bluuebunny/crossref_metadata_2025 huggingface dataset:
Central Vein Cannulation for Hemodialysis: Techniques and Tips for Quick and Safe Temporary Catheter Placement
Authors: Pervez Aslam , Abreo Kenneth
Published: October 2007

Nephrologists have to place temporary dialysis catheters for hemodialysis in emergency situations. Since there is a dearth of literature on this subject, the authors have written guidelines for the safe and successful placement of these catheters. These instructions should be of help to nephrology trainees who want to master the art of central venous line placement. Based on their experience, the authors have provided a number of tips and techniques for temporary catheter placement in the femoral, internal jugular, and subclavian veins, with and without ultrasound guidance. Patient positioning, preparation of the catheter insertion tray, handling of ultrasound probe, cannulation of the central veins, and guide wire and dilator insertion are described in detail. These guidelines should assist the novice in placing temporary catheters with ease and with minimal complications.
F90927: A New Member in the Class of Cardioactive Steroids
Authors: Keller Markus , Pignier Christophe , Egger Marcel , Niggli Ernst
Published: October 2007

F90927 is a newly developed cardioactive drug with a steroid‐like structure. It acts directly and agonistically on the cardiac L‐type Ca2+ channel by shifting its voltage‐dependent activation toward more negative potentials. This leads to an increased influx of Ca2+ and, therefore, to a stronger contraction; however, no arrhythmias occur. Calcium current stimulation can already be observed at nanomolar concentrations, but higher concentrations of F90927 elevate intracellular Ca2+ concentration, causing a reduction of the myocardial compliance and an increased diastolic blood pressure. Vessels also react to F90927 and contract in its presence. Binding of F90927 with the L‐type Ca2+ channel presumably occurs in the vicinity of the transmembrane domains III and IV of the α1 subunit. F90927 exhibits no use dependence and interacts with Ca2+ channel inhibitors of all three known classes of channel modulators (dihydropyridines, phenylalkylamines, and benzothiazepines), suggesting that it is a member of a new class of Ca2+ channel modulators. Due to its adverse effects on blood pressure and vessel contraction, F90927 is not an ideal drug candidate. It has, however, some unique properties, which makes it a promising tool to study the function of the L‐type Ca2+ channel.
The Functional Consequence of the Glu298Asp Polymorphism of the Endothelial Nitric Oxide Synthase Gene in Young Healthy Volunteers
Authors: Godfrey Valerie , Chan Sue‐Lyn , Cassidy Andrew , Butler Robert , Choy AnnaMaria , Fardon Tom , Struthers Allan , Lang Chim
Published: October 2007

Objective—To assess the role of the endothelial nitric oxide synthase (eNOS) gene variant as a risk factor for atherosclerosis we sought to investigate whether the Glu298Asp polymorphism of the eNOS gene is associated with functional changes in the endothelium in healthy volunteers. Methods—Endothelial function was assessed in 68 normal volunteers (ages 18–44 years) by bilateral forearm venous occlusion plethysmography with intraarterial infusions of increasing doses of acetylcholine for endothelial‐dependent vasodilation and, with sodium nitroprusside and verapamil for endothelial‐independent vasodilation. Blood was genotyped by polymerase chain reaction and BanII digestion. Results—Asp homozygotes (TT) had a decreased vasodilatory response to acetylcholine [forearm blood flow (FBF) ratio between infused and control arm, 2.82 ± 1.10] when compared to GG variant (FBF ratio to acetylcholine, 3.97 ± 1.90, p= 0.04) and to a certain extent, the GT variant (FBF ratio to acetylcholine, 3.79 ± 2.28, p= 0.07). There was no effect of eNOS genotype on the response to the endothelial‐independent vasodilators—sodium nitroprusside and verapamil. Conclusions—Our data show that carriage of the Asp298 variant of the eNOS gene is associated with a blunted endothelial‐dependent vasodilation in healthy volunteers. These findings support a genetically determined modulation of endothelial dysfunction, a phenotype of early atherosclerosis in humans.
Role of Poly(ADP‐ribose) polymerase 1 (PARP‐1) in Cardiovascular Diseases: The Therapeutic Potential of PARP Inhibitors
Authors: Pacher Pál , Szabó Csaba
Published: October 2007

Accumulating evidence suggests that the reactive oxygen and nitrogen species are generated in cardiomyocytes and endothelial cells during myocardial ischemia/reperfusion injury, various forms of heart failure or cardiomyopathies, circulatory shock, cardiovascular aging, diabetic complications, myocardial hypertrophy, atherosclerosis, and vascular remodeling following injury. These reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP‐ribose) polymerase 1 (PARP‐1), the most abundant isoform of the PARP enzyme family. PARP overactivation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to the functional impairment or death of the endothelial cells and cardiomyocytes. On the other hand, PARP activation modulates important inflammatory pathways, and PARP‐1 activity can also be modulated by several endogenous factors such as various kinases, purines, vitamin D, thyroid hormones, polyamines, and estrogens, just to mention a few. Recent studies have demonstrated that pharmacological inhibition of PARP provides significant benefits in animal models of cardiovascular disorders, and novel PARP inhibitors have entered clinical development for various cardiovascular indications. Because PARP inhibitors can enhance the effect of anticancer drugs and decrease angiogenesis, their therapeutic potential is also being explored for cancer treatment. This review discusses the therapeutic effects of PARP inhibitors in myocardial ischemia/reperfusion injury, various forms of heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, diabetic cardiovascular complications, myocardial hypertrophy, atherosclerosis, vascular remodeling following injury, angiogenesis, and also summarizes our knowledge obtained from the use of PARP‐1 knockout mice in the various preclinical models of cardiovascular diseases.
Epileptogenesis in the Developing Brain: What Can We Learn from Animal Models?
Authors: Bender Roland A. , Baram Tallie Z.
Published: October 2007

