Neurocognitive and Seizure Outcomes of Selective Amygdalohippocampectomy versus Anterior Temporal Lobectomy for Mesial Temporal Lobe Epilepsy.

Objective. To report our institutional seizure and neuropsychological outcomes for a series of patients with mesial temporal lobe epilepsy (mTLE) undergoing anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SelAH) between 2004 and 2011. Methods. A retrospective study of patients with mTLE was conducted. Seizure outcome was reported using time-to-event analysis. Cognitive outcome was reported using the change principal in component factor scores, one each, for intellectual abilities, visuospatial memory, and verbal memory. The Boston Naming Test was used for naming assessment. Language dominant and nondominant resections were compared separately. Student's t-test was used to assess statistical significance. Results. Ninety-six patients (75 ATL, 21 SelAH) were included; fifty-four had complete neuropsychological follow-up. Median follow-up was 40.5 months. There was no statistically significant difference in seizure freedom or any of the neuropsychological outcomes, although there was a trend toward greater postoperative decline in naming in the dominant hemisphere group following ATL. Conclusion. Seizure and neuropsychological outcomes did not differ for the two surgical approaches which is similar to most prior studies. Given the theoretical possibility of SelAH sparing language function in patients with epilepsy secondary to mesial temporal sclerosis and the limited high-quality evidence creating equipoise, a multicenter randomized clinical trial is warranted

Raised Intracellular Calcium Contributes to Ischemia-Induced Depression of Evoked Synaptic Transmission

Oxygen-glucose deprivation (OGD) leads to depression of evoked synaptic transmission, for which the mechanisms remain unclear. We hypothesized that increased presynaptic [Ca2+]i during transient OGD contributes to the depression of evoked field excitatory postsynaptic potentials (fEPSPs). Additionally, we hypothesized that increased buffering of intracellular calcium would shorten electrophysiological recovery after transient ischemia. Mouse hippocampal slices were exposed to 2 to 8 min of OGD. fEPSPs evoked by Schaffer collateral stimulation were recorded in the stratum radiatum, and whole cell current or voltage clamp recordings were performed in CA1 neurons. Transient ischemia led to increased presynaptic [Ca2+]i, (shown by calcium imaging), increased spontaneous miniature EPSP/Cs, and depressed evoked fEPSPs, partially mediated by adenosine. Buffering of intracellular Ca2+ during OGD by membrane-permeant chelators (BAPTA-AM or EGTA-AM) partially prevented fEPSP depression and promoted faster electrophysiological recovery when the OGD challenge was stopped. The blocker of BK channels, charybdotoxin (ChTX), also prevented fEPSP depression, but did not accelerate post-ischemic recovery. These results suggest that OGD leads to elevated presynaptic [Ca2+]i, which reduces evoked transmitter release; this effect can be reversed by increased intracellular Ca2+ buffering which also speeds recovery

Wavelet-based Gaussian-mixture hidden Markov model for the detection of multistage seizure dynamics: A proof-of-concept study

<p>Abstract</p> <p>Background</p> <p>Epilepsy is a common neurological disorder characterized by recurrent electrophysiological activities, known as seizures. Without the appropriate detection strategies, these seizure episodes can dramatically affect the quality of life for those afflicted. The rationale of this study is to develop an unsupervised algorithm for the detection of seizure states so that it may be implemented along with potential intervention strategies.</p> <p>Methods</p> <p>Hidden Markov model (HMM) was developed to interpret the state transitions of the <it>in vitro </it>rat hippocampal slice local field potentials (LFPs) during seizure episodes. It can be used to estimate the probability of state transitions and the corresponding characteristics of each state. Wavelet features were clustered and used to differentiate the electrophysiological characteristics at each corresponding HMM states. Using unsupervised training method, the HMM and the clustering parameters were obtained simultaneously. The HMM states were then assigned to the electrophysiological data using expert guided technique. Minimum redundancy maximum relevance (mRMR) analysis and Akaike Information Criterion (AICc) were applied to reduce the effect of over-fitting. The sensitivity, specificity and optimality index of chronic seizure detection were compared for various HMM topologies. The ability of distinguishing early and late tonic firing patterns prior to chronic seizures were also evaluated.</p> <p>Results</p> <p>Significant improvement in state detection performance was achieved when additional wavelet coefficient rates of change information were used as features. The final HMM topology obtained using mRMR and AICc was able to detect non-ictal (interictal), early and late tonic firing, chronic seizures and postictal activities. A mean sensitivity of 95.7%, mean specificity of 98.9% and optimality index of 0.995 in the detection of chronic seizures was achieved. The detection of early and late tonic firing was validated with experimental intracellular electrical recordings of seizures.</p> <p>Conclusions</p> <p>The HMM implementation of a seizure dynamics detector is an improvement over existing approaches using visual detection and complexity measures. The subjectivity involved in partitioning the observed data prior to training can be eliminated. It can also decipher the probabilities of seizure state transitions using the magnitude and rate of change wavelet information of the LFPs.</p

