Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current

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Atención de pacientes adultos con crisis epilépticas en servicios de urgencias (Registro ACESUR). Diferencias en función de la edad ≥ 75 años

ObjectivesTo determine whether there are differences in the profile and in the care of adult patients with epileptic seizures in emergency department according to age ≥ 75 years, and if this is independently associated with results in the emergency department and 30 days after discharge.Material and methodsACESUR is a multicentre, prospective, observational cohort multipurpose register that was carried out in 2017. The distribution of the variables corresponding to the clinical presentation and care according to age ≥ 75 years were compared. Subsequently, logistic regression models were performed with the objective of evaluating the effect of age ≥ 75 years on the outcome variables.ResultsA total of 541 (81.5%) cases younger than 75 years were analysed compared to 123 adult patients (18.5%) of ≥ 75 years or more. In the group of long-lived it was observed significantly greater probability of dependence, co-morbidity, polypharmacy, a previous visit to the hospital emergency department, arrived by ambulance, first seizures and a symptomatic aetiopathogenic classification. In the multivariate analysis, after adjusting for the above variables, it is observed that age > 75 years is associated independently with a higher incidence of specific supplementary tests (OR: 2.31; 95% CI: 1.21-4.44), but not pharmacological intervention (OR: 1.63; 95% CI: 0.96-2.80), or hospitalisation or extended stay in emergency departments (OR: 1.56; 95% CI: 0.94-2.59). On adjusting for all previous variables, age > 75 years is associated with lower incidence of adverse events at 30 days (OR: 0.43; 95% CI: 0.25-0.77).ConclusionsIn the ACESUR Registry, differences in clinical presentation and in the care of patients with seizures in emergency departments were identified when comparing those patients > 75 years with those < 75 years. Age ≥ 75 years is not independently associated with a higher incidence of intervention in emergency departments, or with more adverse outcomes at 30 days after discharge.     

复杂性热性惊厥脑电图特征与癫痫发生的相关性

目的：探讨复杂性热性惊厥脑电图特征与癫痫发生的相关性。方法：2012年3 月到2014 年5 月选择在我院诊治为复杂性热 性惊厥的呼吸道感染患儿86 例作为观察组,同期选择在我院诊治的非热性惊厥的呼吸道感染患儿86 例作为对照组,两组都进 行脑电图监测与认知功能判定,对癫痫发生情况进行判定与分析。结果：观察组的言语智商、行为智商与总智商评分都明显低于 对照组(P<0.05)。观察组的癫痫发生率为9.3 %,脑电图异常率为8.1 %;而对照组的癫痫发生率为1.2 %,脑电图异常率为2.3 %, 对比差异都有统计学意义(P<0.05)。在观察组患儿中,Spearman 相关性分析显示脑电图异常与癫痫发生存在明显正向相关性(r=0. 349,P<0.05)。结论：复杂性热性惊厥伴随有脑电图异常,与癫痫发生存在明显正向相关性,损害患儿的认知功能。     

Two Types of Seizures in Homocysteine Thiolactone-Treated Adult Rats,Behavioral and Electroencephalographic Study

d,l-Homocysteine thiolactone (H), a reactive homocysteine metabolite, contributes to total homocysteine pool. The aim of the present study was to determine the effects of H after acute application in increasing doses to rats. Adult Wistar rat were intraperitoneally administered saline or H in increasing doses (5.5, 8.0, or 11.0 mmol/kg). For electroencephalographic (EEG) recordings, three gold-plated screws were implanted into the skull and animals were supervised. We observed H-induced two types of seizures, the coexistence of convulsive and nonconvulsive epilepsy. Dose-related increase in the number and severity (0–4) of displaying convulsions was recorded. In H_5.5 group, the majority of seizure episodes were grade 1 (62.5 and 0% lethality), in H₈ 40% grade 2, and in H₁₁ grade 4 in 42.11% (100% lethal outcome). EEGs recordings in convulsive animals showed a high-voltage spike-wave and polyspikes complexes. The second, absence-like, nonconvulsive seizures were accompanied by the EEGs mostly with 6–8 Hz spikes-and-wave discharges (SWD). Latency time to the generalized clonic-tonic seizures overlapped with the time of the maximal median number and median duration of the SWD per 15 min during 90-min observing period. The results show that acute H administration significantly changes neurons, EEG tracings, and behavioral responses and suggests a possible model for studying petit mal epilepsy.     

Is antiquitin a mitochondrial Enzyme?

Antiquitin is an aldehyde dehydrogenase involved in the catabolism of lysine. Mutations of antiquitin have been linked with the disease pyridoxine‐dependent seizures. While it is well established that lysine metabolism takes place in the mitochondrial matrix, evidence for the mitochondrial localization of antiquitin has been lacking. In the present study, the subcellular localization of antiquitin was investigated using human embryonic kidney HEK293 cells. Three different approaches were used. First, confocal microscopic analysis was carried out on cells transiently transfected with fusion constructs containing enhanced green fluorescent protein with different lengths of antiquitin based on the different potential start codons of translation. Second, immunofluorescence staining was used to detect the localization of antiquitin directly in the cells. Third, subcellular fractionation was carried out and the individual fraction was analyzed for the presence of antiquitin by Western blot and flow cytometric analyses. All the results showed that antiquitin was present not only in the cytosol but also in the mitochondria. J. Cell. Biochem. 109: 74–81, 2010. © 2009 Wiley‐Liss, Inc.     

Novel symptomatology and changing epidemiology of domoic acid toxicosis in California sea lions (Zalophus californianus): an increasing risk to marine mammal health

Harmful algal blooms are increasing worldwide, including those of Pseudo-nitzschia spp. producing domoic acid off the California coast. This neurotoxin was first shown to cause mortality of marine mammals in 1998. A decade of monitoring California sea lion (Zalophus californianus) health since then has indicated that changes in the symptomatology and epidemiology of domoic acid toxicosis in this species are associated with the increase in toxigenic blooms. Two separate clinical syndromes now exist: acute domoic acid toxicosis as has been previously documented, and a second novel neurological syndrome characterized by epilepsy described here associated with chronic consequences of previous sub-lethal exposure to the toxin. This study indicates that domoic acid causes chronic damage to California sea lions and that these health effects are increasing.     

A putative disease-associated haplotype within the SCN1A gene in Dravet syndrome

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is one of the most severe forms of childhood epilepsy. DS is caused by a mutation in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A). However, 25–30% of patients with DS are negative for the SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Recently, the first case of DS caused by a mutation in the neuronal voltage-gated sodium-channel beta-subunit gene (SCN1B) was also reported. In this report we aim to make the molecular analysis of the SCN1A and SCN1B genes in two Tunisian patients affected with DS. The SCN1A and SCN1B genes were tested for mutations by direct sequencing. No mutation was revealed in the SCN1A and SCN1B genes by sequencing analyses. On the other hand, 11 known single nucleotide polymorphisms were identified in the SCN1A gene and composed a putative disease-associated haplotype in patients with DS phenotype. One of the two patients with putative disease-associated haplotype in SCN1A had also one known single nucleotide polymorphism in the SCN1B gene. The sequencing analyses of the SCN1A gene revealed the presence of a putative disease-associated haplotype in two patients affected with Dravet syndrome.     

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re‐filling the tricarboxylic acid (TCA) cycle with C4‐intermediates (anaplerosis). Here, we injected mice with [1,2‐¹³C]glucose 3.5–4 weeks after pilocarpine‐induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of ¹³C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two ¹³C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control‐fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin‐fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin‐fed SE mice showed few changes in most other metabolite levels and their ¹³C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3‐¹³C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C‐4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl‐CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.