Summary:  Knowledge of the processes by which epilepsy is generated (epileptogenesis) is incomplete and has been a topic of major research efforts. Animal models can inform us about these processes. We focus on the distinguishing features of epileptogenesis in the developing brain and model prolonged febrile seizures (FS) that are associated with human temporal lobe epilepsy. In the animal model of FS, epileptogenesis occurs in ∼35% of rats. Unlike the majority of acquired epileptogeneses in adults, this process early in life (in the febrile seizures model as well as in several others) does not require “damage” (cell death). Rather, epileptogenesis early in life involves molecular mechanisms including seizure‐evoked, long‐lasting alterations of the expression of receptors and ion channels. Whereas transient changes in gene expression programs are common after early‐life seizures, enduring effects, such as found after experimental FS, are associated with epileptogenesis. The ability of FS to generate long‐lasting molecular changes and epilepsy suggests that mechanisms, including cytokine activation that are intrinsic to FS generation, may play a role also in the epileptogenic consequences of these seizures.
Intrahippocampal Injection of Endothelin‐1: A New Model of Ischemia‐induced Seizures in Immature Rats
Authors: Tsenov Grygoriy , Mátéffyová Adéla , Mareš Pavel , Otáhal Jakub , Kubová Hana
Published: October 2007

Summary:  The goal of this study was to develop a new model of ischemia‐induced seizures in immature rats using injection of vasoconstrictor Endothelin‐1 (ET‐1) into the brain. ET‐1 (10, 20, or 40 pmol) was infused into the left dorsal hippocampus of freely moving Wistar rats 12 (P12) and 25 (P25) days old. Animals were then video/EEG‐monitored for 100 min and monitoring was repeated 22 h later. Parameters of electrographic seizures (frequency and mean duration) as well as pattern of their behavioral correlates were evaluated. The pattern of behavioral seizures was used to develop model‐specific scoring system. Cresyl violet and Fluoro Jade‐B‐staining were used to evaluate brain damage. Extension of the lesion was correlated with seizure severity. After ET‐1‐injection, seizures occurred in 83–100% animals of all age‐and‐dose groups and persisted for 24 h except P12 rats with 10 pmol. There were no differences in average seizure duration (18–40 s) or seizure frequency (3–7 seizures/100 min) among individual dose‐groups. Between the 1st and 2nd observation period, total seizure duration decreased in 71% of P12 and 47% of P25 rats. Electrographic seizure activity was most frequently accompanied by clonus, incidence of more severe convulsions (barrel rolling or generalized clonic seizures) increased with dose of ET‐1. Morphologic examination did not reveal any dose‐related difference in damage severity, hippocampal damage was however more extensive in P12 compared to P25 animals. Seizure severity correlated positively with severity of the damage in both age groups. Our study presents focal injection of ET‐1 into the brain as a new and practical model of ischemia‐induced seizures in immature rats.
Developmental Patterns in the Regulation of Chloride Homeostasis and GABAAReceptor Signaling by Seizures
Authors: Galanopoulou Aristea S.
Published: October 2007

Summary: GABAAreceptors have dual functions during development. They depolarize immature neurons but hyperpolarize more mature neurons. This functional switch has been attributed to age‐related differences in the relative abundance of cation chloride cotransporters, such as KCC2 and NKCC1, which regulate chloride homeostasis. Certain insults, such as trauma, ischemia, and seizures, if they occur when GABAAergic signaling is hyperpolarizing, such as in the adult brain, can lead to reappearance of the immature, depolarizing synaptic responses to GABAAreceptor activation. In certain cases, this has been associated with either reduced expression of KCC2 or increase in NKCC1. In epilepsy, the depolarizing effects of GABAAreceptors have been proposed to be important for the acquisition and/or maintenance of the epileptic state. Using the kainic acid model of status epilepticus, we have studied the effects of repetitive neonatal episodes of status epilepticus on the expression of cation chloride cotransporter KCC2 in the neonatal hippocampus. In contrast to adults, seizures increased KCC2 mRNA expression in the CA3 region of the neonatal hippocampus. The contrasting patterns of regulation of KCC2 by seizures in mature and immature neurons may be one of the age‐related factors that protect the neonatal brain against the development of epilepsy.
Neurodevelopmental Impact of Antiepileptic Drugs and Seizures in the Immature Brain
Authors: Kim Jin‐Sook , Kondratyev Alexei , Tomita York , Gale Karen
Published: October 2007

