a rare variant of diffuse astrocytomas occurring in young adults with long-term epilepsy and a favorable prognosis, which corresponds to WHO grade I.
 ...
PMID:An isomorphic subtype of long-term epilepsy-associated astrocytomas associated with benign prognosis. 1503 26

Death-associated protein (DAP) kinase is a novel regulator of cell death whose in vivo target(s) and role in neuronal cell death remain uncertain. Since DAP kinase has been implicated in p53-mediated apoptosis, a pathway activated following epileptic brain injury, we examined the relationship between DAP kinase and p53 following seizures. Rats underwent brief (40-min) seizures evoked by intraamygdala kainic acid, which caused the death of ipsilateral CA3 neurons while preserving the contralateral CA3 subfield. Seizures caused a small decline in levels of the approximately 160-kD DAP kinase within injured ipsilateral hippocampus, commensurate with the appearance of an approximately 60-kD fragment, and proteolysis of the p53 inhibitor, murine double minute gene 2 (MDM2). Expression of p53 increased within the ipsilateral hippocampus, and DAP kinase was detected within p53 immunoprecipitates. In contrast, DAP kinase and MDM2 were not proteolyzed within the seizure damage-resistant contralateral hippocampus. Furthermore, DAP kinase and p53 did not interact within the contralateral hippocampus, and p53 cellular localization redistributed from the nucleus to cytoplasm commensurate with p53 proteolysis. These data suggest that DAP kinase may be involved in the p53 pathway during seizure-induced neuronal death.
 ...
PMID:Expression, interaction, and proteolysis of death-associated protein kinase and p53 within vulnerable and resistant hippocampal subfields following seizures. 1513 32

Malignant gliomas arise from two distinct pathways, as de novo lesions or from secondary transformation from low-grade lesions. Herein, we describe the cases of two patients to illustrate the proposition that de novo malignant gliomas can originate as non-enhancing tumors and rapidly progress to a pattern of ring enhancement characteristic of a glioblastoma. Both patients presented with new-onset seizures (simple partial and generalized). Their neurological examinations were unremarkable. Initial MRI evaluations revealed a right precentral gyrus and right medial temporal lobe lesions in each case, respectively. These lesions demonstrated increased T2 signal changes without contrast enhancement. The biopsy of the right frontal lesion in the first patient was consistent with an anaplastic astrocytoma; the second patient was followed expectantly. Repeat MRI for both patients within 17 weeks disclosed ring-enhancing lesions, consistent with an unusually rapid evolution to glioblastoma multiforme (GBM). Subsequent resection of the right medial temporal lesion in the second patient revealed a GBM. Neither tumor displayed abnormal overexpression of P53 by immunohistochemistry. Early MRI of de novo glioblastomas may demonstrate a non-enhancing tumor suggestive of a low-grade lesion. These tumors can rapidly evolve into ring-enhancing lesions more consistent with the traditional imaging findings.
 ...
PMID:Non-enhancing de novo glioblastoma: report of two cases. 1544 98

Cerebral cavernous malformations (CCM) consist of clusters of abnormally dilated blood vessels. Hemorrhaging of these lesions can cause seizures and lethal stroke. Three loci are associated with autosomal dominant CCM, and the causative genes have been identified for CCM1 and CCM2. We have generated mice with a targeted mutation of the Ccm1 gene, but an initial survey of 20 heterozygous mice failed to detect any cavernous malformations. To test the hypothesis that growth of cavernous malformations depends on somatic loss of heterozygosity at the Ccm1 locus, we bred animals that were heterozygous for the Ccm1 mutation and homozygous for loss of the tumor suppressor Trp53 (p53), which has been shown to increase the rate of somatic mutation. We observed vascular lesions in the brains of 55% of the double-mutant animals but none in littermates with other genotypes. Although the genetic evidence suggested somatic mutation of the wild-type Ccm1 allele, we were unable to demonstrate loss of heterozygosity by molecular methods. An alternative explanation is that p53 plays a direct role in formation of the vascular malformations. The striking similarity of the human and mouse lesions indicates that the Ccm1(+/-) Trp53(-/-) mice are an appropriate animal model of CCM.
 ...
PMID:Loss of p53 sensitizes mice with a mutation in Ccm1 (KRIT1) to development of cerebral vascular malformations. 1550 22

