bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Design of Case‐controls Studies with Unscreened Controls
Authors: Moskvina V. , Holmans P. , Schmidt K. M. , Craddock N. 
Published: September 2005

SummaryTraditionally in genetic case‐control studies controls have been screened to exclude subjects with a personal history of illness. This control group has the advantage of optimal power to detect loci involved in illness, but requires more work and may incur substantial cost in recruitment. An alternative approach to screening is to use unscreened controls sampled from the general population. Such controls are generally plentiful and inexpensive, but in general there is a risk that some may have the same disease as the cases, which will reduce power to detect associations. We have quantified the extent of this power loss, and produced mathematical formulae for the number of unscreened controls necessary to achieve the same power as a fixed sample of screened controls. The effect of using unscreened controls will also depend on the ratio of the number of screened controls to cases specified in the original study design, and this is also investigated. We have also investigated the cost‐benefits of the screened and unscreened approaches, according to variation in the relative costs of sampling screened and unscreened controls, together with genotyping costs. We have, thus, identified the range of situations in which using unscreened controls is a cost‐effective alternative to the screened control method and could be considered when designing a study. In many of the typical, real‐world situations in complex genetics, the use of unscreened controls is potentially cost‐effective and can, in general, be considered for disorders with population prevalence Kp < 0.2. With the steady reduction in genotyping costs and the availability of common sets of “population controls” this design is likely to become increasingly cost effective.
High‐Resolution mtDNA Studies of the Indian Population: Implications for Palaeolithic Settlement of the Indian Subcontinent
Authors: Barnabas S. , Shouche Y. , Suresh C. G. 
Published: August 2005

SummaryThe population of the Indian subcontinent represents a very complex social and cultural structure. Occupying a geographically central position for the early modern human migrations, indications are that the founder group that migrated out of East Africa also reached India. In the present study we used the twin strategy of mapping the whole mitochondrial DNA (mtDNA) using the standard 14 restriction enzymes, and sequencing the non‐transcribed HVSI region, to derive maximum maternal lineages from a sample of non‐tribal Indians. The essential features of the reduced median network of the two datasets were the same. Both showed two demographic expansions of two major haplogroups, ‘M’ and ‘N’. The reduced median network was drawn with inputs from other studies on the Indian population, and correlated with data from other ethnic populations. The coalescence time of expansions and genetic diversity were estimated.A reduced median network was also drawn combining data from studies on Africans, Southeast Asians and West‐Eurasians, tracing the migration of ‘M’ from East Africa to India. A time estimate of the migration of major mtDNA haplogroups from Africa was attempted. The comparison of a set of Indian maternal lineages belonging to different geographical regions of the country, with other populations revealed the in‐situ differentiation and antiquity of the Indian population. Our analysis places the ‘southern route’ migration as the source of haplogroup ‘M’. Multiple migrations might have brought the other major haplogroups, ‘N’ and ‘R’, found in our sample to India. Archaeological evidence of modern humans in the subcontinent supports this mtDNA study.
Golli‐MBP Copy Number Analysis by FISH, QMPSF and MAPH in 195 Patients with Hypomyelinating Leukodystrophies
Authors: Vaurs‐Barriere C. , Bonnet‐Dupeyron M‐N. , Combes P. , Gauthier‐Barichard F. , Reveles X. T. , Schiffmann R. , Bertini E. , Rodriguez D. , Vago P. , Armour J. A. L. , Saugier‐Veber P. , Frebourg T. , Leach R. J. , Boespflug‐Tanguy O. 
Published: August 2005

SummaryThe inherited disorders of CNS myelin formation represent a heterogeneous group of leukodystrophies. The proteolipoprotein (PLP1) gene has been implicated in two X‐linked forms, Pelizaeus‐Merzbacher disease (PMD) and spastic paraplegia type 2, and the gap junction protein α12 (GJA12) gene in a recessive form of PMD. The myelin basic protein (MBP) gene, which encodes the second most abundant CNS myelin protein after PLP1, presents rearrangements in hypomyelinating murine mutants and is always included in the minimal region deleted in 18q‐ patients with an abnormal hypomyelination pattern on cerebral MRI. In this study, we looked at the genomic copy number at the Golli‐MBP locus in 195 patients with cerebral MRI suggesting a myelin defect, who do not have PLP1 mutation. Although preliminary results obtained by FISH suggested the duplication of Golli‐MBP in 3 out of 10 patients, no abnormal gene quantification was found using Quantitative Multiplex PCR of Short Fluorescent fragments (QMPSF), Multiplex Amplifiable Probe Hybridization (MAPH), or another FISH protocol using directly‐labelled probes. Pitfalls and interest in these different techniques to detect duplication events are emphasised. Finally, the study of this large cohort of patients suggests that Golli‐MBP deletion or duplication is rarely involved in inherited defects of myelin formation.
Tests of Association Between Quantitative Traits and Haplotypes In A Reduced‐Dimensional Space
Authors: Sha Qiuying , Dong Jianping , Jiang Renfang , Zhang Shuanglin 
Published: August 2005

SummaryCandidate gene association tests are currently performed using several intragenic SNPs simultaneously, by testing SNP haplotype or genotype effects in multifactorial diseases or traits. The number of haplotypes drastically increases with an increase in the number of typed SNPs. As a result, large numbers of haplotypes will introduce large degrees of freedom in haplotype‐based tests, and thus limit the power of the tests.In this study we propose using the principal component method to reduce the dimension, and then construct association tests on the lower‐dimensional space to test the association between haplotypes and a quantitative trait using population‐based samples. The proposed method allows ambiguous haplotypes. We use simulation studies to evaluate the type I error rate of the tests, and compare the power of the proposed tests with that of the tests without dimension reduction, and the tests with dimension reduction by merging rare haplotypes. The simulation results show that the proposed tests have correct type I error rates and are more powerful than other tests in most cases considered in our simulation studies.