bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular determinants of ligand interaction with the capsaicin receptor
Authors: Jordt S.‐E. , Julius D.
Published: May 2003

Birds are indifferent to the pain‐producing effects of capsaicin. However, avian primary sensory neurons exhibit heat‐evoked membrane currents resembling those carried by mammalian capsaicin receptors. We aimed to identify an avian capsaicin receptor homolog, and to map structural determinants for vanilloid sensitivity. We cloned the avian capsaicin receptor ortholog, cVR1 (68% identity to rat VR1), from a chicken DRG library. cVR1 currents responded to noxious heat and acidity, but were insensitive to capsaicin. Structural domains essential for vanilloid interaction were mapped by chimeric analysis, ligand binding assays, mutagenesis and chemical labeling. Vanilloid sensitivity can be conferred to vanilloid‐insensitive capsaicin receptor homologs (cVR1, VRL1 and TRPV4) by a domain within the transmembrane moiety of rat VR1. Genetic and chemical modification studies suggest that capsaicin or the endogenous ligand, anandamide, bind to the receptor from the intracellular side of the plasma membrane and interact with residues near the third putative transmembrane region.
Characterization of VR1 within the BMBF‐Leitproject: ‘Molecular Pain Research’
Authors: Jostock R. , Christoph T. , Schiene K. , Behrendt H.‐J. , Kurreck J. , Grünweller A. , Erdmann V. A. , Jahnel R. , Hucho F. , Gillen C.
Published: May 2003

The vanilloid receptor VR1 is a ligand, heat and proton gated ion channel, expressed predominantly by primary sensory neurons. We show the molecular characterization of VR1 and its involvement in nociceptive behavior. Biochemical analysis of VR1 showed glycosylation at N604 and the predicted tetrameric structure. Reduced pH potentiated the gating of the receptor by NADA and anandamide in recombinant VR1. Acidification could sensitize VR1 and lead to hyperalgesia. Therefore, the VR1 antagonist capsazepine was tested in several animal models. Capsazepine reduced formalin induced nocifensive behavior and CFA induced mechanical hyperalgesia, and was antiallodynic and antihyperalgesic in animal models of neuropathic pain. VR1 antisense oligonucleotides inhibited VR1 expression in vitro and reduced tactile allodynia in vivo. In conclusion, we could provide evidence for a role of VR1 in inflammatory and neuropathic pain pathways.
Dopamine D2 receptors: key regulators of dopaminergic functions
Authors: Borrelli E.
Published: May 2003

Dopamine has a central role in the regulation of a variety of brain functions, ranging from locomotion to motivated behaviors, to learning and memory. Absence or alteration of the dopaminergic control profoundly affects human physiology leading to neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia. Dopamine acts through the interaction with membrane receptors of the G‐protein coupled receptor family. We have approached the study of D2 receptor (D2R) mediated signaling. Interestingly, two D2R isoforms are present in all vertebrates including humans, D2L and D2S, generated by alternative splicing of the same gene. Genetically engineered mice lacking both D2 isoforms show several deficits, among those, motor impairments and aberrant responses to drugs of abuse. Mice lacking only D2L show altered postsynaptic functions while preserve the control of dopamine release, which is mainly regulated by D2S. This functional difference indicates that regulation of splicing constitutes a key step in the control of D2‐mediated functions.
Mechanisms underlying in vivo neuroprotection by the endocannabinoid anandamide and the cannabinoid/vanilloid receptor agonist, arvanil
Authors: Van Der Stelt M. , Veldhuis W. B. , Wadman M. W. , Van Zadelhoff G. , Fezza F. , Veldink G. A. , Vliegenthart J. F. G. , Bär P. R. , Nicolay K. , Di Marzo V.
Published: May 2003

The endocannabinoid anandamide (AEA) and some of its oxidative metabolites are putative ligands for the vanilloid receptor (VR1). AEA affords protection against excitotoxicity induced in vivo by ouabain, a Na+/K+‐ATPase inhibitor. This effect is only partly dependent of the cannabinoid CB1 receptor. Here, we assessed whether VR1 is involved in neuroprotection by AEA and arvanil, which is a hydrolysis‐stable ligand for both VR1 and CB1. Using magnetic resonance imaging we show that: (i) modulation of VR1, by the agonists arvanil and capsaicin and the antagonist capsazepine, leads to neuroprotective effects in the late but not acute phase after i.c. ouabain‐injection; (ii) arvanil is a potent neuroprotectant, acting at both CB1 and VR1; and (iii) the neuroprotective effects of AEA are mediated by CB1 but not by lipoxygenase metabolites or VR1.
NMDA receptors mediate protective activation of extracellular signal regulated kinase1/2
Authors: Gozdz A. , Habas A. , Zielinska M. , Albrecht J. , Hetman M.
Published: May 2003

Neurons are exposed to damaging stimuli, which can trigger cell death and in consequence neurological disorders. Therefore it is important to define defence mechanisms which can be activated in response to damage to reduce neuronal loss. Here we report that cisplatin (CPDD), a neurotoxic anticancer drug that damages DNA triggered apoptosis in cultured cortical neurons from newborn rats. CPDD also activated ERK1/2 whose inhibition by either pharmacological inhibitors or dominant negative mutants increased apoptotic response. Interestingly, the protective ERK1/2 activation was a result of NMDA receptor sensitization. ERK1/2 mobilization was also dependent on activation of PARP. PARP mediated increase of NMDA receptor activity was not accompanied by ATP depletion. This suggests a novel mechanism of PARP‐mediated NMDA receptor regulation. In summary, our results identify a novel compensatory circuitry to defend CNS neurons against DNA damage.
Acid potentiation of the capsaicin receptor determined by a key extracellular site
Authors: Jordt S.‐E.
Published: May 2003

