bluuebunny/crossref_metadata_2025 huggingface dataset:
P2Y2 nucleotide receptor interaction with αV integrin mediates astrocyte migration
Authors: Wang Min , Kong Qiongman , Gonzalez Fernando A. , Sun Grace , Erb Laurie , Seye Cheikh , Weisman Gary A.
Published: August 2005

Astrocytes become activated in response to brain injury, as characterized by increased expression of glial fibrillary acidic protein (GFAP) and increased rates of cell migration and proliferation. Damage to brain cells causes the release of cytoplasmic nucleotides, such as ATP and uridine 5′‐triphosphate (UTP), ligands for P2 nucleotide receptors. Results in this study with primary rat astrocytes indicate that activation of a G protein‐coupled P2Y2 receptor for ATP and UTP increases GFAP expression and both chemotactic and chemokinetic cell migration. UTP‐induced astrocyte migration was inhibited by silencing of P2Y2 nucleotide receptor (P2Y2R) expression with siRNA of P2Y2R (P2Y2R siRNA). UTP also increased the expression in astrocytes of αVβ3/5 integrins that are known to interact directly with the P2Y2R to modulate its function. Anti‐αV integrin antibodies prevented UTP‐stimulated astrocyte migration, suggesting that P2Y2R/αV interactions mediate the activation of astrocytes by UTP. P2Y2R‐mediated astrocyte migration required the activation of the phosphatidylinositol‐3‐kinase (PI3‐K)/protein kinase B (Akt) and the mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MEK/ERK) signaling pathways, responses that also were inhibited by anti‐αV integrin antibody. These results suggest that P2Y2Rs and their associated signaling pathways may be important factors regulating astrogliosis in brain disorders.
Proliferation of microglial cells induced by 1‐methyl‐4‐phenylpyridinium in mesencephalic cultures results from an astrocyte‐dependent mechanism: role of granulocyte macrophage colony‐stimulating factor
Authors: Henze Carmen , Hartmann Andreas , Lescot Thomas , Hirsch Etienne C. , Michel Patrick P.
Published: August 2005

There is evidence that an inflammatory microglial reaction participates in the pathophysiology of dopaminergic neuronal death in Parkinson's disease and in animal models of the disease. However, this phenomenon remains incompletely characterized. Using an in vitro model of neuronal/glial mesencephalic cultures, we show that the dopaminergic neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP+) stimulates the proliferation of microglial cells at concentrations that selectively reduce the survival of DA neurones. The mitogenic action of MPP+ was not the mere consequence of neuronal cell demise as the toxin produced the same effect in a model system of neuronal/glial cortical cultures, where target DA neurones are absent. Consistent with this observation, the proliferative effect of MPP+ was also detectable in neurone‐free microglial/astroglial cultures. It disappeared, however, when MPP+ was added to pure microglial cell cultures suggesting that astrocytes played a key role in the mitogenic mechanism. Accordingly, the proliferation of microglial cells in response to MPP+ treatment was mimicked by granulocyte macrophage colony‐stimulating factor (GM‐CSF), a proinflammatory cytokine produced by astrocytes and was blocked by a neutralizing antibody to GM‐CSF. Thus, we conclude that the microglial reaction observed following MPP+ exposure depends on astrocytic factors, e.g. GM‐CSF, a finding that may have therapeutic implications.
Mitochondrial medicine: neuroprotection and life extension by the new amphiphilic nitrone LPBNAH1 acting as a highly potent antioxidant agent
Authors: Poeggeler Burkhard , Durand Grégory , Polidori Ange , Pappolla Miguel A. , Vega‐Naredo Ignacio , Coto‐Montes Ana , Böker Jutta , Hardeland Rüdiger , Pucci Bernard
Published: August 2005

The search for effective treatments that prevent oxidative stress associated with premature ageing and neurodegenerative diseases is an important area of neurochemical research. As age‐ and disease‐related oxidative stress is frequently associated with mitochondrial dysfunction, amphiphilic antioxidant agents of high stability and selectivity that target these organelles can provide on‐site protection. Such an amphiphilic nitrone protected human neuroblastoma cells at low micromolar concentrations against oxidative damage and death induced by exposure to the β‐amyloid peptide, hydrogen peroxide and 3‐hydroxykynurenine. Daily administration of the antioxidant at a concentration of only 5 μm significantly increased the lifespan of the individually cultured rotifer Philodina acuticornis odiosa Milne. This compound is unique in its exceptional anti‐ageing efficacy, being one order of magnitude more potent than any other compound previously tested on rotifers. The nitrone protected these aquatic animals against the lethal toxicity of hydrogen peroxide and doxorubicin and greatly enhanced their survival when co‐administered with these oxidotoxins. These findings indicate that amphiphilic antioxidants have a great potential as neuroprotective agents in preventing the death of cells and organisms exposed to enhanced oxidative stress and damage.
CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism
Authors: Silva Robert M. , Ries Vincent , Oo Tinmarla Frances , Yarygina Olga , Jackson‐Lewis Vernice , Ryu Elizabeth J. , Lu Phoebe D. , Marciniak Stefan M. , Ron David , Przedborski Serge , Kholodilov Nikolai , Greene Lloyd A. , Burke Robert E.
Published: August 2005

