Loss of neuronal network resilience precedes seizures and determines the ictogenic nature of interictal synaptic perturbations

The mechanisms of seizure emergence, and the role of brief interictal epileptiform discharges (IEDs) in seizure generation are two of the most important unresolved issues in modern epilepsy research. Our study shows that the transition to seizure is not a sudden phenomenon,but a slow process characterized by the progressive loss of neuronal network resilience. From a dynamical perspective, the slow transition is governed by the principles of critical slowing, a robust natural phenomenon observable in systems characterized by transitions between dynamical regimes. In epilepsy, this process is modulated by the synchronous synaptic input from IEDs. IEDs are external perturbations that produce phasic changes in the slow transition process and exert opposing effects on the dynamics of a seizure-generating network, causing either anti-seizure or pro-seizure effects. We show that the multifaceted nature of IEDs is defined by the dynamical state of the network at the moment of the discharge occurrence

Activation of either the ETA or the ETB receptors is involved in the development of electrographic seizures following intrahippocampal infusion of the endothelin-1 in immature rats

The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40pmol/\u3bcl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70nmol/\u3bcl) or ETB receptors (BQ788; 70nmol/1\u3bcl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40pmol/1\u3bcl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10mM PBS or 0.01% DMSO-PBS solution; pH7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptor antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizure duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET-1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures following the application of ET-1 in immature rats. The dissociation between the ischemic-producing and seizure-producing processes suggests that damage is not necessary to induce seizures, although it may exacerbate them

A single reference measurement can predict liver tumor motion during respiration

AimTo evaluate liver tumor motion and how well reference measurement predicts motion during treatment.Material and methodsThis retrospective study included 20 patients with colorectal cancer that had metastasized to the liver who were treated with stereotactic ablative radiotherapy. An online respiratory tumor tracking system was used. Tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were collected to generate patient-specific margins. Reference margins were generated as the mean motion and 95th percentile of motion from measurements recorded for different lengths of time (1, 3, and 5[[ce:hsp sp="0.25"/]]min). We analyzed the predictability of tumor motion in each axis, based on the reference measurement and intra-/interfraction motions.ResultsAbout 96,000 amplitudes were analyzed. The mean tumor motions were 9.9[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]4.2[[ce:hsp sp="0.25"/]]mm, 2.6[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]0.8[[ce:hsp sp="0.25"/]]mm, and 4.5[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]1.8[[ce:hsp sp="0.25"/]]mm in the SI, LL, and AP directions, respectively. The intrafraction variations were 3.5[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]1.8[[ce:hsp sp="0.25"/]]mm, 0.63[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]0.35[[ce:hsp sp="0.25"/]]mm, and 1.4[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]0.65[[ce:hsp sp="0.25"/]]mm for the SI, LL, and AP directions, respectively. The interfraction motion variations were 1.32[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]0.79[[ce:hsp sp="0.25"/]]mm, 0.31[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]0.23[[ce:hsp sp="0.25"/]]mm, and 0.68[[ce:hsp sp="0.25"/]]±[[ce:hsp sp="0.25"/]]0.62[[ce:hsp sp="0.25"/]]mm for the SI, LL, and AP directions, respectively. The Pearson's correlation coefficients for margins based on the reference measurement (mean motion or 95th percentile) and margins covering 95% of the motion during the whole treatment were 0.8–0.91, 0.57–0.7, and 0.77–0.82 in the SI, LL, and AP directions, respectively.ConclusionLiver tumor motion in the SI direction can be adequately represented by the mean tumor motion amplitude generated from a single 1[[ce:hsp sp="0.25"/]]min reference measurement. Longer reference measurements did not improve results for patients who were well-educated about the importance of regular breathing. Although the study was based on tumor tracking data, the results are useful for ITV delineation when tumor tracking is not available

Cardiac Radiosurgery for Malignant Ventricular Tachycardia

Abstract Ventricular tachycardia is a frequent cause of mortality after myocardial infarction. Current treatment includes the implantation of cardioverter defibrillators and adjunctive therapies such as catheter ablation or cardiac surgery. In patients where standard treatment fails, preclinical data showed that radiosurgery ablation of the ectopic substrate might be a viable option. Authors present a case report of cardiac radiosurgery in a patient with malignant ventricular tachycardia. Stereotactic radiosurgery system CyberKnife was used; the applied dose was 25 Gy in one fraction. Within the follow-up period of 120 days, no signs of toxicity were noted no episode of malignant arrhythmia has been detected. This case report demonstrates that stereotactic radiosurgery of recurrent ventricular tachycardia after inefficient catheter ablation might be a viable option for patients unsuitable for cardiosurgical intervention. Further research on this topic is highly warranted

mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus

Background!#!Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy.!##!Methods!#!At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18).!##!Results!#!Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3).!##!Conclusions!#!These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies

Dosimetric comparison of MRI-based HDR brachytherapy and stereotactic radiotherapy in patients with advanced cervical cancer: A virtual brachytherapy study

AimTo evaluate the treatment plans of 3D image-guided brachytherapy (BT) and stereotactic robotic radiotherapy with online image guidance – CyberKnife (CK) in patients with locally advanced cervix cancer.Methods and materialsTen pairs of plans for patients with locally advanced inoperable cervical cancer were created using MR based 3D brachytherapy and stereotaxis CK. The dose that covers 98% of the target volume (HR CTV D98) was taken as a reference and other parameters were compared.ResultsOf the ten studied cases, the dose from D100 GTV was comparable for both devices, on average, the BT GTV D90 was 10–20% higher than for CK. The HR CTV D90 was higher for CK with an average difference of 10–20%, but only fifteen percent of HR CTV (the peripheral part) received a higher dose from CK, while 85% of the target volume received higher doses from BT. We found a significant organ-sparing effect of CK compared to brachytherapy (20–30% lower doses in 0.1[[ce:hsp sp="0.25"/]]cm3, 1[[ce:hsp sp="0.25"/]]cm3, and 2[[ce:hsp sp="0.25"/]]cm3).ConclusionBT remains to be the best method for dose escalation. Due to the significant organ-sparing effect of CK, patients that are not candidates for BT could benefit from stereotaxis more than from classical external beam radiotherapy

Lacosamide and Levetiracetam Have No Effect on Sharp-Wave Ripple Rate

Pathological high-frequency oscillations are a novel marker used to improve the delineation of epileptogenic tissue and, hence, the outcome of epilepsy surgery. Their practical clinical utilization is curtailed by the inability to discriminate them from physiological oscillations due to frequency overlap. Although it is well documented that pathological HFOs are suppressed by antiepileptic drugs (AEDs), the effect of AEDs on normal HFOs is not well known. In this experimental study, we have explored whether physiological HFOs (sharp-wave ripples) of hippocampal origin respond to AED treatment. The results show that application of a single dose of levetiracetam or lacosamide does not reduce the rate of sharp-wave ripples. In addition, it seems that these new generation drugs do not negatively affect the cellular and network mechanisms involved in sharp-wave ripple generation, which may provide a plausible explanation for the absence of significant negative effects on cognitive functions of these drugs, particularly on memory

Manikin-based size-resolved penetrations of CE-marked filtering facepiece respirators

Summarization: The purpose of this manikin-based study was to determine the percentage penetrations of nine CE-marked filtering facepiece respirator models (two samples from each) from filtering classes FFP1, FFP2, and FFP3 and to demonstrate by an independent measurement method the disadvantages and shortcomings of the currently valid European Norm (EN 149: 2001) for filtering facepieces. All of the filtering facepieces were evaluated size-selectively in an experimental chamber using charge-neutralized monodisperse ammonium sulfate in 9 sizes ranging from 20-400 nm of count median diameter (CMD) under flowrate of 95 L/min. The results were then compared to the previous study concerning penetrations of 47-mm diameter filters cut from the filtering material of identical filtering facepieces. Although these two experimental methods for measuring penetrations of filtering materials from filtering facepieces are in good agreement (R-2 = 0.91), the results show within-respirator variations in all three filtering classes (5.5-19.3% for all FFRs in FFP1, 2.8-8.5% in FFP2, and 0.1-2.8% in FFP3). The most penetrating particle size (MPPS) in this study was found to be in the range of 25-65 nm (CMD), which is in agreement with the range of 30-60 nm found in the previous study. Moreover, 7 out of 9 FFR models reached higher penetrations from manikin-based respirator measurements than during measurements of filters from the respective respirators. Furthermore, penetration levels increased up to similar to 50% when the respirator was not sealed around the face of the manikin, indicating that the real protection level provided by these filtering facepieces may be even lower if the respirator does not fit perfectly. Considering that poor filtration efficiency and poor fit may increase under real work conditions, the particle penetration is even higher than was found in this study. Therefore, the CE-marked respirators examined in this study may not be efficient in providing the expected level of protection for workers exposed to nanoparticlesPresented on: Journal of Occupational and Environmental Hygien