The capsaicin receptor, VR1, is a sensory neuron‐specific ion channel that serves as a detector of pain‐producing chemical and physical stimuli. The response of VR1 to capsaicin or heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, ischemia or tumor growth. A molecular determinant for this activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the pore region of the channel. This residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in proton concentration. We also show that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton‐evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus‐specific steps in VR1 activation and offer strategies for the development of analgesic agents.
Blood–brain barrier permeation, a challenge for the CNS chemist
Authors: George P.
Published: May 2003

Blood–brain barrier (BBB) permeation remains, within the optimization process of CNS drugs, a challenge for the medicinal chemist. In vitro tools are available for evaluating at an early stage the BBB permeation properties of drugs. Of particular interest is the in vitro model consisting of a mono‐layer of cocultured endothelial cells, in presence of astrocytes that allows the evaluation of trans‐endothelial permeability properties. This model is useful but presents some drawbacks and limitations. In addition it cannot be taken isolated from others pharmacokinetic parameters for optimizing in vivo BBB permeation properties. Illustrative examples of prototypic situations will be presented, including false positive or negative results, matched and mismatched relations between in vitro and in vivo results. As a conclusion, BBB permeation properties have to be linked to metabolic stability and oral absorption parameters for ideal optimization of CNS drugs.
The application of in situ and in vitro models for screening blood–brain barrier permeation
Authors: Read K. D.
Published: May 2003

The properties of the blood–brain barrier (BBB) are relevant to any program for drug discovery and development. Compounds chosen for their specificity at CNS target sites need to cross the BBB for biological action, yet high affinity for central sites does not guarantee BBB penetration. Conversely, compounds designed to act peripherally need to be tailored for low BBB penetration in order to avoid CNS side‐effects. A combination of in situ and in vitro models of the BBB, together with chemical understanding of the mechanisms of BBB penetration, can aid design and selection of compounds with appropriate properties to permeate, or to be excluded from, the CNS.
Screening of molecules through the BBB: involvement of drug efflux transporters
Authors: Fenart L. , Berezowski V. , Dehouck M. P. , Cecchelli R.
Published: May 2003

Despite remarkable advances in our understanding of mechanisms involved in the development of the brain diseases, drug delivery to the brain remains a challenge. The efflux transporter P‐glycoprotein (P‐gp) is a key element that confers permeability properties to the blood–brain barrier (BBB). Using an in vitro model, we provided evidence of the P‐gp expression and functionality at the BBB level. Furthermore, tissue distribution of multidrug resistance‐associated proteins, recently detected at the BBB site, and the contribution of the different cell populations in their expression level will be discussed.
Vectorization of proteins across the blood–brain barrier: high transcytosis of melanotransferrin (P97)
Authors: Béliveau R.
Published: May 2003

The blood–brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain. There is little transit across the BBB of large, hydrophilic molecules asides from some specific proteins which are taken up be receptor‐mediated endocytosis. Since melanotransferrin (P97) levels are very low in normal serum, we investigated whether P97 may cross the BBB to a greater extent than do other proteins. We thus observed that recombinant human P97 is highly accumulated into the mouse brain following intravenous injection and in situ brain perfusion. Moreover, P97 transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 14‐fold higher than that of transferrin, with no apparent changes in the BBCEC monolayer integrity. The brain accumulation, high rate of P97 transcytosis and its very low level in the blood suggest that P97 could be used as a new delivery system to target drugs directly to the brain.
Mouse models for neurodegenerative diseases and a theory of proteomics
Authors: Klose J.
Published: May 2003

Proteome analysis is usually performed by separating complex cellular protein extracts by two‐dimensional‐electrophoresis followed by protein identification using mass spectrometry. In this way proteins are compared from normal and diseased tissue in order to detect disease related protein changes. In a strict sense, however, this procedure cannot be called proteome analysis: the tools of proteomics are used just to detect some interesting proteins which are then investigated by protein chemistry as usual. Real proteome research would be studying the cellular proteome as a whole, its composition, organization and its kind of action. At present however, we have no idea how a proteome works as a whole; we have not even a theory about that. If we would know how the proteome of a cell type is arranged, we probably would alter our strategy to detect and analyze disease‐related proteins. I will present a theory of proteomics and show some results from our laboratory which support this theory. The results come from investigations of the mouse brain proteome and include mouse models for neurodegenerative diseases.
cDNA microarray to determine early and late gene expression in dopaminergic neurodegeneration
Authors: Weinreb O. , Mandel S. , Youdim M. B. H.
Published: May 2003

Although the etiology of neurodegeneration in Parkinson's disease is not known, biochemical evidence support the roles of iron, oxidative stress and inflammatory processes leading to neurodegeneration. We have investigated in vivo and in vitro, the alterations in gene expression, using the human and mice cDNA expression array membranes where several gene pathways can be analyzed at once, confirmed with quantitative RT‐PCR and protein analyses. Chronic treatment of mice with the neurotoxin MPTP caused alterations of 57 different genes involved in oxidative stress, inflammatory processes, glutamate, nitric oxides synthase and cell cycle. Pretreatment of mice with neuroprotective antiparkinsonian drugs, e.g. Rasagiline, R‐apomorphine and green tea polyphenol, EGCG, prevented the increase or decrease of most of the genes induced neuroprotection of dopamine neurons. Our studies provide new prospects to identify various mechanisms of neurodegeneration and neuroprotection, and discovery of effective neuroprotective antiparkinsonian drugs.
Gene therapy approaches for Parkinson's disease
Authors: Aebischer P. , Pralong W.
Published: May 2003