There is increasing evidence that neuron death in neurodegenerative diseases, such as Parkinson's disease, is due to the activation of programmed cell death. However, the upstream mediators of cell death remain largely unknown. One approach to the identification of upstream mediators is to perform gene expression analysis in disease models. Such analyses, performed in tissue culture models induced by neurotoxins, have identified up‐regulation of CHOP/GADD153, a transcription factor implicated in apoptosis due to endoplasmic reticulum stress or oxidative injury. To evaluate the disease‐related significance of these findings, we have examined the expression of CHOP/GADD153 in neurotoxin models of parkinsonism in living animals. Nuclear expression of CHOP protein is observed in developmental and adult models of dopamine neuron death induced by intrastriatal injection of 6‐hydroxydopamine (6OHDA) and in models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). CHOP is a mediator of neuron death in the adult 60HDA model because a null mutation results in a reduction in apoptosis. In the chronic MPTP model, however, while CHOP is robustly expressed, the null mutation does not protect from the loss of neurons. We conclude that the role of CHOP depends on the nature of the toxic stimulus. For 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.
Autocrine activation of EGF receptor promotes oscillation of glutamate‐induced calcium increase in astrocytes cultured in rat cerebral cortex
Authors: Morita Mitsuhiro , Kozuka Nagisa , Itofusa Rurika , Yukawa Masashi , Kudo Yosihisa
Published: August 2005

We previously reported that astrocytes cultured for more than 2 days in a defined medium containing epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) showed calcium oscillation in response to glutamate, whereas the response pattern was transient in the absence of the exogenous growth factors. In the present study, we found that astrocytes showed glutamate‐induced calcium oscillation, even in growth factor‐free medium, if the cells had been cultured for more than 5 days. The calcium oscillation promoted by the prolonged culture period was suppressed by an inhibitor of EGF receptor tyrosine kinase, but not by a neutralizing antibody to bFGF, indicating that the accumulation of an autocrine factor that activates the EGF receptor leads to calcium oscillation. Astrocytes in our culture system expressed EGF, transforming growth factor α (TGFα), bFGF and acidic fibroblast growth factor (aFGF). Exogenous aFGF, which induced astrocyte immediate early gene expression to the same extent as EGF or bFGF, did not affect calcium oscillation. Exogenous EGF and bFGF promoted astrocyte hypertrophic morphology and proliferation, as well as calcium oscillation. In contrast, these properties did not accompany calcium oscillation induced by the prolonged culture period. These results suggest that astrocytes possess the ability to promote their own calcium oscillation, which is independent of hypertrophic changes to reactive astrocytes.
Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells
Authors: Irace Carlo , Scorziello Antonella , Maffettone Carmen , Pignataro Giuseppe , Matrone Carmela , Adornetto Annagrazia , Santamaria Rita , Lucio Annunziato  , Colonna Alfredo
Published: August 2005

Ferritin, the main iron storage protein, exerts a cytoprotective effect against the iron‐catalyzed production of reactive oxygen species, but its role in brain injury caused by hypoxia/reoxygenation is unclear. Ferritin expression is regulated mainly at post‐transcriptional level by iron regulatory proteins (IRP1 and IRP2) that bind specific RNA sequences (IREs) in the 5′untranslated region of ferritin mRNA. Here, we show that hypoxia decreases IRP1 binding activity in glial cells and enhances it in cortical neurons. These effects were reversed by reoxygenation in both cell types. In glial cells there was an early increase of ferritin synthesis during hypoxia and reoxygenation. Conversely, in cortical neurons, ferritin synthesis increased during the late phase of reoxygenation. Steady‐state analysis of ferritin mRNA levels suggested that ferritin synthesis is regulated mainly post‐transcriptionally by IRPs in glioma cells, both transcriptionally and post‐transcriptionally in type‐1 astrocytes, and mainly at transcriptional level in an IRP‐independent way in neurons. The different regulation of ferritin expression may account for the different vulnerability of neurons and glial cells to the injury elicited by oxygen and glucose deprivation (OGD)/reoxygenation. The greater vulnerability of cortical neurons to hypoxia‐reoxygenation was strongly attenuated by the exogenous administration of ferritin during OGD/reoxygenation, suggesting the possible cytoprotective role exerted by this iron‐segregating protein.
Parent‐Identified Barriers to Pediatric Health Care: A Process‐Oriented Model
Authors: Sobo Elisa J. , Seid Michael , Gelhard Leticia Reyes
Published: September 2005

Objective. To further understand barriers to care as experienced by health care consumers, and to demonstrate the importance of conjoining qualitative and quantitative health services research.