Summary: Seizure incidence during the neonatal period is higher than any other period in the lifespan, yet we know little about this period in terms of the effect of seizures or of the drugs used in their treatment. The fact that several antiepileptic drugs (AEDs) induce pronounced apoptotic neuronal death in specific regions of the immature brain prompts a search for AEDs that may be devoid of this action. Furthermore, there is a clear need to find out if a history of seizures alters the proapoptotic action of the AEDs. Our studies are aimed at both of these issues. Phenytoin, valproate, phenobarbital, and MK801 each induced substantial regionally specific cell death, whereas levetiracetam even in high doses (up to 1,500 mg/kg) did not have this action. In view of our previously findings of neuroprotective actions of repeated seizures in the adult brain, we also examined repeated seizures for a possible antiapoptotic action in the infant rat. Rat pups were preexposed to electroshock seizures (ECS) for 3 days (age 5–7 days) before receiving MK801 on day 7. The effect of ECS, which was consistently a 30% decrease in MK801‐induced programmed cell death (PCD), suggests that repeated seizures can exert an antiapoptotic action in the infant brain. In contrast, PCD induced by valproate was not attenuated by ECS preexposure, suggesting that valproate‐induced PCD is mechanistically distinct from that induced by MK801 and may not be activity‐dependent. Presently, we do not know if this neuroprotective effect of seizures is deleterious or beneficial. If the seizures also enhance the survival of neurons that are destined to undergo naturally occurring PCD, early childhood seizures may have deleterious effects by preventing this necessary component of normal development. While this effect of seizures might be counteracted by AEDs, the fact that several AEDs shift the PCD to the other extreme, and trigger excessive neuronal cell loss, raises concern about whether the drug therapy may be more detrimental than the seizures. In this context, it is encouraging that we have identified at least one AED that is devoid of a proapoptotic action in the infant brain, even in high doses. It is now important to evaluate the long‐term consequences of the changes in PCD in infancy by examining behavioral outcomes and seizure susceptibility in the AED‐ and seizure‐exposed neonates when they reach adulthood.
Voltage Depth Profiles of High‐frequency Oscillations after Kainic Acid‐induced Status Epilepticus
Authors: Bragin Anatol , Wilson Charles L. , Engel Jerome
Published: October 2007

Summary:  High‐frequency oscillations (HFOs) have been described in normal and epileptic brains of animals and humans. These oscillations reflect a short‐term integration within neuronal networks and have important functional consequences for normal and pathological processes. We performed a comparative voltage depth profile analysis of normal and pathological HFOs after intrahippocampal kainic acid injection. Sixteen channel recording probes, with 100–200 μm separation between the tips of microelectrodes, were implanted along the CA1—dentate gyrus axis in the anterior hippocampus of adult rats. Guide cannulae were implanted in the CA3 area. After a week of baseline recording kainic acid (KA) (0.2μg/0.2μl) was injected into the CA3 area. Electrical activity continued to be record for the next 3–4 weeks after KA induced status epilepticus. Voltage depth profiles and power spectral analysis of HFOs were performed off‐line using DataPac software. Ripple oscillations (80–200 Hz) in the CA1 area and gamma activity (40–80 Hz) in the dentate gyrus remained after status epilepticus. In the group of rats that later developed seizures a new pattern consisting of bursts of population spikes (BPS) occurred. The maximum of amplitude for BPS generated in CA1 was in the pyramidal layer and for those generated in the dentate gyrus was in the granular layer. BPS appeared 2–3 days after status epilepticus and remained for the rest of the experiments. The frequencies of intraburst spikes varied between 80 Hz and 600 Hz. With increasing distance from the area of the burst generation, this activity took on the appearance of HFOs. The occurrence of spontaneous BPS appear to be a primary electrophysiological consequence of status epilepticus when progressive epileptogenesis occurs with maximum of amplitude in the cellular layer. In areas outside of the generator of the BPS, this activity looks more like pathological high‐frequency oscillations (pHFO), which were observed in earlier experiments.
Chemoconvulsant‐induced Seizure Susceptibility: Toward a Common Genetic Basis?
Authors: Chaix Yohan , Ferraro Thomas N. , Lapouble Eve , Martin Benoît
Published: October 2007

Summary: Despite the efforts employed, understanding the genetic architecture underlying epilepsy remains difficult. To reach this aim, convulsive epilepsies are classically modeled in mice, where genetic studies are less constricting than in humans. Pharmacogenetic approaches are one major source of investigation where kainic acid, pentylenetetrazol, and the ß‐carboline family represent compounds that are used extensively. Several quantitative trait loci (QTLs) influencing the convulsant effects of these drugs have been mapped using either recombinant inbred strains (RIS) or segregating F2 populations (or both). In our laboratory, we have recently mapped two QTLs for methyl 6, 7‐dimethoxy‐4‐ethyl‐ß‐carboline‐3‐carboxylate (DMCM), and seizure response using an F2 method. One is located on the distal part of Chromosome 1, a region implicated in a number of other studies. Here, we address the general importance of this chromosomal fragment for influencing seizure susceptibility.
Dynamic Changes of Proteases and Protease Inhibitors Revealed by Microarray Analysis in CA3 and Entorhinal Cortex during Epileptogenesis in the Rat
Authors: Gorter Jan A. , Van Vliet Erwin A. , Rauwerda Han , Breit Timo , Stad Robert , Van Schaik Linda , Vreugdenhil Erno , Redeker Sandra , Hendriksen Erik , Aronica Eleonora , Da Silva Fernando H. Lopes , Wadman Wytse J.
Published: October 2007