The CNS delivery of glial cell line‐derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease constitutes one of the more promising clinical applications of neurotrophic factors. Crucial for clinical application will be the ability to deliver GDNF within the target structures, i.e. striatum and/or substantia nigra. We are developing both in vivo and ex vivo gene therapy approaches to reach this goal. We have shown in rodents that both lentiviral vectors coding for GDNF and polymer encapsulated cells genetically engineered to release GDNF are able to protect nigral dopaminergic neurons against various insults including axotomy and neurotoxins such as 6‐hydroxydopamine. Even more important for clinical application is the ability to scale‐up the technology to nonhuman primate application. Neurorestorative and/or neuroprotective properties of GDNF expression were demonstrated with both methods in various nonhuman primate models.
Fast food delivery: the response of nursing astrocytes to an exciting call from neurons
Authors: Pellerin L.
Published: May 2003

It was suggested long time ago that astrocytes might play a prominent role in the distribution of energy substrates to neurons but convincing evidence was lacking. More recently, the excitatory neurotransmitter glutamate was shown to enhance aerobic glycolysis in cultured cortical astrocytes by a mechanism involving glial glutamate transporters. Using specific knockout mice for these transporters, it was demonstrated that a classical metabolic response to neuronal activation in the whisker‐to‐barrel system, 2‐deoxyglucose accumulation, was disrupted in the somatosensory cortex of these animals at postnatal day 10. From these data, it was concluded that a net transfer of some energy substrate, preferentially lactate, must be taking place in order to fulfill increasing neuronal energy needs during periods of enhanced activity. In support of this concept, the presence of specific transporters for lactate, known as monocarboxylate transporters, was recently described both on astrocytes and neurons in vitro as well as in vivo.
Astroglial glutathione export and the supply of glutathione precursors to neurons
Authors: Dringen R. , Hirrlinger J.
Published: May 2003

Neurons rely on the availability of extracellular cysteine for their glutathione (GSH) synthesis. This amino acid is generated by processing of extracellular GSH. Astrocytes play an important role in the GSH metabolism of the brain, since of the different brain cell type investigated only astrocytes release substantial amounts of GSH. The multidrug resistance protein 1 (Mrp1) which is expressed in astrocytes in vitro and in vivo mediates about 60% of the GSH release from cultured astrocytes. Extracellular GSH serves as substrate for the astroglial ectoenzyme gamma‐glutamyl transpeptidase (gGT). Inhibition of this enzyme prevents the astroglia‐mediated increase in the GSH level of cocultured neurons. The dipeptide CysGly, which is produced by gGT, is hydrolysed by the neuronal aminopeptidase N to glycine and cysteine. By providing the glutamate‐precursor glutamine and the dipeptide CysGly astrocytes supply to neurons precursors for all three amino acids which are required for neuronal GSH synthesis.
The potential role of astrocyte glutathione and tetrahydrobiopterin in the neurodegenerative process
Authors: Heales S. , Lam A.
Published: May 2003

Astrocytic generation of nitric oxide (NO) has been implicated in the neurodegenerative process. Cell culture studies reveal that astrocyte NO can cause neuronal mitochondrial damage. However, it appears that this damage may be limited by up‐regulation of neuronal glutathione (GSH) status. Thus, astrocytes have the capacity to release GSH/GSH precursors that can be utilized for neuronal GSH synthesis. Furthermore, the released GSH is prevented form oxidative degradation by the possible concomitant release of superoxide dismutase. Astrocytic NO generation requires the NO synthase cofactor, tetrahydrobiopterin (BH4). However, BH4 availability is compromised as a result of exposure to NO. Under these conditions, peroxynitrite synthesis may occur which could have a more deleterious effect upon adjacent neurones. Therefore, loss of ability to release GSH, by astrocytes, coupled with BH4 deficiency may be a factor in the neurodegenerative process.
Peroxynitrite as a novel neuroprotective intercellular signal
Authors: Bolaños J. P.
Published: May 2003

Peroxynitrite is thought to be a nitric oxide‐derived neurotoxic effector molecule involved in the disruption of key energy‐related metabolic and structural targets. Recent work from our laboratory has reported that (1) l‐arginine released from astrocytes in response to peroxynitrite is efficiently taken up by neighboring neurons, a fact that seems to be focussed to facilitate nitric oxide biosynthesis; and (2) peroxynitrite rapidly and strongly activates the pentose‐phosphate pathway in neurons and in astrocytes, a phenomenon that appears to be associated with glutathione regeneration and neuronal protection against apoptotic death. According to these lines of evidence we suggest that, whereas exerting delayed neurotoxicity, peroxynitrite may initially serve as a neuron/astrocyte intercellular signaling molecule that triggers key metabolic changes aimed at preventing the propagation of neurodegeneration.