Data Sources. Transcripts from focus groups conducted in San Diego with English‐ and Spanish‐speaking parents of children with special health care needs.

Study Design. Participants were asked about the barriers to care they had experienced or perceived, and their strategies for overcoming these barriers. Using elementary anthropological discourse analysis techniques, a process‐based conceptual model of the parent experience was devised.

Principal Findings. The analysis revealed a parent‐motivated model of barriers to care that enriched our understanding of quantitative findings regarding the population from which the focus group sample was drawn. Parent‐identified barriers were grouped into the following six temporally and spatially sequenced categories: necessary skills and prerequisites for gaining access to the system; realizing access once it is gained; front office experiences; interactions with physicians; system arbitrariness and fragmentation; outcomes that affect future interaction with the system. Key to the successful navigation of the system was parents' functional biomedical acculturation; this construct likens the biomedical health services system to a cultural system within which all parents/patients must learn to function competently.

Conclusions. Qualitative analysis of focus group data enabled a deeper understanding of barriers to care—one that went beyond the traditional association of marker variables with poor outcomes (“what”) to reveal an understanding of the processes by which parents experience the health care system (“how,”“why”) and by which disparities may arise. Development of such process‐oriented models furthers the provision of patient‐centered care and the creation of interventions, programs, and curricula to enhance such care. Qualitative discourse analysis, for example using this project's widely applicable protocol for generating experientially based models, can enhance our knowledge of the parent/patient experience and aid in the development of more powerful conceptualizations of key health care constructs.
Towards a Guideline for Design of a Corporate Entrepreneurship Function for Business Development in Medium‐Sized Technology‐Based Companies
Authors: Uittenbogaard Boaz , Broens Lute , Groen Aard J.
Published: August 2005

The speed with which global high‐technology markets evolve makes companies recognize that an effective innovation process is the best way to guarantee competitiveness. However, when (medium‐sized) companies then wish to set up a corporate entrepreneurship function to enhance business development processes, they can find little material available in literature to assist in such processes. In this article we have described a guideline and some backgrounds for creating a corporate entrepreneurship function to realize business development in a high‐tech context.
Spaces for Creativity and Innovation in Two Established Organizations
Authors: Haner Udo‐Ernst
Published: August 2005

Organizational work environments are increasingly strategically designed to support creativity and innovation processes, although a consistent theoretical frame for such an endeavour has not been developed yet. Creativity‐ and innovation‐oriented design of work environments requires an understanding of the principles of the underlying processes and their spatial implications. Both creativity and innovation processes are complex and display in different phases convergent and divergent characteristics. The processes are dependent on both individual and group effort. In this article these dimensions are discussed from a theoretical perspective and are used for evaluating the two cases presented here. The first case, the Interactive Creativity Landscape as integral part of the Fraunhofer Office Innovation Center in Germany has been designed interpreting the convergent and divergent phases of creative processes. The second case, the Learning Garden of a Scandinavian financial institution has been designed having de Bono's procedure in mind. The article concludes with the suggestion that increasingly organizations will offer diversity for spatially supporting creativity and innovation processes; solutions will be manifold but will follow certain principles – some of which are discussed here.
The Piccolomini library in Siena Cathedral: a new reading with particular reference to two compartments of the vault decoration
Authors: May Susan J.
Published: August 2005

The murals of the Piccolomini Library in Siena Cathedral, featuring episodes from the life of Pope Pius II, are usually discussed as distinctly separate from the vault imagery, predominantly all'antica and mythological scenes. The latter, combined with the centrally‐placed, antique statue of The Three Graces, has led some authors to comment on the library's overtly 'pagan' content as shockingly incongruent with its setting in the sacred precincts of the duomo. Little attention is paid to the significance of the stucco relief above the entrance, The Expulsion from Paradise. The article pro‐poses that such a prestigious project for so powerful and erudite a patron as Cardinal Francesco Todeschini Piccolomini, and painted by the highly acclaimed artist Pinturicchio, is unlikely to have been devised without careful attention to its iconographical programme. Focussing primarily on the two largest compartments of the vault, it is demonstrated that the four principal figures there should be interpreted as representatives of the four temperaments. By defining their relationship as such to the Expulsion from Paradise relief and to the historical narratives on the walls, this article shows that the mythological scenes in the vault play an allegorical role within the broader scheme and that a coherent programme underpins the entire decoration, with the writings of Saint Augustine and of his fifteenth century followers at its core.
The stigmatizing of Puritans as Jews in Jacobean England: Ben Jonson, Francis Bacon and the Book of Sports controversy
Authors: McDowell Nicholas
Published: August 2005