Summary:  We investigated expression of genes involved in the proteolytic process during epileptogenesis in a rat model of temporal lobe epilepsy (TLE). In a previous microarray study we found prominent activation of this process, which reached highest expression during the acute and latent phase (1 week after SE) in CA3 and entorhinal cortex (EC). Detailed analysis shows differences in dynamics of the changes of several protease genes such as cathepsins, caspases, matrix metalloproteinases, and plasminogen activators. Most genes were acutely upregulated while others were mainly activated during the latent phase. Interestingly several proteolytic genes were still elevated in the chronic epileptic phase. Various protease inhibitors followed a similar time course. The identification of changes in the activation of genes involved in proteolysis at critical phases during epileptogenesis could point to potential time specific targets for intervention. The fact that several proteolytic genes were still activated in the chronic epileptic phase makes them interesting candidates to modify and slow down seizure progression.
Immature Neurons and GABA Networks May Contribute to Epileptogenesis in Pediatric Cortical Dysplasia
Authors: Cepeda Carlos , André Véronique M. , Wu Nanping , Yamazaki Irene , Uzgil Besim , Vinters Harry V. , Levine Michael S. , Mathern Gary W.
Published: October 2007

Summary:  Cortical dysplasia (CD), a frequent pathological substrate of pediatric epilepsy surgery patients, has a number of similarities with immature cortex, such as reduced Mg2+ sensitivity of N‐methyl‐D‐aspartate (NMDA) receptors and the persistence of subplate‐like neurons and undifferentiated cells. Because γ‐aminobutyric acid (GABA) is the main neurotransmitter in early cortical development, we hypothesized increased GABA receptor‐mediated synaptic function in CD tissue. Infrared videomicroscopy and whole‐cell patch clamp recordings were used to characterize the morphology and electrophysiological properties of immature and normal‐appearing neurons in slices from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy in children (0.2–14 years). In addition, we examined spontaneous and evoked synaptic activity, as well as responses to exogenous GABA application. We demonstrate both the presence of immature pyramidal neurons and networks in young CD tissue and the predominance of GABA synaptic activity. In addition, spontaneous GABA depolarizations frequently induced action potentials, supporting a potential excitatory role of GABA in CD. Evoked synaptic responses mediated by GABA were also prominent, and bath application of 4‐aminopyridine induced rhythmic depolarizations that were blocked by bicuculline. Finally, responses to exogenous application of GABA had depolarized reversal potentials in severe compared to mild and non‐CD cases. The present data support the hypothesis that CD shares features of immature cortex, with predominant and potentially excitatory GABAA receptor‐mediated neurotransmission. These results could partially explain the increased excitability of the cortical network in pediatric CD.
Activity‐dependent Gene Expression Correlates with Interictal Spiking in Human Neocortical Epilepsy
Authors: Rakhade Sanjay N. , Shah Aashit K. , Agarwal Rajeev , Yao Bin , Asano Eishi , Loeb Jeffrey A.
Published: October 2007

Summary:  Interictal spikes are hallmarks of epileptic neocortex that are used commonly in both EEG and electrocorticography (ECoG) to localize epileptic brain regions. Despite their prevalence, the exact relationship between interictal spiking and the molecular pathways that drive the production and propagation of seizures is not known. We have recently identified a common group of genes induced in human epileptic foci, including EGR1, EGR2, c‐fos, and MKP‐3. We found that the expression levels of these genes correlate precisely with the frequency of interictal activity and can thus serve as markers of epileptic activity. Here, we explore this further by comparing the expression of these genes within human epileptic neocortex to both ictal and specific electrical parameters of interictal spiking from subdural recordings prior to surgical resection in order to determine the electrical properties of the human neocortex that correlate best to the expression of these genes. Seizure frequency as well as quantitative electrophysiological parameters of interictal spikes including frequency, amplitude, duration, and area were calculated at each electrode channel and compared to quantitative real‐time RT‐PCR measurements of four activity‐dependent genes (c‐fos, EGR1, EGR2, and MKP‐3) in the underlying neocortical tissue. Local neocortical regions of seizure onset had consistently higher spike firing frequencies and higher spike amplitudes compared to nearby “control” cortex. In contrast, spike duration was not significantly different between these two areas. There was no relationship observed between seizure frequency and the expression levels of activity‐dependent genes for the patients examined in this study. However, within each patient, there were highly significant correlations between the expression of three of these genes (c‐fos, EGR1, EGR2) and the frequency, amplitude, and total area of the interictal spikes at individual electrodes. We conclude that interictal spiking is closely associated with the expression of a group of activity‐dependent transcription factors in neocortical human epilepsy. Since there was little correlation between gene expression and seizure frequency, our results suggest that interictal spiking is a stronger driving force behind these activity‐dependent gene changes and may thus participate in the development and maintenance of the abnormal neuronal hyperactivity seen in human epileptic neocortex.
Timing of the Developmental Switch in GABAA Mediated Signaling from Excitation to Inhibition in CA3 Rat Hippocampus Using Gramicidin Perforated Patch and Extracellular Recordings
Authors: Tyzio Roman , Holmes Gregory L. , Ben‐Ari Yehezkiel , Khazipov Roustem
Published: October 2007