Acknowledgements:  Funded by MCYT Grant SAF2001‐1961 and JCYL Grant SA065/01.
Predicting Acute Renal Failure after Cardiac Surgery: Validation and Re‐definition of a Risk‐Stratification Algorithm
Authors: Thakar Charuhas V. , Liangos Orfeas , Yared Jean‐Pierre , Nelson David A. , Hariachar Srinivas , Paganini Emil P.
Published: May 2003

Background:  Acute renal failure (ARF) after cardiac surgery is associated with significant morbidity and mortality, irrespective of the need for dialysis. Previous studies have attempted to identify predictors of ARF and develop risk stratification algorithms. This study aims to validate the algorithm in an independent cohort of patients that includes a significant proportion of female and black patients and compares two different definitions of renal outcome.

Methods:  A large single center cardiac surgery database was examined (n, 24,660; 1993–2000) which included 29.9% females and 3.7% black patients. Post‐operative ARF was defined as: a) ARF requiring dialysis, b) > 50% reduction in creatinine clearance relative to baseline or requiring dialysis. Clinical variables related to baseline renal function and cardiovascular disease were used in recursive partitioning analysis for both outcome definitions. Chi‐square goodness of fit analysis was performed to validate the algorithm.

Results:  The frequency of post‐operative ARF requiring dialysis ranged between 0.5 and 15.5% based on the risk categories with the area under the receiver operating characteristic (ROC) curve of 0.78. Using the more inclusive definition of ARF, the frequency was significantly higher ranging from 2.6 to 25%(P < 0.001) with an area under ROC curve of 0.65.

Conclusions:  The renal risk stratification algorithm is valid in predicting post‐operative ARF in an independent cohort of patients, well represented by differences in gender and race. Since the need for dialysis remains subjective, a more objective and inclusive definition of ARF may help in identifying a larger number of patients ‘at‐risk’.
Structure and Dosimetric Analysis of Biodegradable Glasses for Prostate Cancer Treatment
Authors: Roberto Wanderley S. , Pereira Marivalda M. , Campos Tarcísio P.R.
Published: May 2003

Abstract: This work analyzes SiO2 and SiO2‐CaO glasses incorporated with samarium atoms produced by sol‐gel synthesis. The goal is to provide biocompatible and biodegradable radioactive seeds as an alternative to be used in brachytherapy for the treatment of prostate cancer. The chemical and physical characteristics of the obtained glasses were analyzed by energy dispersive x‐ray spectroscopy, x‐ray diffraction, He picnometry, and nitrogen adsorption analysis. A theoretical analysis of the process of neutron activation of the samples was also conducted through the calculation of the activity of the seeds and the beta‐ and gamma‐ray doses emitted by the seeds. The results demonstrate the incorporation of samarium atoms in the glass matrix. The experimental data coupled with the theoretical studies in neutron activation suggest that it is possible to obtain radioactive seeds with activities equivalent to 125I seeds used in prostatic brachytherapy.
Rapid and Sensitive Paradigm for Screening Patients With Headache in Primary Care Settings
Authors: Maizels Morris , Burchette Raoul
Published: May 2003

Objective.—To determine the sensitivity and specificity of a brief headache screening paradigm for primary care clinicians.

Background.—Migraine and drug rebound headache are disabling primary headache disorders. Both are underdiagnosed and undertreated. A method for rapid screening of migraine, drug rebound headache, and other daily headache syndromes would be useful. The Brief Headache Screen uses 3 questions—the frequency of severe (disabling) headache, other (mild) headache, and use of symptomatic medication—to generate diagnoses.

Methods.—The Brief Headache Screen was evaluated in an emergency department, a family practice department, and a referral headache clinic. Diagnoses from the Brief Headache Screen were compared to diagnoses of trained researchers and headache specialists.

Results.—Three hundred ninety‐nine patients were screened and interviewed. The criterion of episodic severe (disabling) headache correctly identified migraine in 136 (93%) of 146 patients with episodic migraine and 154 (78%) of 197 patients with chronic migraine, with a specificity for any migraine (episodic or chronic) of 32 (63%) of 51. The inclusion of episodic or daily severe headache identified migraine in 100% of patients with chronic migraine. Only 6 (1.7%) of 343 patients with migraine were not identified by severe (disabling) headache. The combination of severe and mild headache frequency was sensitive to daily headache syndromes in 218 (94%) of 232 patients with a specificity of 87 (54%) of 162. Medication overuse was correctly identified in 146 (86%) of 169 patients with a specificity of 22 (79%) of 28.

Conclusion.—The frequency of severe (disabling) and mild headaches and use of symptomatic medications, rapidly and sensitively screens for migraine, daily headache syndromes, and medication overuse. The use of this paradigm in primary care settings may improve the recognition of these important headache syndromes.
Normalization of High Interictal Cerebrovascular Reactivity in Migraine Without Aura by Treatment With Flunarizine
Authors: Dora Babür , Balkan Sevin , Tercan Evren
Published: May 2003

Background.—Modification of migraine‐associated cerebrovascular reactivity may provide insight into the mechanism of action of a given therapeutic intervention.

Methods.—With transcranial Doppler and a breath‐holding index, cerebrovascular reactivity to hypercapnia was evaluated in 20 patients with migraine without aura interictally and in 11 healthy controls. Patients were started on prophylactic treatment with flunarizine 10 mg per day, and measurements were repeated at the end of every month for 3 months. Headache status was evaluated clinically via a headache index. Headache index; breath‐holding index; systolic, diastolic, and mean blood flow velocities; and pulsatility index measurements were recorded at every session.

