11 research outputs found
Delayed Antagonism of Calpain Reduces Excitotoxicity in Cultured Neurons
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Background and Purpose
Glutamate receptor antagonists can produce protection against the neurotoxicity of excessive glutamate stimulation. However, antagonism of the postreceptor processes that produce cell damage may provide a longer window of opportunity for protecting neurons after the initiation of excitotoxic injury. Among various processes that have been thought to mediate the toxic effects of glutamate are activation of the Ca
2+
-dependent proteases calpain I and II and the activation of nitric oxide synthase. We tested the potential for neuroprotection by delayed application of calpain antagonists after excitotoxic treatment.
Methods
Primary cultures of cerebellar and hippocampal neurons were exposed to the glutamate receptor agonists kainate and
N
-methyl-
d
-aspartate (NMDA) for 20-minute periods, and survival was examined by fluorescent assay after 24 hours. Enzyme antagonists were applied at various time points during this interval.
Results
The neurotoxic effects of NMDA in cultured hippocampal neurons and of kainate in cultured cerebellar neurons have been previously shown to be Ca
2+
dependent. Here we show that in both of these examples of glutamate receptor–mediated toxicity, activation of a calpainlike proteolytic activity occurred, which was blocked by the calpain inhibitor MDL-28170. This inhibitor also limited the toxicity, even when applied at times up to 1 hour after the onset of the toxic exposure. Another protease inhibitor, E-64, also blocked the proteolysis and toxicity produced by kainate in cerebellar neurons. Blocking nitric oxide synthase activity after 1 hour with the antagonist
N
G
-nitro-
l
-arginine was also protective of cerebellar and hippocampal neurons, as was the combination of MDL-28170 and
N
G
-nitro-
l
-arginine.
Conclusions
The activation of calpain is among several enzymatic processes that contribute to the toxicity of glutamate receptor stimulation, and blocking these postreceptor mechanisms can be effective in protecting neurons from excitotoxicity at delayed time points.
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Risk of Second Seizure in Pediatric Patients With Idiopathic Autism
No full textPurpose:Epilepsy is a comorbidity of idiopathic autism spectrum disorder. The aim was to characterize the risk and time of second seizure in children with idiopathic autism spectrum disorder.Methods:A retrospective review was performed at the University of Chicago and NorthShore University HealthSystem. Patients with idiopathic autism spectrum disorder, ≥1 seizure, and age 2 to 23 years were included.Results:153 patients were included; 141 (92%) had a second seizure. The average age at first seizure was 7.14 years (median: 5.08 years) and 8.12 years (median: 7.3 years) at second seizure. Average time between first and second seizure was 7.68 months.Discussion:A high risk of seizure recurrence was found in this population. There was a short time to second seizure, with most having a recurrence within 1 year. These findings may be used to guide therapy in children with autism spectrum disorder and epilepsy.</jats:sec
influx induced by β‐amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation
No full textRhythmic intrinsic bursting neurons in human neocortex obtained from pediatric patients with epilepsy
No full textCorpus callosotomy in multistage epilepsy surgery in the pediatric population
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Object
The object of this study was to evaluate surgical outcome in a select group of patients with medically refractory epilepsy who had undergone corpus callosotomy combined with bilateral subdural electroencephalography (EEG) electrode placement as the initial step in multistage epilepsy surgery.
Methods
A retrospective chart review of 18 children (ages 3.5–18 years) with medically refractory symptomatic generalized or localization-related epilepsy was undertaken. A corpus callosotomy with subdural bihemispheric EEG electrode placement was performed as the initial step in multistage epilepsy surgery. All of the patients had tonic and atonic seizures; 6 patients also experienced complex partial seizures. All of the patients had frequent generalized epileptiform discharges as well as multifocal independent epileptiform discharges on surface EEG monitoring. Most of the patients (94%) had either normal (44%) MR imaging studies of the brain or bihemispheric abnormalities (50%). One patient had a suspected unilateral lesion (prominent sylvian fissure).
Results
Of the 18 patients who underwent corpus callosotomy and placement of subdural strips and grids, 12 progressed to further resection based on localizing data obtained during invasive EEG monitoring. The mean patient age was 10.9 years. The duration of invasive monitoring ranged from 3 to 14 days, and the follow-up ranged from 6 to 70 months (mean 35 months). Six (50%) of the 12 patients who had undergone resection had an excellent outcome (Engel Class I or II). There were no permanent neurological deficits or deaths.
Conclusions
The addition of invasive monitoring for patients undergoing corpus callosotomy for medically refractory epilepsy may lead to the localization of surgically amenable seizure foci, targeted resections, and improved seizure outcomes in a select group of patients typically believed to be candidates for palliative surgery alone.</jats:sec
MOESM1 of Modeling Focal Epileptic Activity in the WilsonâCowan Model with Depolarization Block
No full textFull one parameter bifurcation diagrams. (PDF 106 KB
Neuronal Bursting Properties in Focal and Parafocal Regions in Pediatric Neocortical Epilepsy Stratified by Histology
No full textModeling Focal Epileptic Activity in the Wilson-Cowan Model with Depolarization Block
No full textMeasurements of neuronal signals during human seizure activity and evoked epileptic activity in experimental models suggest that, in these pathological states, the individual nerve cells experience an activity driven depolarization block, i.e. they saturate. We examined the effect of such a saturation in the Wilson–Cowan formalism by adapting the nonlinear activation function; we substituted the commonly applied sigmoid for a Gaussian function. We discuss experimental recordings during a seizure that support this substitution. Next we perform a bifurcation analysis on the Wilson–Cowan model with a Gaussian activation function. The main effect is an additional stable equilibrium with high excitatory and low inhibitory activity. Analysis of coupled local networks then shows that such high activity can stay localized or spread. Specifically, in a spatial continuum we show a wavefront with inhibition leading followed by excitatory activity. We relate our model simulations to observations of spreading activity during seizures
Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease
No full textGenome sequencing is a powerful and comprehensive test that detects multiple variants of different types. The interrogation of variants across the genome enables the identification of multiple molecular diagnoses (MMDs) in a single individual. In this retrospective study, we describe individuals in whom MMDs were associated with the proband's indication for testing (IFT), secondary findings, or incidental findings. An MMD is considered where at least one of the findings is associated with the primary IFT and all variants are classified as either likely pathogenic or pathogenic. Clinical genome sequencing was performed for all individuals as part of the iHope program at the Illumina Laboratory Services between September 2017 and December 2023. The iHope cohort included 1,846 affected individuals, with 872 (47.2%) found to have at least one likely pathogenic or pathogenic variant associated with the primary IFT. Of these, 81 (9.3%) individuals had multiple clinically significant molecular findings, including 76 individuals with reported variants associated with 2 different conditions, and 5 individuals with more than 2 molecular findings. A total of 32 individuals (3.7%) had at least 2 molecular diagnoses related to the primary IFT, while in 49 (5.6%) individuals, the variant(s) reported for the second condition constituted a secondary or incidental finding. Our study highlights that among individuals with a likely pathogenic or pathogenic finding identified through genome sequencing, 9% have MMDs, which may have been missed with different testing methods. Of note, approximately 60% of the 81 individuals with an MMD had a potentially actionable secondary or incidental finding