We evaluated the expression of DNA repair proteins, redox factor-1 (Ref-1) and X-ray repair cross-complementing protein 1 (XRCC1), relevant to neurodegeneration following kainic acid-induced seizures in rats. Neurons with oxidative DNA damage exhibited increased expression and colocalization of Ref-1 and XRCC1. Upregulation of DNA repair proteins was also associated with p53 induction and TUNEL. Coexpression of DNA repair proteins and cell death markers following seizures suggests that the DNA repair response may not be sufficient to prevent excitotoxin-induced neurodegeneration.
 ...
PMID:Induction of DNA repair proteins, Ref-1 and XRCC1, in adult rat brain following kainic acid-induced seizures. 1585 96

To evaluate the role of molecular genetics in the routine clinic, we investigated allelic imbalance at 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in 100 oligodendroglial neoplasms diagnosed at a single treatment center between 2000 and 2003. The -1p/-19q genotype, seen in 64, 34, 77, and 30% of OII, OAII, OIII, and OAIII respectively, was inversely related to p53 mutation and 17p13 loss. Genotype was unrelated to tumor location and could not distinguish high-grade tumors that presented de novo from those that progressed from a previous lower grade malignancy. Presentation with seizures was more common in cases with the -1p/-19q genotype, and these remained stable for longer before treatment. In longitudinal samples, 74% retained their initial histological differentiation, whereas 29% showed new genetic alterations, the -1p/-19q genotype being acquired in three cases. Loss of 1p36 and 19q13, 17p13, chromosome 10, and p53 mutation were significantly associated with survival from presentation in Kaplan-Meier analysis (p < 0.01), and loss of 1p36 and 19q13 and loss of 17p13 retained significance in multivariate analysis. In this recently diagnosed unselected series, clinical differences in tumors with and without the -1p/-19q genotype support a genetic approach to aid diagnosis and prognostication for oligodendroglial neoplasms.
 ...
PMID:Molecular pathology and clinical characteristics of oligodendroglial neoplasms. 1592 38

15-Deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2), a dehydration product of prostaglandin D2, is an important pharmacological molecule, which with the virtue of its electrophilicity, has been reported to covalently modify some cellular proteins (such as nuclear factor-kappa B (NF-kappaB), AP-1, p53, and thioredoxin) and elicit its physiological effects. The aim of the present computational study is to understand the role molecular recognition plays in the association of 15d-PGJ2 with NF-kappaB and other proteins. Another aim is to characterize whether p53 is a direct target for covalent modification by 15d-PGJ2. A docking strategy is applied along with calculation of ab initio electrostatic potential maps to analyze the mode of binding of prostaglandin molecule with critical cysteine-containing sites in each protein. The results provide identification of important sites in the target proteins, which provide recognition and stability to the prostaglandin molecule. Fit of shape and complementarity of electrostatic interactions are derived as significant determinants of molecular recognition of 15d-PGJ2. Further, comparative results indicate that p53 protein may also be a target for direct modification by 15d-PGJ2. The molecular models obtained should allow the rational design of more specific analogs of 15d-PGJ2.
 ...
PMID:Molecular recognition of 15-deoxy-delta(12,14)-prostaglandin J2 by nuclear factor-kappa B and other cellular proteins. 1600 25

The organophosphorus compound soman, an irreversible inhibitor of cholinesterases, produces seizure activity and related brain damage. Studies using various biochemical markers of programmed cell death (PCD) suggested that soman-induced cell damage in the brain was apoptotic rather than necrotic. However, it has recently become clear that not all PCD is apoptotic, and the unequivocal demonstration of apoptosis requires ultrastructural examination. Therefore, the present study was undertaken to reinvestigate the damage produced in the brains of mice sacrificed at various times within the first 24 h or at 7 days after a convulsive dose of soman. Classical histology and ultrastructural examination were performed. The immunohistochemical expression of proteins (p53, Bax) involved in PCD, DNA fragmentation (TUNEL method at light and electron microscopy levels) and the glial reaction were also explored. Our study confirms that the severity of lesions depended on the duration of convulsions and shows that cerebral changes were still occurring as late as 7 days after the onset of long-lasting convulsions. Our observations also establish that there was a large variety of ultrastructurally distinct types of cell damage, including hybrid forms between apoptosis and necrosis, but that pure apoptosis was very rare. A prominent expression of p53 and Bax proteins was detected indicating that PCD mechanisms were certainly involved in the morphologically diverse forms of cell death. Since purely apoptotic cells were very rare, these protein expressions were presumably involved either in nonapoptotic cell death mechanisms or in apoptotic mechanisms occurring in parallel with nonapoptotic ones. Moreover, evidence for DNA fragmentation by the TUNEL method was found in apoptotic but also in numerous other morphotypes of cell damage. Therefore, TUNEL-positivity and the expression of PCD-related proteins, in the absence of ultrastructural confirmation, were here shown not to provide proof of apoptosis. In soman poisoning as well as in other cerebral pathologies, premature conclusions on this question can potentially be misleading and might even lead to detrimental therapies.
 ...
PMID:Soman-induced convulsions: the neuropathology revisited. 1605 42