Summary:  The timing of the developmental switch in the GABAA mediated responses from excitatory to inhibitory was studied in Wistar rat CA3 hippocampal pyramidal cells using gramicidin perforated patch‐clamp and extracellular recordings. Gramicidin perforated patch recordings revealed a gradual developmental shift in the reversal potential of synaptic and isoguvacine‐induced GABAA mediated responses from –55 ± 4 mV at postnatal days P0–2 to −74 ± 3 mV at P13–15 with a midpoint of disappearance of the excitatory effects of GABA at around P8. Extracellular recordings in CA3 pyramidal cell layer revealed that the effect of isoguvacine on multiple unit activity (MUA) switched from an increase to a decrease at around P10. The effect of synaptic GABAA mediated responses on MUA switched from an increase to a decrease at around P8. It is concluded that the developmental switch in the action of GABA via GABAA receptors from excitatory to inhibitory occurs in Wistar rat CA3 pyramidal cells at around P8–10, an age that coincides with the transition from immature to mature hippocampal rhythms. We propose that excitatory GABA contributes to enhanced excitability and ictogenesis in the neonatal rat hippocampus.
The Involvement of the Substantia Nigra Pars Reticulata in Hypoglycemic Seizures
Authors: Velíšková Jana , Chudomel Ondřej , Poon Ka Lai , Marshall Barbara , Velíšek Libor
Published: October 2007

Summary:  Neurological complications of hypoglycemia often include seizures and fasting is a predisposing factor for seizures to occur. The mechanisms involved are unknown. In rats, insulin administration induces hypoglycemia, which may lead to generalized seizures with barrel rotations as a hallmark. Here we compared the incidence of barrel rotations in fasted and nonfasted rats. Further, we investigated the role of the substantia nigra pars reticulata (SNR) in control of barrel rotations using localized bilateral microinfusions of GABAA or GABAB receptor agonists (muscimol or baclofen, respectively) or an N‐methyl‐D‐aspartate (NMDA) receptor antagonist (AP7). The incidence of barrel rotations was significantly higher in fasted compared to nonfasted rats. SNR infusions of muscimol were ineffective, while both baclofen and AP7 significantly decreased occurrence of barrel rotations. These data suggest that during hypoglycemia, the SNR seizure controlling system has different properties than in seizure models not involving a metabolic stress.
GABAA Receptor Internalization during Seizures
Authors: Goodkin Howard P. , Sun Chengsan , Yeh Jwu‐Lai , Mangan Patrick S. , Kapur Jaideep
Published: October 2007

Summary:  A rapid modification in the postsynaptic γ‐aminobutyric acid (GABAA) receptor population occurs during the prolonged seizures of status epilepticus (SE). This rapid modification contributes to a reduction in GABA‐mediated inhibition and the development of benzodiazepine pharmacoresistance. Previous hypotheses to explain the modification have included an alteration in the structural composition or posttranslational modification of the receptors. In a cultured hippocampal neuron model, we found that there was differential subcellular distribution of GABAA receptor subunits and that the constitutive internalization of GABAA receptors containing a β2/3 subunit was rapid and activity‐dependent. Based on this finding, we posit that an activity‐dependent increase in the rate of internalization of synaptic GABAA receptors during SE contributes to the reduction in inhibitory transmission and the development of benzodiazepine pharmacoresistance.
Cell Cycle Reentry and Cell Proliferation as Candidates for the Seizure Predispositions in the Hippocampus of EL Mouse Brain
Authors: Murashima Yoshiya L. , Suzuki Jiro , Yoshii Mitsunobu
Published: October 2007

Summary:  We have recently found that there was DNA fragmentation without cell loss in the hippocampus in EL mice, an epileptic mutant. Neurotrophic factors are also expressed at high levels during the early developmental stages. In the present study, we used EL mice to examine how altered cyclin and the corresponding cyclin dependent kinase (CDK) family are related to cell proliferation during development and during epileptogenesis. Developmental changes of cyclin family and corresponding CDK family (cyclin D/CDK‐4, cyclin E/CDK‐2, cyclin A/CDK‐2, cyclin A/CDK‐1, cyclin B/CDK‐1) were examined by Western blotting in the hippocampus of EL mice and in nonepileptic control animals (DDY mice). In addition, we attempted to quantify cell proliferation during this period. The developmental changes in cell proliferation were determined by using systemic injections of Bromo‐deoxyUridine (BrdU) to label dividing cells. As compared with the control DDY mice, EL mice show an upregulation of cell cycle specific Cyclins/CDKs during early developmental stages suggesting that reentry into the cell cycle is enhanced prior to the onset of seizure activity, possibly due to the abundance of neurotrophic factors. These results show that Cyclins/CDKs are activated during early stages of development in an epileptic animal, before the mouse exhibits seizures. These results suggest that reentry of cells into the cell cycle, with consequent cell proliferation in the hippocampus, contribute to the seizure predispositions of EL mice.
Cholinergic Dysfunction in Temporal Lobe Epilepsy
Authors: Friedman Alon , Behrens Christoph J. , Heinemann Uwe
Published: October 2007