Results.—The baseline breath‐holding index was significantly higher in the migraine group compared to the control group (P  =  .002). No difference in other parameters was found between the groups. The change in the headache index was significant (P<.001), indicating a beneficial effect from flunarizine. The breath‐holding index improved significantly after treatment (P<.001), and the baseline difference in the breath‐holding index between the pretreatment migraine group and the control group was no longer evident at 3 months. There was no significant change with treatment in the other transcranial Doppler parameters.

Conclusion.—Our finding of unchanged blood flow velocities but normalized cerebrovascular reactivity after treatment suggests that the mechanism of action of flunarizine in migraine does not involve a vasodilatory effect on cerebral vessels. It may be instead that flunarizine modifies cerebrovascular reactivity through its action on centrally located structures that subserve autonomic vascular control.
Migraine Prevalence During Menopausal Transition
Authors: Wang Shuu‐Jiun , Fuh Jong‐Ling , Lu Shiang‐Ru , Juang Kai‐Dih , Wang Peng‐Hui
Published: May 2003

Background.—The effect of menopausal transition on the frequency of migraine has never been the focus of a community‐based study.

Methods.—A cross‐sectional community‐based survey was undertaken among Chinese women aged 40 to 54 years in Kinmen, Taiwan. Neurologists diagnosed migraine based on the 1988 International Headache Society classification criteria. Menstrual history including a past or current history of premenstrual syndrome was obtained. Serum levels of estradiol and follicle‐stimulating hormone were measured.

Results.—The 1‐year prevalence of migraine was 16.5% in the 1436 participants. Among the women who had not had hysterectomies and did not report symptoms of premenstrual syndrome, migraine prevalence did not vary according to menopausal status. In contrast, in women with self‐reported premenstrual syndrome, menopausal status was a factor in migraine prevalence: the late perimenopausal group had the highest prevalence (31%) and the spontaneous menopausal group had the lowest (7%). Among all menopausal groups, women who had had hysterectomies reported the highest migraine prevalence (27%), with the highest occurring in those with premenstrual syndrome (44%). The presence of low estrogen (<50 pg/mL) and high follicle‐stimulating hormone levels (>30 mIU/mL) was associated with lower migraine prevalence, even in the premenopausal and early perimenopausal women.

Conclusions.—Our data supported the clinical impression that migraine prevalence increases before menopause and declines after spontaneous menopause. However, in this study, this trend occurred only in women with increased vulnerability to hormonal change, such as those with premenstrual syndrome. The presence of low estrogen and high follicle‐stimulating hormone levels predicted lower migraine prevalence, whereas a history of hysterectomy was related to higher prevalence.
Naratriptan in the Preventive Treatment of Refractory Chronic Migraine: A Review of 27 Cases
Authors: Rapoport Alan M. , Bigal Marcelo E. , Volcy Michel , Sheftell Fred D. , Feleppa Michele , Tepper Stewart J.
Published: May 2003

Objective.—To review the efficacy of naratriptan as preventive treatment in 27 patients with chronic migraine refractory to other commonly used preventive therapies.

Background.—The treatment of chronic migraine often poses a major challenge to the clinician. Even when given expert care, patients with chronic migraine may continue to have daily or near‐daily headaches.

Methods.—Clinical records and headache calendars were reviewed of 27 patients fulfilling the following inclusion criteria: (1) aged 18 to 65 years; (2) diagnosis of chronic migraine (formerly transformed migraine), according to the criteria proposed by Silberstein et al; (3) previous failure of at least 4 preventive medications prescribed as part of a management program that included nonpharmacological measures, preventive medication, acute care medication, and detoxification from overused medication; and (4) have used daily naratriptan for no less than 2 consecutive months. The dose of naratriptan prescribed was 2.5 mg twice daily. We considered the following outcomes: (1) frequency of headache, (2) intensity of pain, (3) number of days per month with severe headache, (4) headache index (frequency times intensity), and (5) proportion of patients who reverted to an episodic pattern of pain after 6 months of treatment.

Results.—There was a statistically significant reduction in the frequency of headache days 2 months (15.3 days versus 24.1 days at baseline, P<.001), 6 months (9.1 days, P<.001), and 1 year (7.3 days, P<.001) after daily treatment with naratriptan was initiated. There was also a statistically significant reduction in the number of days per month of severe pain at 1 month (5.6 days versus 12.5 days at baseline, P<.01), 2 months (5.7 days, P<.01), 6 months (2.8 days, P<.01), and 1 year (2.6 days, P<.01). Similarly, there was a statistically significant reduction in the headache index at 2 months (33 versus 56.4 at baseline, P<.001), 6 months (19.5, P<.001), and 1 year (17.2, P<.001).

Of the 20 patients who continued to use naratriptan daily for at least 6 months, 13 (65%) reverted to an episodic pattern of pain (migraine). At 1 year, 11 (55%) still continued to experience episodic headache, 1 (5%) relapsed to chronic migraine, and 2 (10%) were lost to follow‐up. No patients had intolerability to naratriptan during the treatment period, and no one stopped treatment due to adverse events.

Conclusion.—Naratriptan may have a role in the preventive treatment of intractable chronic migraine. Prospective, controlled studies should be considered.
Transformation Into Daily Migraine With Aura Following Transcutaneous Atrial Septal Defect Closure
Authors: Yankovsky A. E. , Kuritzky A.
Published: May 2003

A link between migraine with aura and cardiac right‐to‐left shunting has been previously reported. Abortion or decreased frequency of migraine with aura attacks after atrial septal defect closure has been reported in the literature. We report the first case of transformation of migraine with aura into a daily pattern after atrial septal defect closure.