John Traske was publicly tortured and sentenced to life imprisonment in London in June 1618 for preaching that Jewish ceremonial laws continued to apply to Christians. Traske's punishment needs to be placed in the context of the government's campaign to discredit Puritan opposition to the Book of Sports, one of the most controversial policies of James's reign. The trial facilitated the polemical identification of Puritan sabbatarianism with the Old Testament legalism of the Jews, who personified the alien, anti‐Christian 'other' in the early modern English imagination even more starkly than Catholics. Francis Bacon, then at the height of his political powers, appears to have been involved in maximizing the publicity value of the Traske affair. This article also examines the stereotypes of the Puritan as Jew that had been developing in England, both in theological tract and on the popular stage, and discusses in particular a play closely associated with anti‐Puritanism and the government's promotion of Sunday sports, Ben Jonson's Bartholomew Fair (1614).
Did Giovanni Maria Manelli publish the Thesoro politico (1589)?*
Authors: Testa Simone
Published: August 2005

This contribution is another step towards establishing the origin of the Thesoro Politico (1589). It is only since 1995 that scholars have started investigating the origin of this book, and this article takes those results as the starting point. Here, I shall comment on manuscript letters found in Paris, some documents from the State Archives in Rome, and two books found in the National Library in Rome and in the British Library, which reveal unknown details about the life of Giovanni Maria Manelli, the person to whom the responsibility for the publication of the Thesoro Politico is attributed. The comparison between one of Manelli's letters and one of the reports in the Thesoro suggests that he can be considered the author of the Relazione delle divisioni di Francia. However, this does not automatically imply that Manelli is also responsible for the publication of the entire collection. Before this can be taken for granted, Manelli's relationship with the Parisian printers needs to be further investigated.
Titus Andronicus and the cultural politics of translation in early modern England
Authors: Oakley‐Brown Liz
Published: August 2005

This essay argues that the material invocation of Ovid's Metamorphoses in The Most Lamentable Roman Tragedie of Titus Andronicus (c. 1594) initiates an interrogation of the cultural politics of translation in early modern England. By comparing Shakespeare's play with Edward Ravenscroft's seventeenth‐century revision, Titus Andronicus, or the Rape of Lavinia (first performed 1678, first published 1687), the discussion focuses on ways in which the processes and products of translation construct the gendered subject.
Importance of Assessing Population Genetic Structure before Eradication of Invasive Species: Examples from Insular Norway Rat Populations
Authors: ABDELKRIM JAWAD , PASCAL MICHEL , CALMET CLAIRE , SAMADI SARAH
Published: September 2005

Abstract:  Determining the inter‐island migration abilities of pest species and delimiting eradication units enable more viable long‐term eradication campaigns because recurrent colonization from neighboring islands is avoided. We examined the genetic structure of the invasive Norway rat (Rattus norvegicus) to identify gene flow between islands and delimit population units at different geographical scales. We investigated variation in eight microsatellite loci in rat populations from 18 islands, representing five archipelagos off the Brittany coast (France). Although most of the islands are isolated from each other, short genetic distances, weak FSTvalues between close islands, and a high level of cross‐assignment showed that individuals collected on different islands could represent a single population unit. A Bayesian clustering method also supported the existence of high levels of gene flow between some neighboring islands. Thus, the statement “one island equals one population” can be false when inter‐island distances are less than a few hundred meters. Genetic studies enable the definition of island clusters among which migration may occur that should be considered eradication units. To avoid reinvasion and to minimize ecological and economic costs, rats on all islands in an eradication unit should be eradicated simultaneously. We suggest that the genetic monitoring we performed here can be applied for management of any pest.
Effectiveness of Existing Reserves in the Long‐Term Protection of a Regionally Rare Butterfly
Authors: GUTIÉRREZ DAVID
Published: September 2005

Abstract: The importance of unprotected habitats for the persistence of species in reserve networks is likely to be high for species living in highly fragmented habitat in which regional persistence depends on metapopulation processes. The dingy skipper butterfly (Erynnis tages) is a regionally rare declining species in Britain. In the Creuddyn Peninsula (North Wales), it inhabits patches of its host plant,Lotus corniculatusL., growing in lightly grazed areas in sheltered microhabitats, and its regional distribution is dominated by metapopulation processes. In this area, 16 (61%) out of 26.20 ha of dingy skipper habitat are located in reserves. The remaining unprotected habitat is mostly located in wasteland areas vulnerable to urban development. Using a metapopulation model, the incidence function model, I evaluated the extent to which the persistence of the dingy skipper in the landscape could be guaranteed with the existing reserve network. According to model projections, the dynamics within the reserve system were relatively stable when the unprotected habitat remained, with a maximum of 4% simulation replicates going extinct in a 100‐year time frame. When unprotected habitat was completely removed, however, the dynamics in the reserve network became markedly unstable, with an increased extinction risk ranging from 15 to 36%. We calculated a relatively simple measure of “patch importance,” the colonization potential, for each patch. The incidence function model predicted that for low and medium levels of regional stochasticity (σ value from 0 to 0.2), protecting only a relatively small number (four to six) of large and well‐connected patches (high colonization potential) in addition to the existing reserves would be enough to decrease notably the extinction risk of the dingy skipper metapopulation. The number of patches needed to be increased (11 patches) for high levels of regional stochasticity (σ= 0.3). My results suggest that long‐term persistence of a regionally rare butterfly in a reserve network may depend on the presence of unprotected habitat. For a more realistic estimate of the efficiency of reserves for protecting rare species, conservation biologists should consider incorporating metapopulation dynamics in their evaluations of persistence in existing reserves.
Regional IUCN Red Listing: the Process as Applied to Birds in the United Kingdom
Authors: EATON M. A. , GREGORY R. D. , NOBLE D. G. , ROBINSON J. A. , HUGHES J. , PROCTER D. , BROWN A. F. , GIBBONS D. W.
Published: September 2005