Summary:  The entorhinal cortex–hippocampus complex is believed to be the site of origin of seizure activity in the majority of patients with temporal lobe epilepsy (TLE). Both these regions are enriched with cholinergic innervation, which plays a key role in the normal control of neuronal excitability and in higher cognitive processes. In TLE, anatomical and functional changes occur in all cellular components of the local neural circuit. Thus, while it is not surprising that cholinergic functions are altered in the epileptic temporal lobe, the exact nature and role of these changes in the pathogenesis of the disease are not known. In this report, we summarize the scientific background and experimental data supporting a “cholinergic hypothesis of TLE.” We conclude that while the exact role of cholinergic dysfunction in TLE is not known, there is a firm basis for suggesting that changes in the expression of key cholinergic proteins—and the associated cholinergic dysfunction—are key factors in the basic mechanisms underlying TLE.
Hyperexcitability of the CA1 Hippocampal Region during Epileptogenesis
Authors: El‐Hassar Lynda , Esclapez Monique , Bernard Christophe
Published: October 2007

Summary:  Temporal Lobe Epilepsy (TLE) is often preceded by a latent (seizure‐free) period during which complex network reorganizations occur. In experimental epilepsy, network hyperexcitability is already present during the latent period, suggesting a modification of information processing. The purpose of this study was to assess the input/output relationship in the hippocampal CA1 region during epileptogenesis. Field recordings in strata pyramidale and radiatum were used to measure the output of CA1 pyramidal cells as a function of the synaptic inputs they receive following the stimulation of Shaffer collaterals in slices obtained from sham and pilocarpine‐treated animals during the latent and chronic periods. We show that there is a transient increase of the input and output field responses during the latent period as compared to sham and epileptic animals. The coupling between excitatory inputs and cell firing was also increased during the latent period. This increase persisted in epileptic animals, although to a lesser extent. We also confirm that paired‐pulse facilitation occurs before the chronic phase. The present data further support the view that hyperexcitability is present at an early stage of epileptogenesis. Network output is more facilitated during the latent than during the chronic period. Hyperexcitability may participate to epileptogenesis, but it is not sufficient in itself to produce seizures.
ABC Transporters during Epilepsy and Mechanisms Underlying Multidrug Resistance in Refractory Epilepsy
Authors: Lazarowski Alberto , Czornyj Liliana , Lubienieki Fabiana , Girardi Elena , Vazquez Silvia , D'Giano Carlos
Published: October 2007

Summary:  It is estimated 20–25% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P‐glycoprotein (P‐gp) and others ABC transporters as multidrug‐resistance‐associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P‐gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P‐gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P‐pg detection in vessel‐related cells and later additional P‐gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P‐gp expression, depending on intensity and time‐constancy of seizure‐injury, was in agreement with the development of “P‐gp‐positive seizure‐axis” proposed by Kwan & Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P‐gp expression in excretory organs suggests that P‐gp have a central role in drug elimination. Persistent low levels of AEDs in plasma and P‐gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of 99mTc‐hexakis‐2‐methoxyisobutylisonitrile (99mTc‐MIBI) (a P‐gp substrate), and the surgically treated cases showed P‐gp brain overexpression. These results suggest the systemic hyperactivity of P‐gp in RE patients, including brain P‐gp over‐expression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P‐gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure‐affected P‐gp‐positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P‐gp‐expressed cells that exhibit lower membrane potential (Δψ0=−10 to –20) compared to normal physiological Δψ0 of –60 mV. Under this situation and irrespective to the P‐gp pharmacoresistant property or type of drug treatment selected, P‐gp‐expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE.
The Effect of Generalized Absence Seizures on the Progression of Kindling in the Rat
Authors: Onat Filiz Yılmaz , Aker Rezzan Gülhan , Gurbanova Ayten Azizova , Ateş Nurbay , Van Luijtelaar Gilles
Published: October 2007

Summary: The involvement of the thalamus in limbic epileptogenesis has recently drawn attention to the connectivity between the nuclei of the thalamus and limbic structures. Thalamo‐limbic circuits are thought to regulate limbic seizure activity whereas thalamocortical circuits are involved in the expression and generation of spike‐and‐wave discharges (SWDs) in the absence epilepsy models. Genetic Absence Epilepsy Rats From Strasbourg (GAERS) and WAG/Rij (Wistar Albino Glaxo from Rijswijk) are well‐defined genetic animal models of absence epilepsy. We aimed to examine the duration of behavioral changes in the kindling process and the relation of SWD activity to the kindling progress in the GAERS and WAG/Rij animals. Electrodes were stereotaxically implanted into the basolateral amygdala and the cortex of rats for stimulation and recording. The animals were stimulated at the threshold for producing afterdischarges. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated using Racine's 5‐stage scale. None of the GAERS animals reached stage 3, 4, or 5 after application of 30 stimulations. The WAG/Rij animals showed different rate of kindling, therefore they were further categorized into the kindling‐resistant, slow‐kindled, and rapid‐kindled groups. The kindling‐resistant animals demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation and shorter duration of afterdischarge than did the kindled WAG/Rij animals. Behavioral durations at stage 2 were longer in kindled Wistar and WAG/Rij animals compared to kindling‐resistant WAG/Rij and GAERS. These results suggest that mechanisms involved in the generation of SWDs act as a counterbalance to the excitability induced by kindling.
Comparison of Cortical Epileptic Afterdischarges in Immature Genetic Absence Epilepsy WAG/Rij Rats with Those in Two Other Strains (ACI and Wistar)
Authors: Mareš Pavel , Tolmacheva Elena
Published: October 2007

