bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality salience effects on modesty and relative self‐effacement
Authors: Wakimoto Ryutaro
Published: September 2006

Terror management theory argues that mortality salience (MS) enhances adherence to cultural norms. Recent cross‐cultural research has suggested that Japanese culture emphasizes modesty and the enhancement of important others compared to the self. Thus, it was predicted that Japanese would show increased modesty and relative self‐effacement in response to MS. In addition, the moderating effects of degree of enculturation were examined in two studies investigating Japanese undergraduates. Those strongly enculturated to the Japanese worldview showed a tendency to evaluate success more negatively (Study 1) and self‐efface more relative to their close friends (Study 2). A view which regards both Easterners’ self‐effacement and Westerners’ self‐enhancement after MS to be a reflection of efforts to fit into cultural norm is presented.
Strategic planning: valuing and managing portfolios of real options
Authors: Smit Han T. J. , Trigeorgis Lenos
Published: September 2006

This article presents a value‐based strategic planning framework suitable for valuing and managing portfolios of corporate real options. The proposed framework combines insights from strategic management theory with novel quantitative valuation tools from finance. Strategic planning is viewed as a process of actively developing and managing portfolios of corporate real options in the context of competitive interactions. As such, the expanded valuation framework recognizes that future growth opportunity value deriving from the firm's resources and capabilities must explicitly account for uncertainty, adaptability, and competitive responsiveness. The resulting expanded valuation framework is able to capture the value of the adaptive resources and capabilities that enable a firm to adapt and re‐deploy assets, develop and exploit synergies, and gain competitive advantage via time‐to‐market and first‐ or second‐mover advantages. We show how two basic metrics in this value‐based framework, current profitability of assets in place and future growth option value, can be obtained from financial market data and how they can be used in active portfolio planning.
Attitudes to externally organising knowledge management tasks: a review, reconsideration and extension of the NIH syndrome
Authors: Lichtenthaler Ulrich , Ernst Holger
Published: September 2006

Companies may carry out all major knowledge management tasks, i.e. knowledge acquisition, accumulation and exploitation, internally and externally. Therefore, we propose the integrate‐or‐relate decision in knowledge accumulation as a complement to the well‐known make‐or‐buy and keep‐or‐sell decisions in knowledge acquisition and exploitation. A key factor for taking adequate decisions, for building up organisational capabilities and for realising a firm's knowledge potential are unbiased attitudes to the knowledge management tasks. While past research has focused on the ‘not‐invented‐here’ (NIH) syndrome as a negative attitude to acquiring external knowledge, a more holistic view is adopted in the present article by extending prior research on two dimensions. Firstly, we consider all major knowledge management tasks and do not limit our analysis to knowledge acquisition. Secondly, we take into account that, apart from overly negative attitudes, excessively positive attitudes may exist. Accordingly, we identify the following six syndromes: ‘NIH’ vs. ‘buy‐in’ in knowledge acquisition, ‘all‐stored‐here’ vs. ‘relate‐out’ in knowledge accumulation and ‘only‐used‐here’ vs. ‘sell‐out’ in knowledge exploitation. After briefly reviewing research into NIH and developing a knowledge management framework, the syndromes are defined, and possible antecedents, consequences and managerial actions are described.
Government policy of technology selection for advanced traveler information systems
Authors: Chen Chung‐Jen , Chung Ming‐Chih , Wei Chien‐Hung
Published: September 2006

Technology selection is widely recognized for its increasing importance in the field of technology management. Different from previous work that only used a single evaluation method, this study uses the grey statistics method with survey techniques and scenario approach to develop a three‐stage model for the technology selection issue. An empirical case of the Advanced Traveler Information System (ATIS) technology selection in Taiwan was chosen to illustrate the application of this model on the technology selection problem. The results indicate that GPS/GIS technology is the preferred ATIS technology developed in Taiwan. The application of the model provides an avenue for government policy makers and researchers to deal effectively with the technology selection issue.
GLOBALIZATION AND CHINA'S ECONOMIC DEVELOPMENT
Authors: Chow Gregory C.
Published: September 2006

Abstract.  This paper studies the nature and implications of globalization in China's economic development since 1978. It covers the four aspects of the flows of goods, capital, technology/information and of people to and from China. It also analyzes the role of the exchange rate of renminbi in transmitting the effects of foreign trade and investment to the Chinese macroeconomy.
ADJUSTED ESTIMATES OF UNITED STATES–CHINA BILATERAL TRADE BALANCES: AN UPDATE
Authors: Fung K. C. , Lau Lawrence J. , Xiong Yanyan
Published: September 2006

Abstract.  Large differences exist between the official United States and Chinese data on trade balances between the two countries. In this paper, four adjustments are made to the export and import data of the two governments: (i) freight along side (f.a.s.)‐free on board (f.o.b.) and cost, insurance and freight (c.i.f.)‐f.o.b. conversions; (ii) re‐exports through Hong Kong (and elsewhere); (iii) re‐export markups; and (iv) trade in services. After adjustments, our best estimate for the 2005 bilateral trade balance is $US170.7 billion, in China's favour, which is much larger than the official Chinese balance of $US114.2 billion but also much smaller than the official US balance of $US201.6 billion.
ASSESSING THE IMPACT OF CHINA'S WTO ACCESSION ON INVESTMENT
Authors: Walmsley Terrie L. , Hertel Thomas W. , Ianchovichina Elena
Published: September 2006