Abstract:  The World Conservation Union (IUCN) has developed guidelines that enable the assessment of extinction risk at a regional scale. We used these guidelines to assess the extinction risk of birds in the United Kingdom for comparison with an existing assessment of conservation status. Sixty‐four species were categorized as regionally threatened, of which 12 were critically endangered. The categorizations of the 223 species assessed agreed broadly with those from the existing U.K. system, which considers more than extinction risk, thus giving a more complete assessment of conservation status. There was, however, a tendency for the IUCN process to give higher risk status to edge‐of‐range species (some of which are relatively recent colonists considered of comparatively low conservation concern) and low status to those that have declined substantially but remain common (such as many farmland birds, the focus of considerable conservation effort in the United Kingdom). The final red list depended heavily on the subjective decisions made during the assessment process. An alternative interpretation of the guidelines could have resulted in as many as 19 or as few as 6 species being listed as critically endangered. We recommend the revision of the IUCN guidelines to reduce this subjectivity, in particular with respect to the effect of extralimital populations on the likelihood of regional extinction, and hence the potential for variation in the manner of application between regional red‐list assessors. Preventing extinction does not have to be the principal driving force behind conservation action at a regional scale if the continuance of a species is safeguarded in other regions.
Cattle Grazing Mediates Climate Change Impacts on Ephemeral Wetlands
Authors: PYKE CHRISTOPHER R. , MARTY JAYMEE
Published: September 2005

Abstract:  Climate change impacts depend in large part on land‐management decisions; interactions between global changes and local resource management, however, rarely have been quantified. We used a combination of experimental manipulations and simulation modeling to investigate the effects of interactions between cattle grazing and regional climate change on vernal pool communities. Data from a grazing exclosure study indicated that 3 years after the removal of grazing, ungrazed vernal pools dried an average of 50 days per year earlier than grazed control pools. Modeling showed that regional climate change could also alter vernal pool hydrology. Increased temperatures and winter precipitation were predicted to increase periods of inundation. We evaluated the ecological implications of interactions between grazing and climate change for branchiopods and the California tiger salamander ( Ambystoma californiense) at four sites spanning a latitudinal climate gradient. Grazing played an important role in maintaining the suitability of vernal pool hydrological conditions for fairy shrimp and salamander reproduction. The ecological importance of the interaction varied nonlinearly across the region. Our results show that grazing can confound hydrologic changes driven by climate change and play a critical role in maintaining the hydrologic suitability of vernal pools for endangered aquatic invertebrates and amphibians. These observations suggest an important limitation of impact assessments of climate change based on experiments in unmanaged ecosystems. The biophysical impacts of land management may be critical for understanding the vulnerability of ecological systems to climate change.
The Role of Immigration in the Decline of an Isolated Migratory Bird Population
Authors: WARD MICHAEL P.
Published: September 2005

Abstract:  Low immigration is rarely considered a potential causal factor in the population decline of migratory birds. Because migratory songbirds exhibit low natal philopatry, however, recruitment is from outside the population. Therefore, if isolation affects immigration the geographic fragmentation of a species' range may result in population declines. I tested four hypotheses on the possible causes of population decline of an isolated population of Yellow‐headed Blackbirds (Xanthocephalus xanthocephalus) in Illinois (U.S.A.): (1) local habitat loss, (2) poor reproductive success, (3) low adult survival, and (4) low immigration. Historical accounts indicate this population has declined and become more isolated over the last century. From 1998 to 2003, I determined the population size, the annual return rate, and mean reproductive success of Yellow‐headed Blackbirds in Illinois. I also determined the amount of suitable habitat for the species in the area. Over the course of the study the population declined by 25%. Although habitat loss was likely to be responsible for the population's historical decline, currently the habitat is not saturated and many seemingly appropriate sites remain unoccupied. The reproductive success of the Illinois population is one of the highest recorded for this species. Adult survival was within the range of survival values found in other stable populations. Yellow‐headed Blackbirds, like most migratory passerines, exhibit low natal philopatry; therefore, recruitment is primarily from outside the population. Recruitment was unusually low in this population, suggesting the population's isolation on the periphery of the species' range has reduced the number of immigrants. Although individuals in the population had high survival and reproduction, the population continued to decline because of low immigration. Conventional management (i.e., restoring habitat) may not mitigate a population's decline if low immigration is responsible for the decline. Greater connectivity at a large scale may be necessary to conserve isolated populations of migratory birds.
Diffusion Tensor Imaging in Late Posttraumatic Epilepsy
Authors: Gupta Rakesh K. , Saksena Sona , Agarwal Atul , Hasan Khader M. , Husain Mazhar , Gupta Vikas , Narayana Ponnada A.
Published: September 2005