Summary:  The aim of this study was to examine the development of cortical epileptic afterdischarges (ADs) in genetic absence epilepsy WAG/Rij rats, and to compare them with two strains with minimal incidence of spike‐and‐wave (SW) episodes (ACI and Wistar). Epileptic ADs were elicited by stimulation of sensorimotor cortex in 12‐, 18‐, and 25‐day‐old rats of the three strains. The threshold current intensities were established for movements accompanying stimulation, for ADs of the SW type and accompanying clonic seizures and for transition into limbic type of ADs (characterized by behavioral automatisms). Individual groups were formed by 7–12 rats. There were no differences among the three strains in the thresholds for elicitation of stimulation‐bound movements. In contrast, WAG/Rij and ACI rats exhibited easier elicitation of SW ADs than Wistar rats at the age of 18 and 25 days. There was no difference among the three strains in transition into the limbic type of ADs in 18‐ and 25‐day‐old rats. Lower thresholds for SW ADs in 18‐ and 25‐day‐old WAG/Rij and ACI rats in comparison with Wistar rats are in agreement with our data from adult animals as well as with development of pharmacologically induced models of absence seizures. The failure to find a specific difference between WAG/Rij rats and the other two strains might indicate a difference in generation of SW episodes and SW cortical AD.
Are Racial Disparities in Alcohol Treatment Completion Associated With Racial Differences in Treatment Modality Entry? Comparison of Outpatient Treatment and Residential Treatment in Los Angeles County, 1998 to 2000
Authors: Bluthenthal Ricky N. , Jacobson Jerry O. , Robinson Paul L.
Published: October 2007

Objective:  To determine whether racial and ethnic disparities in publicly funded alcohol treatment completion are due to racial differences in attending outpatient and residential treatment.

Methods:  Statistical analysis of alcohol treatment completion rates using alcohol treatment patients’ discharge records from all publicly funded treatment facilities in Los Angeles County from 1998 to 2000 (n = 10,591).

Results:  Among these patients, African American (OR = 0.52; 95% CI 0.47, 0.57) and Hispanic (OR = 0.89; 95% CI 0.81, 0.99) patients were significantly less likely to complete treatment as compared with White patients. We found that the odds of being in outpatient versus residential care were 1.42 (95% CI 1.29, 1.55) and 2.05 (95% CI 1.85, 2.26) for African American and Hispanic alcohol treatment patients, respectively, compared with White patients. Adjusting for addiction characteristics, employment, other patient‐level factors that might influence treatment enrollment, and unobserved facility‐level differences through a random effects regression model, these odds increased to 1.89 (95% CI 1.22, 2.94) for African American and to 2.12 (95% CI 1.40, 3.21) for Hispanics. We developed a conditional probability model to assess the contribution of racial differences in treatment modality to racial disparities in treatment completion. Estimates from this model indicate that were African American and Hispanic patients observed in outpatient care in this population to have the same probability of receiving residential care as White patients with otherwise similar characteristics, the White–African American difference in completion rates would be reduced from 13.64% (95% CI 11.58%, 15.71%) to 11.09% (95% CI 8.77%, 13.23%) and the White–Hispanic difference would disappear, changing from 2.63% (95% CI 0.29%, 4.95%) to −0.45% (−3.52%, 2.43%).

Conclusion:  It appears that reductions in racial disparities in treatment completion could be gained by increasing enrollment in residential alcohol treatment for African American and Hispanic alcohol abusers in Los Angeles County. Further research addressing why minority alcohol abusers are less likely to receive residential alcohol treatment should be conducted, as well as research that examines why African American alcohol treatment patients have lower completion rates as compared with White patients regardless of treatment modality.
Two‐Year Outcome of an Intervention Program for University Students Who Have Parents With Alcohol Problems: A Randomized Controlled Trial
Authors: Hansson Helena , Rundberg Jenny , Zetterlind Ulla , Johnsson Kent Ove , Berglund Mats
Published: October 2007

Background:  Only a few intervention studies aiming to change high‐risk drinking behavior have involved university students with heredity for alcohol problems. This study evaluated the effects after 2 years on drinking patterns and coping behavior of intervention programs for students with parents with alcohol problems.

Method:  In total, 82 university students (57 women and 25 men, average age 25 years) with at least 1 parent with alcohol problems were included in the study. The students were randomly assigned to 1 of the 3 programs: (i) alcohol intervention program, (ii) coping intervention program, or (iii) combination program. All the 3 intervention programs were manual based and individually implemented during 2 2‐hour sessions, 4 weeks apart. Before the participants were randomly assigned, all were subjected to an individual baseline assessment. This assessment contained both a face‐to‐face interview and 6 self‐completion questionnaires: the Alcohol Use Disorders Identification Test, estimated Blood Alcohol Concentration, Short Index of Problems, the Symptom Checklist‐90, Coping with Parents’ Abuse Questionnaire, and The Interview Schedule for Social Interaction (ISSI). Follow‐up interviews were conducted after 1 and 2 years, respectively. The results after 1 year have previously been reported.