Contributions of the Hippocampal CA3 Circuitry to Acute Seizures and Hyperexcitability Responses in Mouse Models of Brain Ischemia

The hippocampal circuitry is widely recognized as susceptible to ischemic injury and seizure generation. However, hippocampal contribution to acute non-convulsive seizures (NCS) in models involving middle cerebral artery occlusion (MCAO) remains to be determined. To address this, we occluded the middle cerebral artery in adult C57 black mice and monitored electroencephalographic (EEG) discharges from hippocampal and neocortical areas. Electrographic discharges in the absence of convulsive motor behaviors were observed within 90 min following occlusion of the middle cerebral artery. Hippocampal discharges were more robust than corresponding cortical discharges in all seizure events examined, and hippocampal discharges alone or with minimal cortical involvement were also observed in some seizure events. Seizure development was associated with ipsilateral hippocampal injuries as determined by subsequent histological examinations. We also introduced hypoxia-hypoglycemia episodes in mouse brain slices and examined regional hyperexcitable responses ex vivo. Extracellular recordings showed that the hippocampal CA3 region had a greater propensity for exhibiting single/multiunit activities or epileptiform field potentials following hypoxic-hypoglycemic (HH) episodes compared to the CA1, dentate gyrus, entorhinal cortical (EC) or neocortical regions. Whole-cell recordings revealed that CA3 pyramidal neurons exhibited excessive excitatory postsynaptic currents, attenuated inhibitory postsynaptic currents and intermittent or repetitive spikes in response to HH challenge. Together, these observations suggest that hippocampal discharges, possibly as a result of CA3 circuitry hyperexcitability, are a major component of acute NCS in a mouse model of MCAO

Expression and Functional Studies on the Noncoding RNA, PRINS.

PRINS, a noncoding RNA identified earlier by our research group, contributes to psoriasis susceptibility and cellular stress response. We have now studied the cellular and histological distribution of PRINS by using in situ hybridization and demonstrated variable expressions in different human tissues and a consistent staining pattern in epidermal keratinocytes and in vitro cultured keratinocytes. To identify the cellular function(s) of PRINS, we searched for a direct interacting partner(s) of this stress-induced molecule. In HaCaT and NHEK cell lysates, the protein proved to be nucleophosmin (NPM) protein as a potential physical interactor with PRINS. Immunohistochemical experiments revealed an elevated expression of NPM in the dividing cells of the basal layers of psoriatic involved skin samples as compared with healthy and psoriatic uninvolved samples. Others have previously shown that NPM is a ubiquitously expressed nucleolar phosphoprotein which shuttles to the nucleoplasm after UV-B irradiation in fibroblasts and cancer cells. We detected a similar translocation of NPM in UV-B-irradiated cultured keratinocytes. The gene-specific silencing of PRINS resulted in the retention of NPM in the nucleolus of UV-B-irradiated keratinocytes; suggesting that PRINS may play a role in the NPM-mediated cellular stress response in the skin

Oophorectomy Reduces Estradiol Levels and Long-Term Spontaneous Neurovascular Recovery in a Female Rat Model of Focal Ischemic Stroke

Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials

Sentencing as craftwork and the binary epistemologies of the discretionary decision process