Summary:  Purpose: The main objective of this study was to use diffusion tensor imaging (DTI) to search and quantify the extent of abnormality beyond the obvious lesions seen on the T2 and fluid‐attenuation inversion recovery (FLAIR) magnetic resonance images in patients with chronic traumatic brain injury (TBI) with and without epilepsy.

Methods: DTI was performed on 23 chronic TBI patients (with late posttraumatic epilepsy, n = 14; without epilepsy, n = 9) and 11 age‐matched controls. The ratios of fractional anisotropy (FA) and mean diffusivity (MD) between the regions of interest beyond the T2/FLAIR‐visualized abnormality and the corresponding contralateral normal‐appearing region were calculated. FA and MD ratios were compared for relative changes in these parameters among the TBI subjects with and without epilepsy and controls. Tissue volumes exhibiting abnormalities on DTI also were measured in these patients.

Results: The mean regional FA ratio was significantly lower, whereas the mean regional MD value was higher in patients with TBI compared with controls. The mean regional FA ratio was significantly lower in TBI patients with epilepsy (0.57 ± 0.059) than in those without epilepsy (0.68 ± 0.039). Although the regional MD ratio was higher in TBI patients with epilepsy (1.15 ± 0.140) relative to those without epilepsy (1.09 ± 0.141), the difference did not reach statistical significance. The tissue volume with low FA value also was found to be higher in TBI patients with epilepsy than without.

Conclusions: Severity of injury as predicted by the DTI‐derived increased volume of microstructure damage is associated with delayed posttraumatic epilepsy in TBI patients. These findings could be valuable in predicting epileptogenesis in patients with chronic TBI.
Preclinical Profiling and Safety Studies of ABT‐769: A Compound with Potential for Broad‐spectrum Antiepileptic Activity
Authors: Giardina William J. , Dart Michael J. , Harris Richard R. , Bitner Robert S. , Radek Richard J. , Fox Gerard B. , Chemburkar Sanjay R. , Marsh Kennan C. , Waring Jeffrey F. , Hui Julia Y , Chen Jinhua , Curzon Peter , Grayson George K. , Komater Victoria A. , Ku Yiyin , Lockwood Mark , Miner Holly M. , Nikkel Arthur L. , Pan Jia Bao , Pu Yu‐Ming , Wang Lei , Bennani Youssef , Durmuller Niklaus , Jolly Robert , Roux Sylvain , Sullivan James P. , Decker Michael W.
Published: September 2005

Summary:  Purpose: The objective of this study was to characterize the antiseizure and safety profiles of ABT‐769 [(R)‐N‐(2 amino‐2‐oxoethyl)spiro[2,5]octane‐1‐carboxamide].

Methods: ABT‐769 was tested for protection against maximal electroshock and pentylenetetrazol‐induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence‐like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid β‐oxidation assay. Teratogenic potential was assessed in the mouse.

Results: ABT‐769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol–induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice‐daily dosing of ABT‐769 (0.3 mmol/kg, p.o.) for 4 days. ABT‐769 blocked absence‐like spike–wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT‐769 did not affect inhibitory avoidance performance (0.1–1 mmol/kg, p.o.). ABT‐769 did not affect mitochondrial fatty acid β‐oxidation or induce neural tube defects.

Conclusions: ABT‐769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT‐769 has a broad‐spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.
Ketogenic Diet in Patients with Dravet Syndrome
Authors: Caraballo Roberto Horacio , Cersósimo Ricardo Oscar , Sakr Diego , Cresta Araceli , Escobal Nidia , Fejerman Natalio
Published: September 2005

Summary:  Purpose: The ketogenic diet (KD) has been used as a therapeutic alternative to antiepileptic drugs (AEDs) for refractory epilepsy. Severe myoclonic epilepsy in infants or Dravet syndrome (DS) is one of the most malignant epileptic syndromes. In this retrospective study, we evaluated the efficacy and tolerability of the KD in patients with diagnostic criteria of DS.

Methods: Between March 1, 1990, and August 31, 2004, 52 patients who met diagnostic criteria for DS were enrolled in a study at our department. Twenty of them were placed on the KD with the Hopkins protocol and followed up for a minimum of 1 year.