Results:  All participants finished the baseline assessment, accepted and completed the intervention. Ninety‐five percent of the students completed the 24‐month follow‐up assessment. Only the group receiving the combination program continued to improve their drinking pattern significantly (p < 0.05) from the 12‐month follow‐up to the 24‐month follow‐up. The improvements in this group were significantly better than in the other 2 groups. The group receiving only alcohol intervention remained at the level of improvement achieved at the 12‐month follow‐up. The improvements in coping behavior achieved at the 12‐month follow‐up remained at the 24‐month follow‐up for all the 3 groups, i.e., regardless of intervention program.

Conclusion:  Positive effects of alcohol intervention between 1 and 2 years were found only in the combined intervention group, contrary to the 1‐year results with effects of alcohol intervention with or without a combination with coping intervention.
Application of Assessing Care of Vulnerable Elders‐3 Quality Indicators to Patients with Advanced Dementia and Poor Prognosis
Authors: Wenger Neil S. , Solomon David H. ,   the members of the ACOVE‐3 Clinical Committee, Amin Alpesh , Besdine Richard K. , Blazer Dan G. , Cohen Harvey , Fulmer Terry , Ganz Patricia A. , Grunwald Mark , Hall William J. , Katz Paul R. , Kitzman Dalane W. , Leipzig Rosanne M. , Rosenthal Ronnie A.
Published: October 2007

OBJECTIVES: To use a formal decision‐making strategy to reach clinically appropriate, internally consistent decisions on the application of quality indicators (QIs) to vulnerable elders (VEs) with advanced dementia (AD) or poor prognosis (PP).

DESIGN: Using a conceptual model that classifies QIs principally by aim and burden of the care process, 12 clinical experts rated whether each Assessing Care of Vulnerable Elders‐3 (ACOVE‐3) QI should be applied in evaluating quality of care for older persons with AD or PP. QI exclusions were assessed for each of the 26 conditions and by whether these conditions were mainly medical (e.g., diabetes mellitus), geriatric (e.g., falls), or crosscutting processes of care (e.g., pain management). QI exclusions were also identified for older persons who decided against hospitalization or surgery.

RESULTS: Of 392 ACOVE‐3 QIs, 140 (36%) were excluded for patients with AD and 135 (34%) for patients with PP; 57% of QIs focusing on medical conditions were excluded from patients with AD and 53% from patients with PP, whereas only 20% of QIs for geriatric conditions were excluded from AD and 15% from PP. All QIs with care processes judged to carry a heavy burden were excluded; 86% of moderate‐burden QIs were excluded from AD and 92% from PP. All QIs aimed at long‐term goals were excluded; 83% of intermediate‐term goal QIs were excluded from AD and 98% from PP. Individuals holding a preference to forgo hospitalization or surgery would be excluded from 7% of potentially applicable QIs.

CONCLUSION: Measurement of quality of care for VEs with AD, PP, and less‐aggressive care preferences should include only a subset of the ACOVE‐3 QIs, largely those whose burden is light and whose goal is continuity or short‐term improvement or prevention.
Sleep Complaints in Community‐Living Older Persons: A Multifactorial Geriatric Syndrome
Authors: Vaz Fragoso Carlos A. , Gill Thomas M.
Published: October 2007

In older persons, sleep complaints in the form of insomnia and daytime drowsiness are highly prevalent and are associated with adverse outcomes. The underlying mechanisms are linked to age‐related declines in physiology (normal aging) and age‐related increases in disease prevalence (usual aging). This article describes how normal aging leads to less‐restorative sleep, characterized by reductions in homeostatic and circadian sleep, and to phase advancement of the sleep–wake cycle, characterized by older persons being more alert in the early morning but drowsier in the early evening. It also describes how usual aging leads to sleep complaints through reductions in health status, loss of physical function, and primary sleep disorders. Psychosocial influences are likewise described, and their relevance to sleep complaints is discussed. These aging‐related changes are subsequently incorporated into a conceptual model that describes sleep complaints as a consequence of multiple and interdependent predisposing, precipitating, and perpetuating factors, akin to a geriatric syndrome. The discussion concludes by applying the conceptual model to the sleep‐related care of an older person with insomnia and daytime drowsiness and suggesting that the diagnostic assessment consider, in addition to primary sleep disorders, multiple domains, including medical, physical, cognitive, psychological, and social matters, with the intent of developing an overall therapeutic plan and establishing long‐term follow‐up.
The Geriatric Emergency Department
Authors: Hwang Ula , Morrison R. Sean
Published: October 2007

With the aging of the population and the demographic shift of older adults in the healthcare system, the emergency department (ED) will be increasingly challenged with complexities of providing care to geriatric patients. The special care needs of older adults unfortunately may not be aligned with the priorities for how ED physical design and care is rendered. Rapid triage and diagnosis may be impossible in the older patient with multiple comorbidities, polypharmacy, and functional and cognitive impairments who often presents with subtle clinical signs and symptoms of acute illness. The use of Geriatric Emergency Department Interventions, structural and process of care modifications addressing the special care needs of older patients, may help to address these challenges.