bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic strategies to avoid long‐term adverse outcomes of neonatal antiepileptic drug exposure
Authors: Forcelli Patrick A. , Janssen Megan J. , Stamps Lauren A. , Sweeney Cameron , Vicini Stefano , Gale Karen 
Published: July 2010

SummaryAntiepileptic drugs (AEDs) such as phenobarbital, phenytoin, and valproic acid, when given in therapeutic doses to neonatal rats, cause pronounced neuronal apoptotic cell death. This effect is especially pronounced in the striatum and cortex during the second postnatal week, a period corresponding to the “brain growth spurt” (third trimester of gestation and early infancy) in humans. Of particular concern is the fact that phenobarbital is the most frequently used therapy for neonatal epilepsy. If AED‐induced neuronal cell death leads to long‐term functional impairment, then it becomes crucial to find therapies that avoid this neurotoxicity in the sensitive period. Herein we examine short‐ and long‐term functional effects following exposure of neonatal rat pups to phenobarbital; the functions tested include striatal γ‐aminobutyric acid (GABA)ergic synaptic responses and reflex development in pups, and fear conditioning, emotionality, and sensory‐motor gating in adults. In all cases, phenobarbital exposure during the second postnatal week was sufficient to cause significant impairment. In contrast, adult animals exposed as pups to lamotrigine (given in a dose that does not cause apoptotic neuronal death) were not impaired on the tasks we examined. Our data suggest that treatments devoid of proapoptotic actions may be promising therapies for avoiding adverse outcomes after neonatal exposure. In addition, our findings identify early exposure to certain AEDs as an important potential risk factor contributing to psychiatric and neurologic abnormalities later in life.
Seizures triggered by food intake in antimuscarinic‐treated fasted animals: Evaluation of the experimental findings in terms of similarities to eating‐triggered epilepsy
Authors: Enginar Nurhan , Nurten Asiye 
Published: July 2010

SummaryFood intake triggers convulsions in fasted mice and rats treated with antimuscarinic drugs, scopolamine or atropine. Bearing some similarities in triggering factor and manifestations of the seizures in patients with eating‐evoked epilepsy, seizures in fasted animals may provide insight into the mechanism(s) of this rare and partially controlled form of reflex epilepsy.
Effects of direct brain stimulation depend on seizure dynamics
Authors: Jiruska Premysl , Powell Andrew D. , Deans Jacqueline K. , Jefferys John G.R. 
Published: July 2010

SummaryBrain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during epileptic seizures can differ from those observed under normal conditions. Several studies suggest a potentially greater beneficial therapeutic effect of strong depolarizing and overactivating stimulations than hyperpolarizing ones in the treatment of seizures. The potential relevance of these results to other therapeutic stimulation protocols is discussed.
Outcome of vagus nerve stimulation for epilepsy in Budapest
Authors: Müller Katalin , Fabó Dániel , Entz László , Kelemen Anna , Halász Péter , Rásonyi György , Erőss Loránd 
Published: July 2010

SummaryVagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients with intractable epilepsy. Better clinical outcomes were recorded in nonfocal and Lennox‐Gastaut syndrome (LGS). We conducted a 2‐year, open label, prospective study to measure the seizure outcome of 26 VNS patients. The seizure numbers were assessed using clinician’s global impression scale (CGI) and patient diaries. The average seizure reduction was 23% at the first year and 22% at the second year. Seizure reduction was more pronounced among patients with nonfocal than with focal epilepsy. The response rate was 50% at first year and 30% at the second year. The best CGI record for clinically significant improvement was 15% in the LGS group. The only statistically significant result was the reduction of the generalized tonic–clonic seizures (GTCS). The side‐effect profile was good; however, the large number of mild and reversible effects influenced the stimulation parameters and thus probably the effectiveness of the therapy. We suggest that VNS is an optional treatment mostly in cases of therapy‐resistant Lennox‐Gastaut syndrome. Patients with GTCS may experience improvement such as reduction of seizure severity. We conclude that VNS is a safe neuromodulatory treatment, but future developments of neuromodulatory approaches are needed.
CB1 receptor antagonism impairs the induction of epileptiform activity by group I metabotropic glutamate receptor activation
Authors: Karr Linda , Pan Yu‐Zhen , Rutecki Paul A. 
Published: July 2010

SummaryExposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxy phenylglycine (DHPG) induces epileptiform activity in the CA3 region of the hippocampus that persists following washout of DHPG. DHPG also can cause long‐term depression of synaptic transmission, and at some synapses this may be mediated by endocannabinoids. We evaluated whether the selective cannabinoid type 1 (CB1) receptor antagonists SR 141716 or AM 251 could modify induction of epileptiform activity produced by DHPG exposure. The induction of epileptiform activity by DHPG exposure was significantly reduced by CB1 receptor antagonists, SR 141716 or AM 251. Minimal effects on epileptiform activity were noted once the activity had been induced. In control slices, exposure to DHPG for 30 min produced long‐term depression (LTD) of synaptic transmission, on average about a 70% reduction in slope of the field excitatory postsynaptic potential (EPSP). When slices were exposed to both DHPG and SR 141716 (3 μm), LTD did not occur and the population EPSP remained at control values or greater. These results suggest that CB1 receptors mediate some of DHPG effects that result in persistent epileptiform activity, and antagonism of CB1 receptors has antiepileptogenic properties. Paradoxically DHPG also caused LTD of excitatory synaptic transmission in the CA3 region and CB1 receptor antagonism prevents the depression. We hypothesize that the ictal activity induced by DHPG requires depression of synaptic strength and CB1 receptor antagonism prevents this depression and the induction of ictal activity.
Effects and mechanisms of progestogens and androgens in ictal activity
Authors: Frye Cheryl A. 
Published: July 2010

SummarySteroid hormones, such as progestogens and androgens, influence seizures. Progestogens and androgens exert organizational and/or activational effects that may mitigate vulnerability to, and/or expression of, some seizure disorders. Progestogens, such as progesterone (P4) and its 5α‐reduced metabolite, 5α‐pregnan‐3α‐ol‐20‐one (3α,5α‐THP), which vary across the reproductive cycle and lifespan, may protect against seizures through actions at intracellular progestin receptors (PRs) and membrane receptors, such as γ‐aminobutyric acid (GABA)A receptors. Similarly, androgens, such as testosterone (T), which also vary across the reproductive cycle and the lifespan, can have antiseizure effects. Some of these effects of T may be due to aromatization to estrogen and/or 5α‐reduction to dihydrotestosterone (DHT), and its subsequent conversion through 3α‐hydroxysteroid dehydrogenase to 5α‐androstane‐3α,17α‐diol (3α‐diol). Sensitivity to steroids in some individuals may be mitigated by differences in stress, developmental phase, reproductive status, endocrine status, and treatments, such as antiepileptic drugs (AEDs), which alter levels of these ligands and/or function of their target sites. The evidence implicating sex steroids in differences associated with hormonal, reproductive, developmental, stress, seizure type, and/or therapeutics are discussed.
Comparative study of cellular and synaptic abnormalities in brain tissue samples from pediatric tuberous sclerosis complex and cortical dysplasia type II
Authors: Cepeda Carlos , André Véronique M. , Yamazaki Irene , Hauptman Jason S. , Chen Jane Y. , Vinters Harry V. , Mathern Gary W. , Levine Michael S. 
Published: July 2010