Results: Three of the 20 original children stayed on the diet for 12 months, four children for 2 years, four children for 3 years, and two children for 4 years. One year after initiating the diet, 13 (65%) of the initial patients remained on the diet. Two (15%) patients were seizure free, eight (61.7%) children had a 75–99% decrease in seizures, and the remaining three (23%) children had a 50–74% decrease in seizures. Thus 1 year after starting the diet, 10 (77%) children had achieved a >75% decrease in their seizures. Four patients have been off the diet for >2 years; one of them is seizure free, two have sporadic seizures, and one, who abandoned the diet after 2 years of adhering to it, relapsed. No differences in seizure control when compared with age, sex, or seizure type were found.

Conclusions: Considering the severity and intractability of seizures in patients with DS, the fact that 10 of the 13 children who remained on the diet had a significant reduction in number of seizures shows that the KD is at present an interesting therapeutic alternative. Even in patients in whom seizure reduction was not dramatic, quality of life improved, and in all of them, the number of AEDs was reduced to one or two. We consider that children with DS should be offered the KD immediately after three adequate trials of AEDs have failed.
Unusual Findings in Brain Biopsies of Two Patients with Acute Magnetic Resonance Imaging Lesions Associated with Focal Seizures
Authors: McClelland Shearwood , Libien Jenny M. , Chin Steven S. , Adams David J. , Resor Stanley R. , Chan Stephen , Goodman Robert R.
Published: September 2005

Summary:  Purpose: Patients with focal seizures often have magnetic resonance imaging (MRI) abnormalities in the brain region of their presumed seizure focus. Neoplasms, ischemic infarctions, inflammatory processes, and other specific pathologic entities have been diagnosed by biopsies of such MRI abnormalities. Two patients with this presentation had brain lesion biopsies with a leading presumptive diagnosis of glial neoplasm but were found to have indistinct histopathology.

Methods: Each patient was initially seen with focal seizures (right parietal region, right hippocampus) corresponding with focally increased T2 signal on MRI. In both patients, the preoperative clinical suspicion was for neoplastic or inflammatory processes.

Results: Several weeks after seizure onset, craniotomy in patient 1 and stereotactic needle biopsy in patient 2 revealed mild gliosis with reactive vascular changes and perivascular hemosiderin deposition, not diagnostic of but compatible with venous congestion (or possibly venous thrombosis). Postoperatively, patient 1 had brief sensory seizures that stopped 5 months after surgery, whereas subsequent seizures did not develop in patient 2. Both patients had normalization of their MRI (except for postoperative changes) and have remained seizure free.

Conclusions: We describe two patients who had brain biopsies of striking focal increased T2 signal MRI abnormalities associated with seizures. Pathologic findings contradicted our preoperative suspicions (neoplasm or inflammatory process), compatible with (but not conclusive for) subacute venous congestion/thrombosis. These findings indicate that patients with seizures may have an associated discrete intraaxial MRI lesion that is not neoplastic. To our knowledge, this is the first report of focal seizure–associated MRI lesions with biopsy findings compatible with venous congestion/thrombosis.
The Accuracy of Outcome Prediction Models for Childhood‐onset Epilepsy
Authors: Geelhoed Miranda , Boerrigter Anne Olde , Camfield Peter , Geerts Ada T. , Arts Willem , Smith Bruce , Camfield Carol
Published: September 2005

Summary:  Purpose: Two large prospective cohort studies of childhood epilepsy (Nova Scotia and the Netherlands) each developed a statistical model to predict long‐term outcome. We sought to evaluate the accuracy of a prognostic model based on the two studies combined.

Methods: Analyses with classification tree models and stepwise logistic regression produced predictive models for the combined dataset and the two separate cohorts. The resulting models were then externally validated on the opposite cohort. Remission was defined as no longer receiving daily medication for any length of time at the end of follow‐up.

Results: The combined cohorts yielded 1,055 evaluable patients. At the end of follow‐up (≥5 years in >96%), 622 (59%) were in remission. By using the combined data, the classification tree model and the logistic regression model predicted the outcome correctly in ∼70%. The classification tree model split the data on epilepsy type and age at first seizure. Predictors in the logistic regression model were: seizure number before treatment, age at first seizure, absence seizures, epilepsy types of symptomatic generalized and symptomatic partial, preexisting neurologic signs, intelligence, and the combination of febrile seizures and cryptogenic partial epilepsy. When the prediction models from each cohort were cross‐validated on the opposite cohort, the outcome was predicted slightly less accurately than did the model from the combined data.

Conclusions: Based on currently available clinical and EEG variables, predicting the outcome of childhood epilepsy may be difficult and appears to be incorrect in about one of every three patients.
Safety and Tolerability of the Ketogenic Diet in Pediatric Epilepsy: Effects of Valproate Combination Therapy
Authors: Lyczkowski David A. , Pfeifer Heidi H. , Ghosh Soumit , Thiele Elizabeth A.
Published: September 2005

Summary:  Purpose: To evaluate safety and tolerability of ketogenic diet (KGD) and valproate (VPA) cotherapy in the treatment of intractable seizures.