A 48‐year‐old male who had been suffering from rather infrequent attacks of migraine with sensory and visual aura underwent transcutaneous closure of an atrial septal defect. His migraine attacks changed into a daily pattern the day following the procedure and remained so for 6 months. This change in pattern may be related to a changed intra‐atrial pressure after the closure or some other unknown factor.
Seizure Characterization and Electroencephalographic Features in Glut‐1 Deficiency Syndrome
Authors: Leary Linda D. , Wang Dong , Nordli Douglas R. , Engelstad Kristin , De Vivo Darryl C.
Published: May 2003

Summary: Purpose:To characterize seizure types and electroencephalographic features of glucose transporter type 1 deficiency syndrome (Glut‐1 DS).

Methods:Twenty children with clinical and laboratory features of Glut‐1 DS were evaluated. Age at seizure diagnosis, seizure classification, and response to treatment were determined by chart review. Thirty‐two continuous 24‐h EEG monitoring sessions and reports of 42 routine EEG studies were assessed.

Results:Age at seizure diagnosis was between 4 weeks and 18 months (mean, 5 months). Seizure types were generalized tonic or clonic(14), absence(10), partial (nine), myoclonic (six), or astatic (four). During 24‐h EEGs, background activity showed generalized 2.5‐ to 4‐Hz spike–wave discharges (41%), generalized slowing or attenuation (34%), no abnormalities (34%), focal epileptiform discharges (13%), or focal slowing or attenuation (9%). No seizures were captured during 69% of the studies; the remainder had absence (19%), myoclonic (9%), or partial seizures (3%). On evaluation of routine and 24‐h EEG studies, focal epileptiform discharges (24%) and slowing (11%) were more frequent in ages 0–24 months. In older children (2–8 years), generalized epileptiform discharges (37.5%) and slowing (21%) were more common.

Conclusions:In all ages, a normal interictal EEG was the most common EEG finding. When abnormalities occurred, focal slowing or epileptiform discharges were more prevalent in the infant. In older children (2 years or older), a generalized 2.5‐ to 4‐Hz spike–wave pattern emerged. Seizure types observed included, absence, myoclonic, partial, and astatic.
Topiramate and Psychiatric Adverse Events in Patients with Epilepsy
Authors: Mula Marco , Trimble Michael R. , Lhatoo Samden D. , Sander Josemir W. A. S.
Published: May 2003

Summary:  Purpose: The aim of this study was to determine the prevalence of psychiatric adverse events (PAEs) in patients with epilepsy treated with topiramate (TPM). Classification, relation to TPM dosing, and outcome were evaluated to identify a patient profile at risk of developing PAEs.

Methods: We evaluated the data of the first consecutive and prospectively collected patients in therapy with TPM.

Results: Follow‐up information was available for 431 patients. PAEs occurred in 103 (23.9%) patients; M/F ratio, 55:48; mean age (±SD), 36.5 ± 11.2. In 46 (10.7%) patients, an affective disorder developed; in 16 (3.7%), a psychotic disorder; in 24 (5.6%), aggressive behavior with or without irritability; in 17 (3.9%), other behavior abnormalities such as agitated behavior, anger/hostility behavior, or anxiety. High starting dose and rapid titration schedule were relevant for the development of PAEs. Family psychiatric history and family history of epilepsy, personal history of febrile convulsions, psychiatric history, and presence of tonic–atonic seizures were found to be significant risk factors. Low seizure frequency before starting TPM and TPM/lamotrigine coadministration had a protective effect for PAEs.

Conclusions: We found that PAEs associated with TPM were related to the titration schedule of the drug and that a unique patient profile is suggested by the clinical history.
Effects of Valproic Acid, Carbamazepine, and Phenobarbitone on the Fatty Acid Composition of Erythrocyte Membranes in Children
Authors: König Stephan A. , Knolle Julia , Friedewald Steffen , Koelfen Wolfgang , Longin Elke , Lenz Tamara , Hannak Dieter
Published: May 2003

Summary:  Purpose: To investigate a possible relation between antiepileptic drugs (AEDs) and the fatty acid composition of membranes.

Methods: Fatty acid (FA) composition of erythrocytes was studied in children with epilepsy receiving AED monotherapy. Children taking valproate (VPA, n = 28), carbamazepine (CBZ, n = 17), or phenobarbitone (PB, n = 14) were compared with healthy controls (n = 25). FAs were measured by capillary‐gas chromatography (GC‐FID).

Results: Significant changes (p < 0.05) in the FA composition of membranes were found. In children treated with VPA, C13:0 was decreased (8.2 ± 2% vs. 10.7 ± 4% in controls) and C14:0 increased (1.4 ± 0.5% vs.1 ± 0.5% in controls). C17:0 again was reduced (9.9 ± 4% vs. 13.2 ± 6% in controls), whereas the long‐chained acids were enhanced: C18:2n‐6 (6 ± 2.4% vs. 3.9 ± 2.5% in controls), and C20:4n‐6 (1.9 ± 1.7% vs. 1.4 ± 0.5% in controls). The nonidentified FAs also increased with VPA therapy: 2.5 ± 0.8% versus 1.7 ± 0.9% in controls. Children treated with CBZ showed only minimal changes of FA composition: C13:0 was decreased compared with controls (8 ± 2% vs. 10.7 ± 4%). No changes were seen in patients taking PB. The mean corpuscular volume (MCV) showed important differences between the study groups: MCV was 84.7 ± 6.0 fl during VPA therapy (p < 0.001) and 85.7 ± 4.1 fl with CBZ (p < 0.001). During PB, the MCV increased to 82.87 ± 3.29 fl compared with controls (78.73 ± 4.92 fl; p < 0.01).