SummaryTuberous sclerosis complex (TSC) and severe cortical dysplasia (CD), or CD type II according to Palmini classification, share histopathologic similarities, specifically the presence of cytomegalic neurons and balloon cells. In this study we examined the morphologic and electrophysiologic properties of cells in cortical tissue samples from pediatric patients with TSC and CD type II who underwent surgery for pharmacoresistant epilepsy. Normal‐appearing pyramidal neurons from TSC and CD type II cases had similar passive membrane properties. However, the frequency of excitatory postsynaptic currents (EPSCs) was higher in neurons from TSC compared to severe CD cases, particularly the frequency of medium‐ and large‐amplitude synaptic events. In addition, EPSCs rise and decay times were slower in normal cells from TSC compared to severe CD cases. Balloon cells were found more frequently in TSC cases, whereas cytomegalic pyramidal neurons occurred more often in CD type II cases. Both cell types were similar morphologically and electrophysiologically in TSC and severe CD. These results suggest that even though the histopathology in TSC and severe CD is similar, there are subtle differences in spontaneous synaptic activity and topographic distribution of abnormal cells. These differences may contribute to variable mechanisms of epileptogenesis in patients with TSC compared with CD type II.
Interneurons, GABA currents, and subunit composition of the GABAA receptor in type I and type II cortical dysplasia
Authors: André Véronique M. , Cepeda Carlos , Vinters Harry V. , Huynh My , Mathern Gary W. , Levine Michael S. 
Published: July 2010

SummaryInterneurons, γ‐aminobutyric acid (GABA)A receptor density, and subunit composition determine inhibitory function in pyramidal neurons and control excitability in cortex. Abnormalities in GABAergic cells or GABAA receptors could contribute to seizures in malformations of cortical development. Herein we review data obtained in resected cortex from pediatric epilepsy surgery patients with type I and type II cortical dysplasia (CD) and non‐CD pathologies. Our studies found fewer interneurons immunolabeled for glutamic acid decarboxylase (GAD) in type II CD, whereas there were no changes in tissue from type I CD. GAD‐labeled neurons had larger somata, and GABA transporter (VGAT and GAT1) staining showed a dense plexus surrounding cytomegalic neurons in type II CD. Functionally, neurons from type I CD tissue showed GABA currents with increased half maximal effective concentration compared to cells from the other groups. In type II CD, cytomegalic pyramidal neurons showed alterations in GABA currents, decreased sensitivity to zolpidem and zinc, and increased sensitivity to bretazenil. In addition, pyramidal neurons from type II CD displayed higher frequency of spontaneous inhibitory post synaptic currents. The GABAergic system is therefore, altered differently in cortex from type I and type II CD patients. Alterations in zolpidem, zinc, and bretazenil sensitivity and spontaneous inhibitory postsynaptic currents (IPSCs) suggest that type II CD neurons have altered GABAA receptor subunit composition and receive dense GABA inputs. These findings support the hypothesis that patients with type I and type II CD will respond differently to GABA receptor–mediated antiepileptic drugs and that cytomegalic neurons have features similar to immature neurons.
A human systems biology approach to discover new drug targets in epilepsy
Authors: Loeb Jeffery A. 
Published: July 2010

SummaryOne of the major challenges in developing novel therapeutics for human epileptic disorders comes from the wide range of brain abnormalities capable of producing epilepsy. In children and adults that undergo epilepsy surgery for treatment of refractory seizures, these abnormalities range from developmental defects to injuries, infections, tumors, and ischemia. Given the many molecular mechanisms likely involved in each of these, finding common therapeutic targets seems a futile task. However, patients undergoing surgery for neocortical seizures have surprisingly similar electrophysiologic abnormalities, which consist of the synchronous firing of large neuronal populations. Surgical removal of these regions is the only means at present time to permanently reduce or eliminate seizures. The precise locations of these hypersynchronous firing regions that produce seizures can be revealed using long‐term subdural electrical high‐density recordings. This therapeutic strategy not only can dramatically reduce seizures, but also offers the potential to generate molecular and cellular information that can be used to ask why certain regions of the cortex become and remain epileptic. We have taken advantage of these detailed clinical and electrophysiologic human studies by taking a “systems biology” approach to identify novel biomarkers and drug targets in neocortical human epilepsy. In this article, we describe our multidisciplinary systems approach that utilizes a relational database to interrelate clinical, quantitative electrophysiologic, pathologic, and gene expression profiling data together as a means to identify and validate new biomarkers and potential drug targets for human epilepsy.
Infantile spasms: A U.S. consensus report
Authors: Pellock John M. , Hrachovy Richard , Shinnar Shlomo , Baram Tallie Z. , Bettis David , Dlugos Dennis J. , Gaillard William D. , Gibson Patricia A. , Holmes Gregory L. , Nordli Douglas R. , O’Dell Christine , Shields W. Donald , Trevathan Edwin , Wheless James W. 
Published: July 2010