This article contends that it is time to take a critical look at a series of binary categories which have dominated the scholarly and reform epistemologies of the sentencing decision process. These binaries are: rules versus discretion; reason versus emotion; offence versus offender; normative principles versus incoherence; aggravating versus mitigating factors; and aggregate/tariff consistency versus individualized sentencing. These binaries underpin both the 'legal-rational' tradition (by which I mean a view of discretion as inherently suspect, a preference for the use of philosophy of punishment justifications and an explanation of the decision process through factors or variables), and also the more recent rise of the 'new penology'. Both approaches tend to rely on 'top-down' assumptions of change, which pay limited attention to the agency of penal workers. The article seeks to develop a conception of sentencing craftwork as a social and interpretive process.1 In so doing, it applies and develops a number of Kritzer's observations (in this issue) about craftwork to sentencing. These craftwork observations are: problem solving (applied to the rules - discretion and reason - emotion dichotomies); skills and techniques (normative penal principles and the use of cognitive analytical assumptions); consistency (tariff versus individualized sentencing); clientele (applied to account giving and the reality of decision making versus expression). By conceiving of sentencing as craftwork, the binary epistemologies of the sentencing decision process, which have dominated (and limited) the scholarly and policy sentencing imaginations, are revealed as dynamic, contingent, and synergistic. However, this is not to say that such binaries are no more than empty rhetoric concealing the reality of the decision process. Rather, these binaries serve as crucial legitimating reference points in the vocabulary of sentencing account giving

Real-world treatment trajectories of adults with newly diagnosed asthma or COPD

Background There is a lack of knowledge on how patients with asthma or chronic obstructive pulmonary disease (COPD) are globally treated in the real world, especially with regard to the initial pharmacological treatment of newly diagnosed patients and the different treatment trajectories. This knowledge is important to monitor and improve clinical practice. Methods This retrospective cohort study aims to characterise treatments using data from four claims (drug dispensing) and four electronic health record (EHR; drug prescriptions) databases across six countries and three continents, encompassing 1.3 million patients with asthma or COPD. We analysed treatment trajectories at drug class level from first diagnosis and visualised these in sunburst plots. Results In four countries (USA, UK, Spain and the Netherlands), most adults with asthma initiate treatment with short-acting ß2 agonists monotherapy (20.8%-47.4% of first-line treatments). For COPD, the most frequent first-line treatment varies by country. The largest percentages of untreated patients (for asthma and COPD) were found in claims databases (14.5%-33.2% for asthma and 27.0%-52.2% for COPD) from the USA as compared with EHR databases (6.9%-15.2% for asthma and 4.4%-17.5% for COPD) from European countries. The treatment trajectories showed step-up as well as step-down in treatments. Conclusion Real-world data from claims and EHRs indicate that first-line treatments of asthma and COPD vary widely across countries. We found evidence of a stepwise approach in the pharmacological treatment of asthma and COPD, suggesting that treatments may be tailored to patients' needs.</p

Real-world treatment trajectories of adults with newly diagnosed asthma or COPD

Background There is a lack of knowledge on how patients with asthma or chronic obstructive pulmonary disease (COPD) are globally treated in the real world, especially with regard to the initial pharmacological treatment of newly diagnosed patients and the different treatment trajectories. This knowledge is important to monitor and improve clinical practice. Methods This retrospective cohort study aims to characterise treatments using data from four claims (drug dispensing) and four electronic health record (EHR; drug prescriptions) databases across six countries and three continents, encompassing 1.3 million patients with asthma or COPD. We analysed treatment trajectories at drug class level from first diagnosis and visualised these in sunburst plots. Results In four countries (USA, UK, Spain and the Netherlands), most adults with asthma initiate treatment with short-acting ß2 agonists monotherapy (20.8%-47.4% of first-line treatments). For COPD, the most frequent first-line treatment varies by country. The largest percentages of untreated patients (for asthma and COPD) were found in claims databases (14.5%-33.2% for asthma and 27.0%-52.2% for COPD) from the USA as compared with EHR databases (6.9%-15.2% for asthma and 4.4%-17.5% for COPD) from European countries. The treatment trajectories showed step-up as well as step-down in treatments. Conclusion Real-world data from claims and EHRs indicate that first-line treatments of asthma and COPD vary widely across countries. We found evidence of a stepwise approach in the pharmacological treatment of asthma and COPD, suggesting that treatments may be tailored to patients' needs.</p