Conclusions: VPA therapy is associated with changes of the FA composition of membranes, which is not the case with PB therapy. The implications of this finding remain to be established.
Epileptic Spasms and Partial Seizures as a Single Ictal Event
Authors: Pachatz Christa , Fusco Lucia , Vigevano Federico
Published: May 2003

Summary:  Purpose: To investigate the phenomenon of epileptic spasms (ESs) associated with other seizure types in a single ictal event and to study the predictive value of this phenomenon regarding etiology and prognosis.

Methods: We selected retrospectively eight female and five male patients, who had ESs and other seizure types within a single seizure event and for whom a video‐EEG recording of the phenomenon was performed in at least one situation.

Results: The seizure type associated with ESs was a partial seizure in all patients. We identified three groups with different seizure patterns regarding the temporal association of ES and partial seizures (PSs): (a) PS followed by ES; (b) PS appearing during a cluster of ESs without interrupting the cluster; and (c) complex seizure interaction with a succession of ESs and PSs in a close but variable temporal association. Underlying disorders included cortical dysplasia (three patients), complex cerebral malformations (two patients), and perinatal anoxic–ischemic injuries (two patients); four cases were classified as cryptogenic, and in two children, etiology was unknown, but prenatal origin was suspected. Outcome was poor in nine cases with intractable epilepsy; four cases had a favorable outcome, defined as complete cessation of epileptic seizures.

Conclusions: The phenomenon of associated ESs and PSs as a single ictal event can be related to different etiologies and should not be considered distinctive for cortical malformations or severe brain damage. Different seizure patterns of associated ESs and PSs provide no hint for etiology or prognosis. Outcome is prevalently but not constantly unfavorable in patients with the phenomenon.
EEG‐related Functional MRI in Benign Childhood Epilepsy with Centrotemporal Spikes
Authors: Boor Stephan , Vucurevic Goran , Pfleiderer Christian , Stoeter Peter , Kutschke Georg , Boor Rainer
Published: May 2003

Abstract:The localization of epileptic foci is an important issue in children with extratemporal epilepsies. However, the value of noninvasive methods such as the EEG‐assisted functional magnetic resonance imaging (fMRI) has not been sufficiently investigated in children.

As a model of extratemporal epilepsies, we studied 7 patients aged 5 to 12 (median 10) years with benign childhood epilepsy and centrotemporal (rolandic) spikes. Interictal spikes were recorded during the fMRI acquisition on a MR‐compatible battery‐powered digital EEG system with 16 channels. The fMRI sequences were correlated off‐line with the EEG spikes and analyzed with the software Statistical Parametrical Mapping SPM99.

The fMRI results demonstrated the spike‐related activation in the perisylvian central region in three patients; we could not demonstrate fMRI activation despite active spiking in 2 patients, and 2 patients did not produce sufficient spikes for fMRI analysis. We currently consider the spike‐related fMRI as a research tool that localizes epileptic activity in selected patients. Further improvements of the technique are necessary to allow a clinical application of this method.
A Retrospective Analysis of Hippocampal Pathology in Human Temporal Lobe Epilepsy: Evidence for Distinctive Patient Subcategories
Authors: De Lanerolle Nihal C. , Kim Jung H. , Williamson Anne , Spencer Susan S. , Zaveri Hitten P. , Eid Toye , Spencer Dennis D.
Published: May 2003

Summary:  Purpose: This study is a retrospective analysis of the pathology of the hippocampus from patients with medically intractable temporal lobe epilepsy. We attempted to relate neuronal density, immunohistochemistry, electrophysiologic data, and surgical outcome.

Methods: Immunostaining patterns for neuropeptide Y, somatostatin, substance P, and dynorphin defined the immunohistochemical characteristics of the hippocampi. Neuronal densities were determined by microscopic cell counts. Sharp electrode recordings from dentate granule cells determined measures of inhibition and excitation.

Results: Patient hippocampi without evidence of sclerosis generally resembled autopsy controls on the basis of neuronal densities of hippocampal subfields and patterns of immunostaining. The nonsclerotic hippocampi were divisible into two subgroups on the basis of neuronal density correlations between hippocampal subfields, the excitability of dentate granule cells, etiology, and surgical outcome. Hippocampi with sclerosis were divisible into those with significant neuronal loss confined to area CA1 and those with neuronal loss throughout the hippocampus and dentate gyrus. In the former, the dentate gyrus resembled in morphology the nonsclerotic hippocampi but with slightly increased excitability of the dentate granule cells. The hippocampi with more extensive neuronal loss had changes in immunostaining patterns associated with the dentate gyrus, correlated with significant hyperexcitability of dentate granule cells. The surgical outcome, with the exception of one group, was good in ∼70–90%.