Abstract.  After a boom in foreign direct investment (FDI) in China in the early 1990s, FDI slowed in the late 1990s. More recently, with China's accession to the World Trade Organization (WTO) a reality, FDI has once again picked up. This paper explores the linkage between WTO accession and investment in China. We find that investment and capital stocks increase substantially. Moreover, foreign ownership of Chinese assets doubles by 2020. Central to this increase is the expected catch‐up in the productivity of the services sectors driven by reforms. These estimates are far larger than those predicted by earlier studies, which ignored the reforms affecting Chinese services sectors, and abstracted from international capital mobility.
ALLOCATION UNDER INCREASING AND DECREASING RETURNS
Authors: Beckmann Martin J.
Published: September 2006

Abstract.  Efficient Allocation of labour among a set of machines (say) operating under initially increasing and then decreasing returns is studied first for identical machines and then for the case when machines can be ranked by their productivity. Essentially it is a question of the number of machines to be operated. At critical input levels this number jumps and the intensity of machine use is reduced discontinuously.
Oxcarbazepine and atypical evolution of benign idiopathic focal epilepsy of childhood
Authors: Grosso S. , Balestri M. , Di Bartolo R. M. , Corbini L. , Vatti G. , Curatolo P. , Balestri P.
Published: September 2006

Patients that have benign epilepsy with centrotemporal spikes (BECTS) may occasionally experience an atypical development in their course when treated with drugs such as carbamazepine. Three patients with electroclinical patterns consistent with BECTS showed seizure exacerbation during oxacarbazepine (OXC) therapy. Two manifested atypical absences, neuropsychological disturbances, and generalized spike‐and‐wave discharges in their electroencephalograms (EEGs) that became continuous during sleep. The third patient showed, during OXC therapy, more frequent partial motor seizures which ended with ictal vomiting and post‐ictal obnubilation. EEGs recorded during sleep showed discontinuous paroxysmal activity in the right centrotemporal area. Symptoms were reversed following discontinuation of the OXC therapy. Although electroclinical findings were consistent with a BECTS diagnosis, all patients had some atypical features. Our observations show that BECTS patients, in particular those presenting with atypical findings, might be at risk for developing paradoxical reactions to OXC therapy. We suggest that OXC should be included in the list of drugs that may cause electroclinical deterioration in these patients.
Matrix metalloproteinases 2 and 9 in human atherosclerotic and non‐atherosclerotic cerebral aneurysms
Authors: Caird J. , Napoli C. , Taggart C. , Farrell M. , Bouchier‐Hayes D.
Published: September 2006

Matrix metalloproteinases 2 and 9 (MMP 2 and ‐9) have been implicated in the pathogenesis of atherosclerosis and aneurysm formation. The goal of the study was to establish the role of these metalloproteinases in both human atherosclerotic and non‐atherosclerotic cerebral aneurysms. Eleven cerebral aneurysms (four atherosclerotic, seven non‐atherosclerotic) were immunohistochemically stained for MMP 2 and ‐9. As controls, atherosclerotic and normal Circle of Willis arteries were similarly immunostained. All specimens were retrieved at autopsy and were paraffin‐embedded. In order to evaluate the real MMP 2 and ‐9 activities, gelatin zymography was also performed in only two available specimens of non‐atherosclerotic intracranial aneurysms, because of the relative unavailability of fresh intracranial aneurysm tissue (i.e. reluctance to excise the aneurysm fundus at surgery). Our data establish that MMP 2 and ‐9 were expressed minimally or not at all in normal Circle of Willis arteries but were strongly expressed in medial smooth muscle cells of atherosclerotic Circle of Willis arteries. In the aneurysm group, both MMP 2 and ‐9 were strongly expressed in the atherosclerotic aneurysms, but MMP 2 alone was detected in the non‐atherosclerotic aneurysms. Zymography revealed a weak enzyme activity correlating to MMP 9 standard recombinant protein. MMP 2 activity was not demonstrated in either specimen. This study shows that the expression of MMP 2 and ‐9 is associated with atherosclerosis, be it in aneurysmal or non‐aneurysmal cerebral vessels but MMP 2 appears to be specifically expressed in aneurysms devoid of atherosclerosis perhaps suggesting a pathogenic role for MMP 2 in the alteration of the extracellular matrix of cerebral arteries during aneurysm formation.
Thiamine (vitamin B1) deficiency and associated brain damage is still common throughout the world and prevention is simple and safe!
Authors: Harper C.
Published: September 2006

Many different population groups throughout the world have thiamine deficiency and are at risk of developing severe neurological and cardiac disorders. Alcoholics are most at risk but other important clinical groups should be monitored carefully. The most severe, potentially fatal disease caused by thiamine deficiency is the neurological disorder Wernicke–Korsakoff syndrome. This can be difficult to diagnose and many cases remain undiagnosed. Treatment with thiamine generally results in a dramatic clinical improvement. Thiamine supplementation of stable food products like flour is an effective, simple and safe public health measure that can improve the thiamine status of all population groups.
EFNS guidelines on the treatment of cluster headache and other trigeminal‐autonomic cephalalgias
Authors: May A. , Leone M. , Áfra J. , Linde M. , Sándor P. S. , Evers S. , Goadsby P. J.
Published: September 2006