SummaryThe diagnosis, evaluation, and management of infantile spasms (IS) continue to pose significant challenges to the treating physician. Although an evidence‐based practice guideline with full literature review was published in 2004, diversity in IS evaluation and treatment remains and highlights the need for further consensus to optimize outcomes in IS. For this purpose, a working group committed to the diagnosis, treatment, and establishment of a continuum of care for patients with IS and their families—the Infantile Spasms Working Group (ISWG)—was convened. The ISWG participated in a workshop for which the key objectives were to review the state of our understanding of IS, assess the scientific evidence regarding efficacy of currently available therapeutic options, and arrive at a consensus on protocols for diagnostic workup and management of IS that can serve as a guide to help specialists and general pediatricians optimally manage infants with IS. The overall goal of the workshop was to improve IS outcomes by assisting treating physicians with early recognition and diagnosis of IS, initiation of short duration therapy with a first‐line treatment, timely electroencephalography (EEG) evaluation of treatment to evaluate effectiveness, and, if indicated, prompt treatment modification. Differences of opinion among ISWG members occurred in areas where data were lacking; however, this article represents a consensus of the U.S. approach to the diagnostic evaluation and treatment of IS.
Opioid Utilization and Health‐Care Costs among Patients with Diabetic Peripheral Neuropathic Pain Treated with Duloxetine vs. Other Therapies
Authors: Wu Ning , Chen Shih‐Yin , Hallett Lindsay A. , Boulanger Luke , Fraser Kimberly A. , Patel Chintan K. , Zhao Yang 
Published: July 2010

AbstractObjective: This retrospective cohort study assessed subsequent opioid utilization and health‐care costs among patients with diabetic peripheral neuropathic pain (DPNP) who initiated duloxetine vs. other standard of care (SOC) treatments.Methods: Medical and pharmacy claims were analyzed for commercially‐insured individuals aged 18–64. Two study cohorts were constructed from DPNP patients who initiated duloxetine or SOC medications (tricyclic antidepressants, venlafaxine, gabapentin, pregabalin) between March 1, 2005 and December 31, 2005. Initiation was defined as a prior 90‐day period without access of the medication. The dispense date of the first initiation was denoted as the index date. Patients with opioids dispensed in the prior 90 days were excluded. Opioid utilization including total days, number of prescriptions filled, and morphine equivalent dosage was assessed for overall, long‐acting, and short‐acting opioids. Health‐care costs and opioid use in the 12‐month post‐index period were examined via multivariate regression analyses.Results: Four hundred and ninety‐nine DPNP patients (272 duloxetine, 227 SOC) were identified. SOC patients had higher prevalence of comorbidities and pre‐index health‐care costs than duloxetine patients. Controlling for cross‐cohort differences, duloxetine patients were significantly less likely to use any opioids than SOC patients. Also, duloxetine patients had 20 fewer adjusted opioid supply days (largely due to the use of short‐acting opioids,P < 0.05) and significantly lower adjusted total costs ($8,088,P < 0.05) and diabetes‐related costs ($3,092,P < 0.05) in the 12‐month post‐index period, with most of the cost differences from lower outpatient costs.Conclusions: DPNP patients who initiated duloxetine therapy were less likely to have subsequent opioid use and had lower health‐care costs than SOC patients.
Bipolar Radiofrequency Lesion Geometry: Implications for Palisade Treatment of Sacroiliac Joint Pain
Authors: Cosman, Jr. Eric R. , Gonzalez Christian D. 
Published: July 2010

AbstractEx vivo photographic temperature mapping of bipolar radiofrequency (RF) lesions in animal tissue is performed over a wide range of electrode tip spacings, tip lengths, tip diameters, tip temperatures, and lesion times. In vivo temperature measurements collected during clinical treatment of sacroiliac joint (SIJ) pain corroborate those collected ex vivo. Generation of a “strip lesion” connecting two separated bipolar electrode tips is demonstrated ex vivo for tip spacings as large as 20 mm. A rounded rectangular bipolar lesion with midline dimensions 12 mm × 15 mm × 8 mm (L × W × D) is demonstrated using 10 mm parallel tip spacing, 10 mm tip lengths, 20 gauge cannulae, 90°C tip temperature, and 3‐minute lesion time. Lesion length can be increased to 18 mm by using 15 mm tip lengths. Lesion width can be increased to 17 mm by using 12 mm tip spacing. The size of conventional bipolar lesions can exceed the size of lesions produced both by conventional monopolar RF (12 mm × 7 mm × 7 mm ellipsoidal) and by cooled monopolar RF as used in spinal pain management (10 mm × 10 mm × 10 mm spherical). SIJ pain is treated by placing 5 to 7 straight RF cannulae perpendicular to the dorsal sacrum and producing 4 to 6 overlapping bipolar RF lesions between the dorsal sacral foramina and the ipsilateral SIJ. This bipolar “palisade” (a defensive fence) creates a continuous lesion spanning the region through which multiple sacral lateral branch nerves travel along irregular, branching paths to reach the SIJ.
A Double‐blind, Randomized, Placebo‐controlled Study of the Efficacy and Safety of Duloxetine for the Treatment of Chronic Pain Due to Osteoarthritis of the Knee
Authors: Chappell Amy S. , Desaiah Durisala , Liu‐Seifert Hong , Zhang Shuyu , Skljarevski Vladimir , Belenkov Yuri , Brown Jacques P. 
Published: July 2010

AbstractObjective:  To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee.Methods:  This was a 13‐week, randomized, double‐blind, placebo‐controlled trial in patients meeting American College of Rheumatology clinical and radiographic criteria for osteoarthritis of the knee. At baseline, patients were required to have a ≥ 4 weekly mean of the 24‐hour average pain ratings. Patients were randomized to either duloxetine 60 mg once daily (QD) or placebo. At week 7, the duloxetine dosage was increased, in a blinded fashion, to 120‐mg QD in patients reporting < 30% pain reduction. The primary efficacy measure was Brief Pain Inventory (BPI) 24‐hour average pain. Secondary efficacy measures included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); Clinical Global Impressions of Severity (CGI‐S). Safety and tolerability was also assessed.Results:  Of the total (n = 256) patients, 111 (86.7%) in placebo group and 93 (72.7%) in duloxetine group completed the study. Patients treated with duloxetine had significantly (P ≤ 0.001) greater improvement at all time points on BPI average pain and had significantly greater improvement on BPI pain severity ratings (P ≤ 0.05), WOMAC total (P = 0.044) and physical functioning scores (P = 0.016), and CGI‐S (P = 0.009) at the study endpoint. Frequency of treatment‐emergent nausea, constipation, and hyperhidrosis were significantly higher in the duloxetine group (P ≤ 0.05). Significantly more duloxetine‐treated patients discontinued the trial because of adverse events (P = 0.002).Conclusions:  Treatment with duloxetine 60 mg to 120 mg QD was associated with significant pain reduction and improved function in patients with pain due to osteoarthritis of the knee.
Evidence for acoustic communication in the parasitoid wasp Glyptapanteles flavicoxis
Authors: Danci Adela , Takács Stephen , Schaefer Paul W. , Gries Gerhard 
Published: July 2010

AbstractFemales of the parasitoid wasp Glyptapanteles flavicoxis (Marsh) (Hymenoptera: Braconidae) deposit sex pheromone on substrate that elicits attraction and wing fanning in conspecific males. We tested the hypothesis that wing fanning sound induces a behavioral response from females which, in turn, affects the males’ orientation toward them. Females exposed to playback of the males’ wing fanning sound engaged in short flights, with sound characteristics different from those of the males’ wing fanning sound. In two‐choice bioassays, playback of the females’ flight sound attracted significantly more males than a silent control stimulus, and in combination with pheromone‐containing body extract of females it attracted more males than female body extract alone. Our data support the conclusion that the males’ wing fanning induces sound and visual reply signals from females that help males orient toward them.