Conclusions: Hippocampi from patients with intractable temporal lobe epilepsy can be assigned to several groups on the basis of pathophysiology. Different pathologies may represent differing causative mechanisms of intractable temporal lobe epilepsy and be predictive of surgical outcome.
Anticonvulsant Effect of Flutamide on Seizures Induced by Pentylenetetrazole: Involvement of Benzodiazepine Receptors
Authors: Ahmadiani Abolhassan , Mandgary Ali , Sayyah Mohammad
Published: May 2003

Summary:  Purpose: There is some structural similarity between the androgen receptor antagonist, flutamide (Flut) and benzodiazepines (BZDs). We evaluated the possible anticonvulsant effect and interaction of Flut with BZD receptors in common seizure models.

Methods: (a) Different groups of mice each were pretreated i.p. with Flut, and after 0.5 h, they received chemoconvulsants [pentylenetetrazole (PTZ), bicuculline, aminophylline, strychnine or kainic acid]. Latency and incidence of a clonic seizure were recorded. (b) Mice were pretreated i.p. with Flut, and after 0.5 h, transauricular electroshock was applied. Occurrence of a tonic seizure was observed. (c) Amygdala‐kindled rats were pretreated i.p. with Flut, and 0.5, 1, or 2 h later, they were stimulated at afterdischarge threshold. Then the seizure parameters (afterdischarge duration, seizure severity, and stage 5 duration) were recorded. (d) The effect of Flut on clonic seizure threshold was determined by i.v. infusion of bicuculline or PTZ to different groups of Flut‐receiving mice. To determine the possible interaction of Flut with BZD receptors, the flumazenil (FMZ)+Flut effect on clonic seizure threshold was compared with the effect of Flut. (e) Neurotoxicity of Flut was evaluated by rotarod test at 30 min after administration.

Results: Flut produced a dose‐dependent anticonvulsant effect against PTZ‐induced seizures [median effective dose (ED50), 67.0 mg/kg]. Moreover, Flut elevated the clonic seizure threshold induced by bicuculline or PTZ. FMZ reversed the effect of Flut on the threshold of PTZ seizures. A median toxic dose (TD50) value of 124.8 mg/kg was obtained for Flut.

Conclusions: Flut both blocks PTZ‐induced clonic seizures and elevates the threshold of PTZ or bicuculline‐induced clonic seizures, through interaction with BZD receptors.
Respiratory Pattern in a Rat Model of Epilepsy
Authors: Campos Ruy R. , Tolentino‐Silva Fatima R. P. , Mello Luiz E. A. M.
Published: May 2003

Summary:  Purpose: Apnea is known to occur during seizures, but systematic studies of ictal respiratory changes in adults are few. Data regarding respiratory pattern defects during interictal periods also are scarce. Here we sought to generate information with regard to the interictal period in animals with pilocarpine‐induced epilepsy.

Methods: Twelve rats (six chronically epileptic animals and six controls) were anesthetized, given tracheotomies, and subjected to hyperventilation or hypoventilation conditions. Breathing movements caused changes in thoracic volume and forced air to flow tidally through a pneumotachograph. This flow was measured by using a differential pressure transducer, passed through a polygraph, and from this to a computer with custom software that derived ventilation (VE), tidal volume (VT), inspiratory time (TI), expiratory time (TE), breathing frequency (f), and mean inspiratory flow (VT/TI) on a breath‐by‐breath basis.

Results: The hyperventilation maneuver caused a decrease in spontaneous ventilation in pilocarpine‐treated and control rats. Although VE had a similar decrease in both groups, in the epileptic group, the decrease in VE was due to a significant (p < 0.05) increase in TE peak in relation to that of the control animals. The hypoventilation maneuver led to an increase in the arterial Paco2, followed by an increase in VE. In the epileptic group, the increase in VE was mediated by a significant (p < 0.05) decrease in TE peak compared with the control group. Systemic application of KCN, to evaluate the effects of peripheral chemoreception activation on ventilation, led to a similar increase in VE for both groups.

Conclusions: The data indicate that pilocarpine‐treated animals have an altered ability to react to (or compensate for) blood gas changes with changes in ventilation and suggest that it is centrally determined. We speculate on the possible relation of the current findings on treating different epilepsy‐associated conditions.
Safety and Efficacy of Intravenous Valproate in Pediatric Status Epilepticus and Acute Repetitive Seizures
Authors: Yu Kian‐Ti , Mills Sandra , Thompson Nanora , Cunanan Cedric
Published: May 2003

Summary: Purpose:To evaluate the safety and efficacy of intravenous valproate (VPA) loading in children with status epilepticus (SE) or acute repetitive seizures.

Methods:Retrospective review was performed on 40 pediatric patients with intravenous VPA loading. Patients were classified into two groups: SE (n = 18) and acute repetitive seizures (n = 22). Thirty‐one patients were VPA naïve and received a full loading dose of 25 mg/kg; nine had subtherapeutic plasma VPA levels and received a partial loading dose. Average infusion rate was 2.8 mg/kg/min. Heart rate and blood pressure were measured before, during, and after infusion.

Results:Intravenous VPA loading stopped seizures in 18 patients with SE within 20 min. All 18 patients regained baseline mental status within 1 h of seizure cessation. Among 22 patients with acute repetitive seizures, only one had further seizures after VPA infusion. One patient in the SE group complained of transient tremors. No significant changes in blood pressure or heart rate were found in either group. Postinfusion plasma VPA levels ranged from 51 to 138 μg/ml (mean ± SD = 88 ± 21.5 μg/ml).

Conclusions:Intravenous VPA loading is safe and effective for treating acute seizure emergencies in children.