Cluster headache and the other trigeminal‐autonomic cephalalgias [paroxysmal hemicrania, short‐lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome] are rare but very disabling conditions with a major impact on the patient's quality of life. The objective of this study was to give evidence‐based recommendations for the treatment of these headache disorders based on a literature search and consensus amongst a panel of experts. All available medical reference systems were screened for any kind of studies on cluster headache, paroxysmal hemicrania and SUNCT syndrome. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies resulting in level A, B or C recommendations and good practice points. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7 l/min over 15 min and 6 mg subcutaneous sumatriptan are drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy or tolerability). Although no class I or II trials are available, steroids are clearly effective in cluster headache. Therefore, the use of at least 100 mg methylprednisone (or equivalent corticosteroid) given orally or at up to 500 mg i.v. per day over 5 days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as alternative treatments. Surgical procedures, although in part promising, require further scientific evaluation. For paroxysmal hemicranias, indomethacin at a daily dose of up to 225 mg is the drug of choice. For treatment of SUNCT syndrome, large series suggest that lamotrigine is the most effective preventive agent, with topiramate and gabapentin also being useful. Intravenous lidocaine may also be helpful as an acute therapy when patients are extremely distressed and disabled by frequent attacks.
Eosinophilic folliculitis in a Caucasian patient: association with toxocariasis?
Authors: Gesierich A , Herzog S , Grunewald SM , Tappe D , Bröcker E‐B , Schön MP
Published: September 2006

Sterile eosinophilic folliculitis, a clinical entity first described by Ofuji in 1970, is a rather rare skin disorder, in particular in the non‐Asian population. We report the first case of eosinophilic folliculitis associated with toxocariasis in a Caucasian patient. Topical and systemic anti‐inflammatory and antiphlogistic therapy along with systemic antihelminthic treatment resulted in complete remission of the skin lesions. In addition, there was a marked decrease of antibodies to Toxocara antigens in the patient's serum following antihelminthic therapy. Given that (I) some cases of eosinophilic folliculitis have been reported which were associated with infestation with metazoan parasites; (2) infestations with the roundworm Toxocara canis are known to induce eosinophilic reactions in some tissues; and (3) therapy‐induced remission of eosinophilic folliculitis was accompanied by a decrease of Toxocara‐directed antibodies in the patient's serum, we propose that there is an aetiopathogenic link between toxocariasis and eosinophilic folliculitis in this patient.
Six polymorphic microsatellite markers for Plantago maritima
Authors: NILSSON EMIL , GYLLENSTRAND NICLAS , WOLFF KIRSTEN
Published: September 2006

Plantago maritima displays an extraordinary variation in breeding system. In northern Europe, the species occurs as either self‐incompatible or self‐compatible, and as unisexual females or co‐sexual hermaphrodites. The isolation of polymorphic codominant markers will provide the necessary tools to investigate the proportion of self‐fertilized seeds and levels of inbreeding depression in natural populations of this species. Isolation of microsatellite loci was achieved using a membrane‐enrichment method for four loci, and a streptavidin‐coated‐beads method for two loci. Primers were designed in microsatellite flanking sequences and were analysed using fluorescent labels.
Trade and Environmental Policy: A Race to the Bottom?
Authors: Sheldon Ian
Published: September 2006

The focus of this paper is the issue of regulatory chill and a race to the bottom in environmental standards and policies. In particular, it explores the possibility that resolution of this problem may lie in a more flexible application of the existing General Agreement on Tariffs and Trade/World Trade Organization (GATT/WTO) rules. The structure of the discussion is divided into four parts: (i) the standard analysis of trade and environmental policy is laid out; (ii) the theoretical analysis of and empirical evidence for the existence of pollution havens is reviewed; (iii) the main arguments as to why governments may weaken domestic environmental policy with greater trade liberalisation is outlined; and (iv) some recent analysis of border tax adjustments for environmental taxes is laid out, leading to the basic conclusion of the paper: a method for countering any tendency for regulatory chill and a race to the bottom in environmental policies is already embedded in existing GATT/WTO rules.
Rural–Urban Impacts of CAP Measures in Greece: An Inter‐regional SAM Approach
Authors: Psaltopoulos Demetrios , Balamou Eudokia , Thomson Kenneth J.
Published: September 2006

This paper evaluates the inter‐regional impacts of CAP measures implemented in the rural town of Archanes (Crete, Greece), an area which received considerable EU Agricultural Guarantee and rural development funds during the 1990s. A hybrid, three‐area Social Accounting Matrix (SAM) with three groups of households defined by income level is constructed to describe inter‐linkages between three rural–urban localities, namely the rural area of Archanes, the less‐developed, agriculturally dependent, neighbouring rural area of N. Kazantzakis, and the adjacent urban centre of Heraklion. Results are reported on the diffusion patterns of economic impacts generated by three types of CAP measure: farm income support; aids to increased agricultural productivity; aids to economic diversification. These show that the diffusion of policy‐induced economic impacts from Archanes is lower than might be expected for a small open local economy, and that benefits leak primarily to Heraklion and marginally to rural N. Kazantzakis. Finally, generated income benefits seem to accrue mostly in favour of high‐income households, especially in the case of Guarantee subsidies.
The Effectiveness of Antidumping Measures: Some Evidence for Farmed Atlantic Salmon
Authors: Kinnucan Henry W. , Myrland Øystein
Published: September 2006

Counterfactual simulations of a partial equilibrium model of the world salmon market suggest safeguard tariffs imposed by the European Commission on salmon imports from Norway, Chile, and the Faroe Islands would do more to punish producers in the named exporting countries than to reward United Kingdom producers. The reason is that export supply is less elastic than import demand on a bilateral basis, which means that most of the tariff's incidence is borne by the targeted producers rather than EU consumers. The incidence problem is exacerbated by the feed quota (now biomass limit) that Norway uses to limit its production. A marketing fee that expands market demand is shown to be less distortionary than its tariff equivalent, and thus may be preferred from a second‐best perspective.
Productivity and Environmental Performance in Marketing Cooperatives: An Analysis of the Spanish Horticultural Sector
Authors: Galdeano‐Gómez Emilio , Céspedes‐Lorente José , Rodríguez‐Rodríguez Manuel
Published: September 2006

The paper analyses the productivity of marketing cooperatives incorporating environmental inputs/outputs. In the European agriculture, expectations for attaining sustainable and competitive agriculture rely to a great extent on the cooperative sector's ability to adapt to new market conditions. These challenges have led marketing cooperatives in the fruit and vegetables sector to consider improvements in productivity and sound environmental performance. The study analyses the total factor productivity related to environmental variables in this sector using a parametric‐stochastic approach and panel data on Spanish cooperatives over the period 1994–2002. Additionally, the determinants of environmental productivity are examined econometrically. The estimates obtained show an increase in efficiency for the period under study and a relationship between productivity changes and management factors, such as labour quality, capital intensity and environmental spillover.
Access to a Telephone and Factor Market Participation of Rural Households in Bangladesh
Authors: Chowdhury Shyamal K.
Published: September 2006

This paper assesses the impact of access to a telephone on rural households’ factor market opportunities. It answers two questions. First, does the use of a telephone have any impact on rural households’ factor market participation? Second, correcting for market participation, does the use of a telephone have any impact on the type of factor market participation? For the first question, the paper uses a bivariate probit to correct for omitted variable bias and for the second question, the paper uses a two‐stage probit. The empirical findings suggest that access to a telephone has a significant positive impact on factor market participation. The difference in market participation between telephone users and non‐users is around 14%. However, once a household participates in the market, the use of a telephone does not have any impact on specific factor market participation.
Effects of Dibutyryl Cyclic AMP on Na+, K+‐ATPase Activity and Intracellular Na+ and K+ in Primary Cultures of Astrocytes from DBA and C57 Mice
Authors: Li Jun , Chow Sien‐Yao
Published: September 2006

Summary: Effects of chronic treatment of dibutyryl cyclic AMP (db‐cyclic AMP) on Na+, K+‐ATPase activity in cell homogenates and intracellular N a f and K+ contents [(Na+)i and (K+)i] were studied in primary cultures of astrocytes derived from cerebral cortex of neonatal audiogenic seizure‐susceptible DBA and audiogenic seizure‐resistant C57 mice. Na+, K+‐ATPase activity in cell homogenates was greater and (Na+)i was less in DBA astrocytes than in C57 astrocytes. There was no difference in (K+)i between astrocytes from DBA and C57 mice. Addition of db‐cyclic AMP to the medium from day 14 to day 21 in culture (final concentration 0.25 mM) increased Na+, K+‐ATPase activity in cell homogenates and decreased (Na+)i, but had no significant effect on (K+)i in astrocytes from either DBA or C57 mice. Chronic treatment with db‐cyclic AMP altered cell growth. Protein and DNA content of cultured astrocytes from both DBA and C57 mice was decreased. DNA was more affected than protein. Modifying K+ and Na+ concentration in medium altered Na+, K+‐ATPase activity in cell homogenates as well as (Na+)i and (K+)i in cultured astrocytes of both DBA and C57 mice. Changes in (Na+)i and (K+)i at different K+ concentrations in medium paralleled those in Na+, K+‐ATPase activity in cell homogenates. Results indicate that the ability to transport Na+ across the cell membrane and the response of Na+, K+‐ATPase to db‐cyclic AMP and to the changes in K + in medium of cultured astrocytes from audiogenic seizure‐susceptible DBA mice are sufficient.
Focal Cerebral Magnetic Resonance Changes Associated with Partial Status Epilepticus
Authors: Henry Thomas R. , Drury Ivo , Brunberg James A. , Pennell Page B. , McKeever Paul E. , Beydoun Ahmad
Published: September 2006

Summary: We report 2 patients with transient abnormalities on magnetic resonance imaging (MRI) associated with partial status epilepticus (SE). A man with a 4‐month history of partial seizures had complex partial SE for 9 days, with left temporal maximum on ictal EEG. Left temporal lobe T2 signal was increased on MRI during SE, but cerebral MRI was normal 9 weeks later. A woman with “cryptogenic” temporal lobe epilepsy for 16 years had complex partial SE for 1 week, with right temporal maximum on ictal EEG. T2 Signal was increased over the entire right temporal lobe, extending into the insula, without mass effect, on MRI 1 month after SE ended. Repeat MRI 1 month later showed marked decrease in volume of increased T2 intensity, without gadolinium enhancement, but with mild mass effect over the right anteroinferomesial temporal areas. A gemistocytic astrocytoma was resected. Focal cerebral MRI abnormalities consistent with cerebral edema may be due to partial SE but also may indicate underlying glioma, even in long‐standing partial epilepsy. Focal structural imaging changes consistent with neoplasm should be followed to full resolution after partial SE.
Nonconvulsive Status Epilepticus: EEG Analysis in a Large Series
Authors: Granner Mark A. , Ik Lee Soo
Published: September 2006

Summary: We analyzed EEG characteristics comprehensively in a large series of nonconvulsive status epilepticus (NCSE) cases. Eighty‐five ictal episodes in 78 patients were analyzed. The ictal discharges were generalized (group G) in 59 episodes (69%), diffuse with focal predominance (group GF) in 15 (18%), and focal (group F) in 11 (13%). The morphologies and patterns of persistence varied greatly. Frequency of ictal discharge was also variable and was almost always <3 Hz. Demonstration of focal epileptic features in response to intravenous (i.v.) diazepam (DZP) and the presence of interictal focal epileptiform discharges in some cases in groups G and GF suggested possible focal onset secondarily generalized in these cases. This study suggests that electrographically NCSE is a highly heterogeneous epileptic state, and i.v. DZP may serve as a valuable diagnostic tool in differentiating generalized from focal onset NCSE.
Idiopathic Generalized Epilepsy: Magnetic Stimulation of Motor Cortex Time‐Locked and Unlocked to 3–Hz Spike‐and Wave Discharges
Authors: Gianelli Maria , Cantello Roberto , Civardi Carlo , Naldi Paola , Bettucci Diego , Schiavella M. Pia , Mutani Roberto
Published: September 2006

Summary: In 20 patients with idiopathic generalized epilepsy who showed typical 3‐Hz spike‐and‐wave (SW) EEG complexes, we studied the corticospinal motor output with a transcranial electromagnetic stimulator. First we measured the corticospinal discharge threshold for both hemispheres in the patient group and compared it with that of 10 ageand sex‐matched volunteers. Threshold was significantly higher in the patient group, regardless of whether subjects were treated with antiepileptic drugs (AEDs). In 4 patients with very frequent SW paroxysms, we were able to study motor evoked potential (MEP) changes time‐locked to epileptic EEG transients. The EEG signal was recorded bipolarly (C3–P3, C4–P4) by scalp needle‐electrodes. For a given stimulus intensity, we collected and measured MEPs occurring during the spike or the wave portion of the SW complexes. Data were compared with those of MEPs obtained time‐locked to normal EEG segments. MEP size was significantly decreased when the cortical stimulus was time‐locked to the wave component, and was decreased or unchanged when the stimulus was time‐locked to the spike. Magnetic stimulation never produced remarkable side effects.
EEG Slow Waves and Memory Performance During the Intracarotid Amobarbital Test
Authors: Jones‐Gotman M. , Bouwer M. S. , Gotman J.
Published: September 2006

Summary: During intracarotid sodium amobarbital (ISA) testing, EEG slow waves appear in the injected hemisphere and usually also contralaterally. They are frequently used to estimate duration of drug effect and thus the window of valid memory testing, but the relationship between slow waves and memory performance is not established. In 50 tests, we examined recognition for stimuli presented after amobarbital injection in relation to the quantified EEG. Performance was compared for injection ipsilateral versus contralateral to epileptic focus, with slow waves present bilaterally, unilaterally, or dissipated. Results showed that memory was impaired after injections contralateral to the focus when slow waves were present on the side of the focus (contralateral to injection). Injection contralateral to focus did not interfere with memory if slow waves were not also present, and slow waves contralateral to injection did not interfere with memory if the focus was not also present. This result emphasizes the functional significance of slow waves, which probably reflect decreased neuronal functioning.
Allopurinol as Add‐on Therapy in Refractory Epilepsy: A Double‐Blind Placebo‐Controlled Randomized Study Italy, on his retirement.
Authors: Zagnoni P. G. , Bianchi A. , Zolo P. , Canger R. , Cornaggia C. , D'Alessandro P. , DeMarco P. , Pisani F. , Gianelli M. , Verzé L. , Viani F. , Zaccara G.
Published: September 2006

Summary: The antiepileptic effect of allopurinol was assessed in a double‐blind, randomized, placebo‐controlled, cross‐over trial in 84 patients with epileptic seizures refractory to standard antiepileptic drugs (AEDs). During a retrospective baseline period, patients experienced at least four seizures of any type per month. The effects of allopurinol and matching placebo were examined for 4‐month periods. Allopurinol dosage was 150 mg daily for children weighing <20 kg and 300 mg daily for other patients. Efficacy analysis based on the Wilcoxon rank‐sum test was conducted for the 80 patients who completed the study. No significant period effect or treatment‐period interaction was noted. Allopurinol significantly reduced total seizures (p = 0.00S), and secondarily generalized seizures (p = 0.0015). Median seizure reduction for total seizures was 10.5 and 27.9% for secondarily generalized seizures. Subjective preferences by clinicians evaluated blindly significantly favored allopurinol. No significant change occurred in the plasma concentration of concomitant AEDs between treatment periods, but serum urate decreased by 32% during allopurinol treatment. No clinically relevant side effects or changes in routine laboratory clinical chemistry or hematology were ascribed to allopurinol.
Lamotrigine Therapy for Partial Seizures: A Multicenter, Placebo‐Controlled, Double‐Blind, Cross‐Over Trial
Authors: Messenheimer J. , Ramsay R. E. , Willmore L. J. , Leroy R. F. , Zielinski J. , Mattson R. , Pellock J. M. , Valakas A. M. , Womble G. , Risner M.
Published: September 2006

Summary: The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double‐blind, placebo‐controlled, cross‐over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mglday. Seizure frequency with LTG decreased by ≥50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2: 1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEds. Adverse experiences were generally minor and most frequently were CNS‐related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice‐daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.
Protection from Phenytoin‐Induced Congenital Malformations by Coadministration of the Antiepileptic Drug Stiripentol in a Mouse Model
Authors: Finnell Richard H. , Kerr Brad M. , van Waes Michael , Steward Rebecca L. , Levy Renté H.
Published: September 2006

Summary: To test the hypothesis that the cytochrome P‐450‐inhibiting antiepileptic drug (AED) Stiripentol (STP) can reduce the incidence of phenytoin (PHT) induced congenital malformations, we chronically administered the AEDs to three inbred mouse strains. The frequency of congenital defects in PHT‐treated animals was dosage dependent, ranging from 7 to 55%. When STP was coadministered orally with PHT, there was a significant reduction in fetal defects in SWV and C57BL/6J mouse strains. A replication of the experiment was conducted with addition of a seventh group of mice that received the high dosage of PHT together with STP. In the replicate, all three strains demonstrated a significant reduction in fetal defects in fetuses exposed to PHT (60 mg/kg) and STP (200 mg/kg) as compared with PHT (60 mg/kg) monotherapy. These results strongly suggest that oxidative metabolites activated by cytochrome P‐450 are the primary teratogenic molecules involved in PHT‐induced teratogenesis and that clinical management of pregnant epileptic patients may be improved through heightened awareness of these drug interactions.
Evaluation of the Mechanisms of Antiepileptic Drug‐Related Chronic Leukopenia
Authors: O'Connor Carolyn Riester , Schraeder Paul L. , Kurland Alan H. , O'Connor William H.
Published: September 2006

Summary: Antiepileptic drug (AED)‐related chronic leukopenia [white blood cell (WBC) count <4,000/μl] is a dilemma, especially when the AED is effective in controlling seizures. We evaluated the possible mechanisms of leukopenia in 7 patients. Mean WBC count was 3,000/μ1 with a mean of 42% polymorphonuclear leukocytes (PMN). The AEDs were carbamazepine (CBZ) alone in 1 patient or CBZ combined with phenytoin (PHT), primidone (PRM), phenobarbital (PB) and/or valproate (VPA) in 5 patients; one patient was receiving PHT only. Bone marrow (BM) aspirates and PMN antibody studies using chemiluminescence were normal. Two liver‐spleen scans showed mild relative splenomegaly. After exercise, WBC count (n = 7) increased by 54% (SEM 12%), while the WBC counts in controls (n = 5) increased by 52 ±16%. Antinuclear antibodies (Hep‐2) were absent in 6 patients and positive (1:160) in 1. PMN adhesion to nylon wool was decreased (54 ±10% in patients vs. 80 ± 5% in controls: n = 13, p < 0.00s). Our data, particularly the appropriate WBC response to the stress of exercise, and normal BM examinations suggest that continuation of AED therapy when leukopenia is stable and the percentage of PMN is normal is probably safe. Caution should be used if the absolute PMN count is consistently <1,000/μl. BM examinations need not be performed routinely for every patient with neutropenia due to AEDs, especially if the leukopenia fluctuates in the range of 2,000–4,000 cells/μ1.
Rapid Reversibility of Autoinduction of Carbamazepine Metabolism After Temporary Discontinuation
Authors: Schaffler Leonard , Bourgeois Blaise F. D. , Lüders Hans O.
Published: September 2006

Summary: Patients in whom carbamazepine (CBZ) monotherapy is discontinued for preoperative EEG/video monitoring often display toxicity if their previous maintenance dosage is resumed, even after a few days without CBZ. To determine whether this is due to rapid reversibility of autoinduction of CBZ metabolism, single‐dose studies of CBZ pharmacokinetics were performed before and after discontinuation for monitoring in 6 adults receiving CBZ monotherapy. The CBZ‐free period was 5.7 ± 1.1 days (mean ± SD). The pharmacokinetic parameters of CBZ before and after discontinuation were volume of distribution (Vd) 1.28 ± 0.29 versus 1.22 ± 0.331/kg (NS), elimination half‐life (t 1/2) 13.7 ± 1.67 versus 22.2 ± 2.36 h (p < 0.001), and clearance (CI) 1.54 ± 0.39 versus 0.92 ± 0.32 L/kg/day (p = 0.012). Assuming that deinduction is a first‐order process, a deinduction t 1/2 of 3.84 days was obtained by log linear regression analysis. We showed that after CBZ discontinuation half of the enzymatic autoinduction is already lost after 3.84 days, indicating very rapid deinduction. Our results also provide the necessary information to predict clearance and appropriate dosage reduction for CBZ at time of reintroduction.
Interictal Autonomic Nervous System Function in Patients with Epilepsy
Authors: Devinsky Orrin , Perrine Kenneth , Theodore William H.
Published: September 2006

Summary: We studied 24 patients with partial seizures receiving carbamazepine (CBZ) monotherapy and 40 normal controls, 17 of whom were tested with and without CBZ therapy. Autonomic nervous system assessment included baseline heart rate (HR) and blood pressure (BP); BP and HR changes during orthostasis and cold pressor test (CPT); and HR changes during sinus arrhythmia, Valsalva maneuver, and cold face test with apnea (CFTA). Our study demonstrated normal interictal autonomic function in patients with epilepsy, but, variations in BP and HR during orthostasis and CPT were significantly (p CBZ. Epilepsy patients had higher initial increases in BP and greater subsequent decreases in BP than did nonmedicated controls during CPT. Controls with CBZ had higher HR during orthostasis and CFTA than did those without CBZ. CBZ levels correlated with baseline and orthostatic BP and HR during deep breathing (sinus arrhythmia). Our results showed that patients with epilepsy have greater BP and HR variability and reactivity than controls, attributable in part to CBZ levels.
Interaction of Phenobarbital and Phenytoin in an Experimental Model of Seizures in Rats
Authors: Stringer Janet L. , Higgins Michael G.
Published: September 2006

Summary: The combination of phenobarbital (PB) and phenytoin (PHT) was recommended for many years for treatment of epilepsy in humans. We tested the effectiveness of the combination in a model of hippocampal seizures termed maximal dentate activation (MDA). Two parameters of MDA were measured: duration and time to onset. Neither the vehicle controls nor PHT 80 mg/kg had an effect on duration or time to onset of MDA. PB 20 mg/kg delayed the normal increase in MDA duration and had no effect on time to onset. Addition of increasing doses of PHT to the 20–mg/kg dose of PB caused a dose–dependent decrease in MDA duration and a dosedependent increase in time to onset. These effects do not appear to be due to an increase in serum level of either drug when administered together. We showed that the combination of PB and PHT has actions in an experimental model of limbic seizures that are not produced by either drug alone. Therefore, clinical use of the combination does have some experimental justification.
Valproate Effect on γ‐Aminobutyric Acid Release in Pars Reticulata of Substantia Nigra: Combination of Push‐pull Perfusion and Fluorescence Histochemistry
Authors: Wolf Rainer , Tscherne Ursula
Published: September 2006

Summary: To study further the previously demonstrated suppressive in vivo effect of sodium valproate (VPA) on y‐aminobutyric acid (GABA) release in the preoptic area, we examined GABA neurotransmission in substantia nigra (SN), using the push‐pull cannula technique in freely moving ovariectomized rats. To clarify whether the area in the substantia nigra that is actually perfused is pars reticulata, known to receive rich GABAergic input from striatum, we used the retrograde fluorescence tracer fast blue (FB) after each perfusion experiment, applying the tracer through the push‐pull cannula. Nigral perfusion with VPA caused significant suppression of local GABA release. This effect was more marked in a subgroup of animals showing retrograde labeled cell bodies in striatum, i.e., animals with a tracer application site and therefore also a perfusion site precisely in pars reticulata. Our data suggest that VPA inhibits GABA release in rat SN as it does in the preoptic area, which may be in agreement with our hypothesis of enhanced GABAergic neurotransmission by VPA, causing suppression of presynaptic GABA release through negative feedback actions on the GABA autoreceptor complex. Furthermore, the combination of push‐pull cannula technique and retrograde fluorescence tracer application appears to be an important tool to prove afferent connections of the area actually perfused in neuronal networks.
Idiosyncratic Reactions: New Methods of Identifying High‐risk Patients
Authors: Glauser Tracy A.
Published: September 2006

Summary: This article describes the mechanisms of idiosyncratic drug reactions (IDRs) and provides an analysis of potential methods for identifying patients at high risk for antiepileptic idiosyncratic drug reactions. IDRs may be caused by toxic metabolites, either directly or indirectly (by way of an immunologic response or a free radical‐mediated process). Four methods to potentially identify patients at high risk for AED IDRs are discussed: development of an “at‐risk” clinical profile for a particular AED; identification of biomarkers that measure the formation of a toxic metabolite by a previously unrecognized bioactivation pathway for a particular AED; identification of biomarkers indicating deficient detoxification abilities [e.g., deficient free radical scavenging enzyme activities or low calculated oxidative protection (COP) ratios 1 and 2]; and identification of at‐risk genetic markers. Clinical profiles for patients receiving valproic acid (VPA), felbamate (FBM), and lamotrigine (LTG) and who are at risk for development of AED IDRs are presented; Patients with VPA IDRs have deficient erythrocyte glutathione peroxidase activity, low plasma selenium concentrations, low COP1 ratios, and low COP2 ratios compared with age‐matched controls. Patients with FBM‐associated aplastic anemia have deficient erythrocyte glutathione peroxidase, superoxide dismutase (SOD), and glutathione reductase activities compared with age‐matched controls. Use of at‐risk clinical profiles (for VPA, FBM, and LTG) and measurement of erythrocyte glutathione peroxidase activity, erythrocyte SOD activity, and calculation of COP1 and COP2 ratios (for VPA and FBM) are inexpensive, simple methods of identifying high‐risk patients for IDRs. Research is needed to further characterize the mechanism of IDRs, to investigate the clinical utility of free radical‐scavenging enzyme activity measurement and calculation of COP ratios for other AED IDRs, and to develop additional methods of identifying patients at high risk for AED IDRs.
Antiepileptic Drug Interactions
Authors: French Jacqueline A. , Gidal Barry E.
Published: September 2006

Summary: This article reviews the potential interactions of antiepileptic drugs (AEDs) and the pharmacokinetic and pharmacodynamic principles involved. It describes the absorptive and distributive properties of AEDs and the effects on protein binding, hepatic metabolism, and elimination resulting from co‐administration of AEDs with food or other drugs. Drug behavior is a function of absorption, metabolism, distribution, and elimination. Administration of either multiple AEDs or a combination of AEDs plus drugs for other conditions can modify any of these physiologic processes, possibly resulting in complex interactions. These may include alterations in the bioavailability and absorption of a drug and changes in half‐life and serum level through induction or inhibition of hepatic metabolism. In most cases, increases or decreases in serum concentrations will signal a drug interaction. In other cases, clinically significant drug interactions remain undetected owing to apparently stable serum concentrations. Co‐administration of drugs may affect the rate of clearance of one or both drugs. The effect on clearance varies, owing to genetic factors, patient characteristics (age and presence of co‐morbidities), and individual responses. AEDs that induce hepatic metabolism can also influence the metabolism of concomitantly administered non‐epilepsy medications and can interfere with oral contraceptives, as well as vitamins D and K. Patients with renal insufficiency or advanced age may experience incomplete renal excretion and should receive reduced dosages of drug. Understanding the pharmacokinetics and pharmacodynamic properties of AEDs and the route of metabolism of all competing drugs is important for optimal management of patients with epilepsy and for prevention of avoidable drug interactions.
Controversies in Blood‐level Monitoring: Reexamining Its Role in the Treatment of Epilepsy
Authors: Glauser Tracy A. , Pippenger C. E.
Published: September 2006

Summary: This article reexamines the role of blood‐level monitoring (therapeutic drug monitoring, TDM) of antiepileptic drugs (AEDs) in the current treatment of epilepsy and identifies situations in which TDM can be useful. Basic pharmaco‐kinetic and pharmacodynamic principles are reviewed, with specific emphasis on kinetics of absorption/distribution/metabolism, elimination half‐life, time to steady state, and plasma drug concentrations. The relationship between AED intensity of effect (pharmacodynamics) and plasma concentration (pharmacokinetics) is expressed mathematically, examined in the context of the major old and new AEDs, and integrated with a historical look at the role of TDM. Situations in which TDM can be useful in the modern treatment of epilepsy are presented and discussed. For both older and newer AEDs, TDM is useful in six clinical situations: establishing “baseline” effective concentrations, evaluating potential causes for lack of efficacy, evaluating potential causes for toxicity, evaluating potential causes for loss of efficacy, judging “room to move’ or when to change AEDs, and minimizing predictable problems. TDM remains a valuable tool in the modern treatment of epilepsy. It can be selectively and appropriately utilized to help maximize seizure control and minimize side effects if levels are obtained in response to a patient‐specific pharmacokinetic or pharmacodynamic issue or problem.
Epilepsy in North America: A Report Prepared under the Auspices of the Global Campaign against Epilepsy, the International Bureau for Epilepsy, the International League Against Epilepsy, and the World Health Organization
Authors: Theodore William H. , Spencer Susan S. , Wiebe Samuel , Langfitt John T. , Ali Amza , Shafer Patricia O. , Berg Anne T. , Vickrey Barbara G.
Published: September 2006

Summary:  In North America, overall epilepsy incidence is approximately 50/100,000 per year, highest for children below five years of age, and the elderly. The best data suggest prevalence of 5–10/1000. Potential effects of gender, ethnicity, access to care and socioeconomic variables need further study. Studies of epilepsy etiology and classification mainly were performed without modern imaging tools. The best study found an overall standardized mortality ratio (SMR) for epilepsy relative to the general population of 2.3. There is evidence to suggest a greater increase in patients with symptomatic epilepsy, particularly children. People with epilepsy are more likely to report reduced Health‐related Quality of Life than controls. They have reduced income, and are less likely to have full‐time employment. They suffer from persistent stigma throughout the region, in developed as well as developing countries. Poor treatment access and health care disparities for people with epilepsy may be related to insufficient economic resources, rural isolation, gender, ethnicity, and lack of public and physician knowledge of modern approaches to epilepsy care. Despite high costs and severe disability, epilepsy may attract somewhat less research funding from public and private sources than other less common chronic neurological disorders. A Plan for Epilepsy in North America should address: basic and clinical research; primary prevention research; translation to care; stigma, quality of life, and self‐management; industry relations; government and regional relations; and regional integration and resource sharing.