DNA repair plays a critical, but imprecisely defined role in excitotoxic injury and neuronal survival throughout adulthood. We utilized an excitotoxic injury model to compare the location and phenotype of degenerating neurons in mice (strain 129-C57BL) deficient in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), an enzyme required for nonhomologous end joining (NHEJ). Brains from untreated adult heterozygous and DNA-PKcs null mice displayed comparable cytoarchitecture and undetectable levels of cell death. By day 1, and extending through 4 days following kainic acid-induced seizures, brains from DNA-PKcs null mice showed widespread neurodegeneration that encompassed the entire hippocampal CA1-CA3 pyramidal cell layer, entorhinal cortex, and lateral septum, with relative sparing of the dentate gyrus granule cell layer and hilus, as judged by toluidine blue, Fluoro-Jade B, and terminal dUTP nick end labeling staining. In contrast, seizure-related neurodegeneration in heterozygous littermates was limited to the CA3 region of the hippocampus. NeuN and calbindin staining revealed a selective decrease in the number and density of NeuN-positive neurons in the pyramidal layers of degenerating regions in both heterozygous and DNA-PKcs null mice. To elucidate the mechanisms leading to cell death, we examined an involvement of the p53 pathway, known to be induced by DNA damage. Addition of pifithrin-alpha, a p53 inhibitor, or expression of a dominant-negative p53 rescued neurons from kainate-induced excitotoxic cell death in primary cortical cultures derived from wildtype, DNA-PKcs heterozygous, or DNA-PKcs null neonatal mice. Moreover, pifithrin-alpha prevented kainate-induced loss of mitochondrial membrane potential, dendrite degeneration, and cell death. Results suggest that NHEJ plays a neuroprotective role in excitotoxicity, within the perforant, Schaffer collateral, hippocampal-septal, and temperoammonic pathways, in part by repairing DNA damage that would otherwise result in activation of a p53-dependent apoptotic cascade.
 ...
PMID:DNA damage and nonhomologous end joining in excitotoxicity: neuroprotective role of DNA-PKcs in kainic acid-induced seizures. 1621 17

Several genes have been implicated as influencing the outcome following traumatic brain injury (TBI). Currently the most extensively studied gene has been APOE. APOE can influence overall and rehabilitation outcome, coma recovery, risk of posttraumatic seizures, as well as cognitive and behavioral functions following TBI. Pathologically, APOE is associated with increased amyloid deposition, amyloid angiopathy, larger intracranial hematomas and more severe contusional injury. The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition, disruption of cytoskeletal stability, cholinergic dysfunction, oxidative stress, neuroprotection and central nervous system plasticity in response to injury. Other putative genes have been less extensively studied and require replication of the clinical findings. The COMT and DRD2 genes may influence dopamine dependent cognitive processes such as executive/frontal lobe functions. Inflammation which is a prominent component in the pathophysiological cascade initiated by TBI, is in part is mediated by the interleukin genes, while apoptosis that occurs as a consequence of TBI may be modulated by polymorphisms of the p53 gene. The ACE gene may affect TBI outcome via mechanisms of cerebral blood flow and/or autoregulation and the CACNA1A gene may exert an influence via the calcium channel and its effect on delayed cerebral edema. Although several potential genes that may influence outcome following TBI have been identified, future investigations are needed to validate these genetic studies and identify new genes that might influence outcome following TBI.
 ...
PMID:Genetic influences on outcome following traumatic brain injury. 1734 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>