Methods: The patient records of children who underwent KGD initiation at the Massachusetts General Hospital for Children from February 2002 to September 2004 were retrospectively assessed. Efficacy was measured by comparing reported seizure frequency at baseline and at 3‐month intervals thereafter. Adverse events and reasons for terminating the diet were tabulated.

Results: Of 71 patients who underwent KGD initiation, 24 were concomitantly using VPA at the time of initiation. The most serious adverse events were two cases of acute pancreatitis (2.8%), both of which occurred in patients not taking VPA. The most common complications in both groups were acidosis (39.4%), nausea and vomiting (23.9%), hypertriglyceridemia (21.1%), lethargy (18.3%), and behavioral changes and irritability (15.5%). No significant difference in adverse‐event profiles was found between the VPA group and the non‐VPA group. At 1 year, 32 patients remained on the diet, including 11 in the VPA group. Efficacy was nearly identical in these two groups.

Conclusions: KGD and VPA combination therapy is relatively safe and effective in refractory pediatric epilepsy. Adverse‐event profiles of patients on KGD and VPA cotherapy are similar to those of patients on the KGD without VPA. In considering possible treatment options for intractable seizures, cotherapy with these two modalities should not be excluded for safety or tolerability concerns. In some patients, this combination may provide optimal seizure control.
Photic‐ and Pattern‐induced Seizures: A Review for the Epilepsy Foundation of America Working Group
Authors: Fisher Robert S. , Harding Graham , Erba Giuseppe , Barkley Gregory L. , Wilkins Arnold
Published: September 2005

Summary: Purpose:This report summarizes background material presented to a consensus conference on visually provoked seizures, convened by the Epilepsy Foundation of America.

Methods:A comprehensive review of literature was performed.

Results:Photosensitivity, an abnormal EEG response to light or pattern stimulation, occurs in ∼0.3–3% of the population. The estimated prevalence of seizures from light stimuli is ∼1 per 10,000, or 1 per 4,000 individuals age 5–24 years. People with epilepsy have a 2–14% chance of having seizures precipitated by light or pattern. In the Pokemon cartoon incident in Japan, 685 children visited a hospital in reaction to red–blue flashes on broadcast television (TV). Only 24% who had a seizure during the cartoon had previously experienced a seizure. Photic or pattern stimulation can provoke seizures in predisposed individuals, but such stimulation is not known to increase the chance of subsequent epilepsy. Intensities of 0.2–1.5 million candlepower are in the range to trigger seizures. Frequencies of 15–25 Hz are most provocative, but the range is 1–65 Hz. Light–dark borders can induce pattern‐sensitive seizures, and red color also is a factor. Seizures can be provoked by certain TV shows, movie screen images, video games, natural stimuli (e.g, sun on water), public displays, and many other sources.

Conclusions:Recommendations on reducing risk of seizures have been developed by agencies in the United Kingdom, Japan, and the International Telecommunications Union, affiliated with the United Nations. The Epilepsy Foundation of America has developed a consensus of medical experts and scientists on this subject, reported in an accompanying work.
Brainstem Seizure Severity Regulates Forebrain Seizure Expression in the Audiogenic Kindling Model
Authors: Merrill Michelle A. , Clough Richard W. , Jobe Phillip C. , Browning Ronald A.
Published: September 2005

Summary:  Purpose: Although sound‐induced (audiogenic) seizures in the genetically epilepsy‐prone rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR‐3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR‐9s, audiogenic kindling produces posttonic all‐limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR‐9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR‐9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR‐3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study.

Methods: Lesions of the superior colliculus or treatment with low‐dose phenytoin were used to suppress audiogenic seizure severity in GEPR‐9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR‐3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed.

Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR‐9s increased the incidence forebrain seizure behavior. Kindled GEPR‐9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR‐3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling.

Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR‐9s. It appears that the severe brainstem seizure of the GEPR‐9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
Monozygous Twin Brothers Discordant for Photosensitive Epilepsy: First Report of Possible Visual Priming in Humans
Authors: De Haan Gerrit‐Jan , Trenité Dorothee Kasteleijn–Nolst , Stroink Hans , Parra Jaime , Voskuyl Rob , Van Kempen Marian , Lindhout Dick , Bertram Ed
Published: September 2005

Summary:  Purpose: The interaction of genetic predisposition and the environment in the development of epilepsy is often discussed, but, aside from some animal reflex epilepsies, little evidence supports such interaction in the development of reflex epilepsy in humans.

Methods: We describe the history of a 16‐year‐old boy in whom photosensitive epilepsy developed after a period of weekly exposures to high‐intensity light flashes.

Results: Both he and his clinically unaffected monozygotic twin were found to be photosensitive.

Conclusions: This case report suggests that some genetic forms of human reflex epilepsy may be elicited by repeated environmental exposure to the appropriate stimulus, similar to some of the stimulus‐induced epilepsies seen in animals.