Epileptic high-frequency network activity in a model of non-lesional temporal lobe epilepsy

High-frequency cortical activity, particularly in the 250–600 Hz (fast ripple) band, has been implicated in playing a crucial role in epileptogenesis and seizure generation. Fast ripples are highly specific for the seizure initiation zone. However, evidence for the association of fast ripples with epileptic foci depends on animal models and human cases with substantial lesions in the form of hippocampal sclerosis, which suggests that neuronal loss may be required for fast ripples. In the present work, we tested whether cell loss is a necessary prerequisite for the generation of fast ripples, using a non-lesional model of temporal lobe epilepsy that lacks hippocampal sclerosis. The model is induced by unilateral intrahippocampal injection of tetanus toxin. Recordings from the hippocampi of freely-moving epileptic rats revealed high-frequency activity (4100 Hz), including fast ripples. High-frequency activity was present both during interictal discharges and seizure onset. Interictal fast ripples proved a significantly more reliable marker of the primary epileptogenic zone than the presence of either interictal discharges or ripples (100–250 Hz). These results suggest that fast ripple activity should be considered for its potential value in the pre-surgical workup of non-lesional temporal lobe epilepsy

Clinical assessment of hand oedema: A systematic review

Introduction: Assessment of oedema after trauma or surgery is important to determine whether treatment is effective and to detect change over time. Volumetry is referred to as the ‘gold standard’ method of measuring volume. However, this has practical limitations and other methods are available. The aim of this systematic review was to evaluate the psychometric properties of alternative methods used to assess hand oedema. Methods: A search of electronic bibliographic databases was undertaken for any studies published in English reporting the psychometric evaluation of a method for measuring hand oedema, in an adult population with hand swelling from surgery, trauma or stroke. The Consensus‐based Standards for the Selection of health Measurement Instruments (COSMIN) checklist was used to evaluate the methodological quality. Results: Six studies met the inclusion criteria. Three methods were identified assessing hand oedema: perometry, visual inspection and the figure-of-eight tape measure, all were compared to volumetry. Four different psychometric properties were assessed. Studies scored fair or poor on COSMIN criteria. There is low-quality evidence supporting the use of the figure-of-eight tape measure to assess hand volume. The perometer systematically overestimated volume and visual estimation had poor sensitivity and specificity. Discussion: The figure-of-eight tape measure is the best alternative to volumetry for hand oedema. Benefits include reduced cost and time while having comparable reliability to the ‘gold standard’. Further research is needed to compare methods in patients with greater variability of conditions and with isolated digit oedema. Visual estimation of hand oedema is not recommended

The Majorana Project

Building a \BBz experiment with the ability to probe neutrino mass in the inverted hierarchy region requires the combination of a large detector mass sensitive to \BBz, on the order of 1-tonne, and unprecedented background levels, on the order of or less than 1 count per year in the \BBz signal region. The MAJORANA Collaboration proposes a design based on using high-purity enriched Ge-76 crystals deployed in ultra-low background electroformed Cu cryostats and using modern analysis techniques that should be capable of reaching the required sensitivity while also being scalable to a 1-tonne size. To demonstrate feasibility, the collaboration plans to construct a prototype system, the MAJORANA DEMONSTRATOR, consisting of 30 kg of 86% enriched \Ge-76 detectors and 30 kg of natural or isotope-76-depleted Ge detectors. We plan to deploy and evaluate two different Ge detector technologies, one based on a p-type configuration and the other on n-type.Comment: paper submitted for the 2008 Carolina International Symposium on Neutrino Physic

The Majorana experiment: an ultra-low background search for neutrinoless double-beta decay

The observation of neutrinoless double-beta decay would resolve the Majorana nature of the neutrino and could provide information on the absolute scale of the neutrino mass. The initial phase of the Majorana experiment, known as the Demonstrator, will house 40 kg of Ge in an ultra-low background shielded environment at the 4850' level of the Sanford Underground Laboratory in Lead, SD. The objective of the Demonstrator is to determine whether a future 1-tonne experiment can achieve a background goal of one count per tonne-year in a narrow region of interest around the 76Ge neutrinoless double-beta decay peak.Comment: Presentation for the Rutherford Centennial Conference on Nuclear Physic

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

The MAJORANA DEMONSTRATOR: A Search for Neutrinoless Double-beta Decay of Germanium-76

The {\sc Majorana} collaboration is searching for neutrinoless double beta decay using $^{76}$Ge, which has been shown to have a number of advantages in terms of sensitivities and backgrounds. The observation of neutrinoless double-beta decay would show that lepton number is violated and that neutrinos are Majorana particles and would simultaneously provide information on neutrino mass. Attaining sensitivities for neutrino masses in the inverted hierarchy region, $15 - 50$ meV, will require large, tonne-scale detectors with extremely low backgrounds, at the level of $\sim$1 count/t-y or lower in the region of the signal. The {\sc Majorana} collaboration, with funding support from DOE Office of Nuclear Physics and NSF Particle Astrophysics, is constructing the {\sc Demonstrator}, an array consisting of 40 kg of p-type point-contact high-purity germanium (HPGe) detectors, of which $\sim$30 kg will be enriched to 87% in $^{76}$Ge. The {\sc Demonstrator} is being constructed in a clean room laboratory facility at the 4850' level (4300 m.w.e.) of the Sanford Underground Research Facility (SURF) in Lead, SD. It utilizes a compact graded shield approach with the inner portion consisting of ultra-clean Cu that is being electroformed and machined underground. The primary aim of the {\sc Demonstrator} is to show the feasibility of a future tonne-scale measurement in terms of backgrounds and scalability.Comment: Proceedings for the MEDEX 2013 Conferenc

The MAJORANA DEMONSTRATOR: A Search for Neutrinoless Double-beta Decay of Germanium-76

The observation of neutrinoless double-beta decay would determine whether the neutrino is a Majorana particle and provide information on the absolute scale of neutrino mass. The MAJORANA Collaboration is constructing the DEMONSTRATOR, an array of germanium detectors, to search for neutrinoless double-beta decay of 76-Ge. The DEMONSTRATOR will contain 40 kg of germanium; up to 30 kg will be enriched to 86% in 76-Ge. The DEMONSTRATOR will be deployed deep underground in an ultra-low-background shielded environment. Operation of the DEMONSTRATOR aims to determine whether a future tonne-scale germanium experiment can achieve a background goal of one count per tonne-year in a 4-keV region of interest around the 76-Ge neutrinoless double-beta decay Q-value of 2039 keV.Comment: Submitted to AIP Conference Proceedings, 19th Particles & Nuclei International Conference (PANIC 2011), Massachusetts Institute of Technology, Cambridge, MA, USA, July 24-29, 2011; 3 pages, 1 figur

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme