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While national governments increasingly deploy digital diplomacy communication strategies to harness the power of social media, political scientists have paid sparse attention to certain aspects of this development. Our study endeavors to address this lacuna by employing content analysis and data-analytic methodologies to examine U.S. Twitter diplomacy. We leverage a robust dataset of tweets posted by leading foreign policy officials in the Obama administration to determine whether Twitter diplomacy exhibited a coherent communication strategy (per the rational actor model of foreign policy), or a more ad-hoc and disjointed practice (per the pluralist and bureaucratic politics models). Furthermore, this study assesses several variables relating to the efficacy of Twitter statecraft, including the formatting of tweets, and the resonance and geographic reach of tweets. We find that Twitter diplomacy under the Obama administration was largely rational; that is, it reflected the rational actor model, as the topic focus of tweets was proportional to stated U.S. foreign policy priorities.

Predictions that Brexit will precipitate the disintegration of the European Union (EU) have greatly overstated the prospect of such an event. Britain's centuries-long conflicted relationship with E...

Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and is often associated with substantial side effects. In addition, most current therapeutic paradigms offer treatment, but not cure, and no therapies are able to modify the underlying disease, that is, can prevent or halt the process of epileptogenesis or alleviate the cognitive and psychiatric comorbidities. Preclinical research in the field of epilepsy has been extensive, but unfortunately, not all the animal models being used have been validated for their predictive value. The overall goal of TASK2 of the AES/ILAE Translational Task Force is to organize and coordinate systematic reviews on selected topics regarding animal research in epilepsy. Herein we describe our strategy. In the first part of the paper we provide an overview of the usefulness of systematic reviews and meta-analysis for preclinical research and explain the essentials for their conduct. Then we describe in detail the protocol for a first systematic review, which will focus on the identification and characterization of outcome measures reported in animal models of epilepsy. The specific goals of this study are to define systematically the phenotypic characteristics of the most commonly used animal models, and to effectively compare these with the manifestations of human epilepsy. This will provide epilepsy researchers with detailed information on the strengths and weaknesses of epilepsy models, facilitating their refinement and future research. Ultimately, this could lead to a refined use of relevant models for understanding the mechanism(s) of the epilepsies and developing novel therapies.

State sponsorship has played a significant facilitating role in terrorist violence. The scope and impact of state support has not, however, remained fixed; nor has its threat potential. This article identifies and depicts three distinct phases of state sponsorship: the peak (1970s-80s), intermediate (1990-2001), and low (2001-present) phases. The causal factors behind the steady pattern of decline in the number of states sponsoring terrorism and the intensity of support provided to terrorist clients are analyzed here. Despite this clear contraction, state sponsorship continues to merit close attention as the salience of state-sponsored terrorism relates not only to the number of sponsors and level of support, but also to the threat potential of the support sponsors can provide. Therefore, paradoxically, at a time when the number of state sponsors is at its nadir, the threat potential of terrorism is at its apex, as the proliferation of nuclear technology to terrorist sponsors has significantly elevated the potential consequences of state sponsorship. Related Articles Owens, John. 2006. “Presidential Power and Congressional Acquiescence in the ‘War’ on Terrorism: A New Constitutional Equilibrium?” Politics & Policy 34 (2): 258-303. http://onlinelibrary.wiley.com/doi/10.1111/j.1747-1346.2006.00015.x/abstract Dumbrell, John. 2006. “Working with Allies: The United States, the United Kingdom, and the War on Terror.” Politics & Policy 34 (2): 452-472. http://onlinelibrary.wiley.com/doi/10.1111/j.1747-1346.2006.00021.x/abstract Maggio, J. 2007. “The Presidential Rhetoric of Terror: The (Re)Creation of Reality Immediately after 9/11.” Politics & Policy 34 (2): 810-835. http://onlinelibrary.wiley.com/doi/10.1111/j.1747-1346.2007.00085.x/abstract Related Media Belfer Center for Science & International Affairs. 2013. “Nuclear Terrorism.” http://belfercenter.ksg.harvard.edu/topic/6/nuclear_terrorism.html Council on Foreign Relations. 2013. “State Sponsors of Terrorism.” http://www.cfr.org/issue/state-sponsors-of-terrorism/ri151

There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy. Here we propose and discuss a strategy for implementing a "phase II" multicenter preclinical drug trial model based on clinical phase II/III studies designed to generate more rigorous preclinical data for efficacy. The goal is to improve the evidence resulting from preclinical studies for investigational new drugs that have shown strong promise in initial preclinical "phase I" studies. This should reduce the risk for expensive clinical studies in epilepsy and therefore increase the appeal for funders (industry and government) to invest in their clinical development.

Two toxicologic studies of vigabatrin were conducted with immature Sprague Dawley rats to characterize intramyelinic edema (IME) formation and assess potential impact on behavioral measures. Study 1 was a dosage-ranging characterization of overall toxicity of vigabatrin in young, developing rats. Study 2 evaluated vacuolar brain lesions found in Study 1.During Study 1, immature Sprague Dawley rats were orally administered deionized water (vehicle control), or vigabatrin at 5, 15, or 50mg/kg/day for ≤ 9 weeks, beginning at postnatal day 4 (PND 4) and followed by a recovery period. Toxicologic observations were collected, including adverse clinical signs, body weight gains, food consumption, ophthalmoloscopy, electroretinograms, sexual maturation, motor activity, memory, and learning behaviors. At sacrifice, CNS tissues were examined by light microscopy for evidence of IME. In Study 2, immature Sprague Dawley rats were again orally administered vigabatrin (50mg/kg/day for ≤ 9 weeks, beginning at PND 4). At sacrifice, CNS tissues were examined by both light and transmission electron microscopy for evidence of IME.At 5-50mg/kg/day, dosage-related reduced food consumption, decreased body weight, and delayed sexual maturation were found. Persisting through recovery, effects were more pronounced in males. Increased degrees of vacuolation were observed on PND 67 only after a dosage of 50mg/kg/day, and were attenuated during recovery. Vacuolar-change morphology was characteristic of IME, with no evidence of cellular or neuritic degeneration. Ultrastructural analyses revealed brain vacuoles initiated as splits of myelin sheaths along intra-period lines. These splits expanded, evolving into large membrane-rich vacuoles, and were more prominent at later stages of myelin development. Hypomyelination and gliopathy were noted from PNDs 4-15, and were likely related to vigabatrin exposure during active myelination. A lesser degree of hypomyelination was observed from PNDs 4-46 and 4-65. Vacuolation was markedly attenuated in post-recovery-period rats.The present studies indicated toxicities in young rats at vigabatrin dosages lower than those reported for toxicities in older rats. Dosages50mg/kg/day did not affect CNS, behavior, and reproductive development. However, at the greatest dosage, some retardation of physical growth, delay in sexual maturation, reduction in physical strength, and induction of CNS stimulation (handling-induced spasms) occurred. The key pathologic finding was vacuolar brain lesions in the white and gray matter, which generally reversed upon drug discontinuation. Vacuoles were confined to myelin sheaths, consistent with observations in adult rats. Vigabatrin delayed but did not eliminate myelination despite continued dosing, an effect greatest during active myelination.

Heme oxygenase-1 (HO-1) induction by hemin or Panhematin protects against experimental pancreatitis. As a preclinical first step toward determining whether HO-1 upregulation is a viable target in acute pancreatitis (AP) patients, we tested the hypothesis that HO-1 expression in peripheral blood mononuclear cell (PBMC) subsets of hospitalized patients with mild AP is upregulated then normalizes upon recovery and that cells from AP patients have the potential to upregulate their HO-1 ex vivo if exposed to Panhematin. PBMCs were isolated on days 1 and 3 of hospitalization from the blood of 18 AP patients, and PMBC HO-1 levels were compared with PMBCs of 15 hospitalized controls (HC) and 7 volunteer healthy controls (VC). On day 1 of hospitalization, AP patients compared with VCs had higher HO-1 expression in monocytes and neutrophils. Notably, AP monocyte HO-1 levels decreased significantly upon recovery. Panhematin induced HO-1 in ex vivo cultured AP PBMCs more readily than in HC or VC PBMCs. Furthermore, PBMCs from acutely ill AP patients on day 1 were more responsive to HO-1 induction compared with day 3 upon recovery. Similarly, mouse splenocytes had enhanced HO-1 inducibility as their pancreatitis progressed from mild to severe. In conclusion, AP leads to reversible PBMC HO-1 upregulation that is associated with clinical improvement and involves primarily monocytes. Leukocytes from AP patients or mice with AP are primed for HO-1 induction by Panhematin, which suggests that Panhematin could offer a therapeutic benefit.

Background and aim Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1) + macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis. Methods We defined the distribution of radiolabelled haemin, then used in vivo HO-1–luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay. Results Intravenously administered Panhematin induces rapid recruitment of HO-1 + cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant. Conclusions Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1 + cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.

This article examines the origins and outcomes of the indigenous-based Zapatista rebellion launched 15 years ago in Chiapas, Mexico. The precursors responsible for the resistance movement are assessed, as well as the proximate events which convinced the indigenous communities to embrace a militarized approach. International relations conflict theory is plumbed for explanations of the conflict and for conflict resolution strategies relevant to this particular event. This study finds that the conflict in Chiapas was the consequence of two antecedent conditions – systematic human rights abuses and extreme material deprivation; and two proximate factors – NAFTA ratification and pending revisions to communal land laws. The article also explains how violence mitigation was subsequently achieved as a result of the behavior of state and non-state actors.

This article examines the capacity of regional trade agreements (RTAs) to assist and foster democracy in their respective regions. While the principal raison d'etre of RTAs is to stimulate economic growth among its member states, several regional trade associations have embedded democratic requirements into their governance documents. These requirements elevate democracy to a fundamental value of the associations, and mandate (in most instances) that both current and candidate members possess and uphold democratic political systems and practices. This article examines the regional impact of democracy requirements in trade blocs by exploring four leading RTAs: the European Union, NAFTA Mercosur, and ASEAN. The article finds that the ability to promote democracy is impacted by three primary RTA characteristics: (1) the material benefits of membership; (2) the intensity of political and economic integration among member states; and (3) the level of democratic consolidation exhibited by member states. Este articulo examina la capacidad de los acuerdos comerciales regionales para ayudar y fomentar la democracia en sus respectivas regiones. Mientras que la principal razon de ser de los acuerdos comerciales es la de estimular el crecimiento economico entre sus estados miembros, muchas asociaciones comerciales regionales han incluido requerimientos democraticos dentro de sus documentos de gobierno. Estos requerimientos elevan a la democracia como un valor fundamental de las asociaciones, y ordenan que (en la mayoria de los casos) tanto los estados miembro como los candidatos, posean y mantengan los sistemas politicos democraticos y sus practicas. Este articulo examina el impacto regional de los requerimientos de la democracia en bloques comerciales al explorar cuatro acuerdos comerciales regionales destacados: la Union Europea, TLCAN, Mercosur, y ASEAN. El estudio encuentra que la habilidad de promover la democracia es influida por tres caracteristicas de dichos acuerdos: (1) los beneficios materiales de la membresia; (2) la intensidad de la integracion politica y economica entre sus miembros; y (3) el nivel de la consolidacion democratica demostrada por sus estados miembros.

A large randomized study was conducted in patients with newly diagnosed infantile spasms to compare 2 doses of vigabatrin in achieving spasm cessation. High (100-148 mg/kg/d) and low (18-36 mg/kg/d) oral doses of vigabatrin were evaluated in a randomized, single-blind study of 14 to 21 days with subsequent open-label treatment up to 3 years. Spasm cessation was defined as 7 consecutive days of spasm freedom beginning within the first 14 days, confirmed by video-electroencephalogram. A total of 221 subjects comprised the modified intent-to-treat cohort. More subjects in the high-dose group achieved spasm cessation compared with the low-dose vigabatrin group (15.9% [17/107] vs 7.0% [8/114]; P = .0375). During follow-up, 39 of 171 (23%) subjects relapsed; 28 of 39 (72%) regained spasm freedom. Adverse events were primarily mild to moderate in severity. Vigabatrin had a dose-dependent effect in spasm reduction. Spasm cessation occurred rapidly and was maintained in the majority of infants.

Recent discourse on U.S. efforts to promote democracy has focused on military activities; especially the strategic and normative perils of democracy promotion at the point of bayonets. This paper explores the United States' use of economic statecraft to foster democratization, with particular attention to democracy incentive and assistance strategies. Incentive approaches attempt to promote democracy from the top-down, by leveraging aid and trade privileges to persuade authoritarian leaders to implement political reform. Assistance approaches aim to induce democratization from the inside, through funding and technical assistance to state institutions, and from the bottom-up, by providing support to civil society and elections. This study finds that while top-down incentive approaches can stimulate democratic change, this strategy tends to work only when aid and trade benefits are conditional; that is, when benefits are withheld until recipient states meet rigorous democratic benchmarks. Washington has historically eschewed democratic conditionality, however, and thus can claim very few aid-induced or trade-induced democratization events. Scant evidence exists to demonstrate that inside approaches—that is, institutional aid—possesses significant capacity to induce democracy. It is the bottom-up approach—empowering the masses to compel democratic change—that has registered the greatest number of democracy promotion successes.

SUMMARY Purpose: This randomized, double-blind, doseranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS). Methods: Sixty-eight patients with LGS aged 2– 26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/ day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study. Results: Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of ‡25%, ‡50%, and ‡75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued. Conclusions: Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced.

Although vigabatrin irreversibly constricts the visual field, it remains a potent therapy for infantile spasms and a third-line drug for refractory epilepsies. In albino animals, this drug induces a reduction in retinal cell function, retinal disorganization, and cone photoreceptor damage. The objective of this study was to investigate the light dependence of the vigabatrin-elicited retinal toxicity and to screen for molecules preventing this secondary effect of vigabatrin.Rats and mice were treated daily with 40 and 3mg vigabatrin, respectively. Retinal cell lesions were demonstrated by assessing cell function with electroretinogram measurements, and quantifying retinal disorganization, gliosis, and cone cell densities.Vigabatrin-elicited retinal lesions were prevented by maintaining animals in darkness during treatment. Different mechanisms including taurine deficiency were reported to produce such phototoxicity; we therefore measured amino acid plasma levels in vigabatrin-treated animals. Taurine levels were 67% lower in vigabatrin-treated animals than in control animals. Taurine supplementation reduced all components of retinal lesions in both rats and mice. Among six vigabatrin-treated infants, the taurine plasma level was found to be below normal in three patients and undetectable in two patients.These results indicate that vigabatrin generates a taurine deficiency responsible for its retinal phototoxicity. Future studies will investigate whether cotreatment with taurine and vigabatrin can limit epileptic seizures without inducing the constriction of the visual field. Patients taking vigabatrin could gain immediate benefit from reduced light exposures and dietetic advice on taurine-rich foods.

Summary Purpose: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS). Methods: Medical records and 332 cranial MRIs from 205 infants (aged ≤24 months) with IS treated at 10 sites in the United States and Canada were collected. Similarly, 2,074 images from 668 children (aged 2–16 years) and adults (aged >16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T2-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated. Results: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p

Catastrophic childhood epilepsies such as infantile spasms (IS), progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS) are rare but debilitating and frequently persist into adulthood. Early, targeted use of medications that have demonstrated efficacy in the management of LGS or its associated epilepsies may simplify the patient’s treatment regimen and reduce the incidence of adverse events. Key to the overall benefit to the patient is to maximize seizure control while minimizing adverse effects, especially behavioral and cognitive problems. Clobazam has demonstrated clinical benefit and has been administered safely in more than 50 European studies in which data were reported on greater than 3000 pediatric and adult patients with epilepsy, 300 of whom were diagnosed with LGS; therefore, its use is now being investigated in the U.S. This review will explore the use of clobazam in the treatment of epilepsy, particularly with regard to its potential benefit in LGS. Though not currently approved for use in the U.S., a program is underway to gain Food and Drug Administration approval for the treatment of pediatric and adult patients with refractory epilepsy, specifically in LGS. A phase 2 study will be completed in late 2006 to investigate the safety and efficacy of clobazam as adjunctive therapy in 68 pediatric and adult patients with LGS.

This study examines the efficacy of various strategies of dissuading state support for terrorism. Libya represents the principle case study employed to test the impact of military force, unilateral economic sanctions, and multilateral economic sanctions against states which provide support to international terrorist organizations. The frequency of Libyan-supported terrorist attacks declined after the application, in 1986, of U.S. unilateral economic sanctions and military force against the regime of Muammar Qaddafi. However, these measures were unable to reduce the lethality of Libyan-supported terrorism, as the number of individuals killed by Libyan terrorism escalated substantially in the years following American airstrikes and sanctions. After the application of multilateral sanctions in 1992, however, Libya essentially dismantled its terrorist support program. In the decade since the imposition of UN sanctions on Libya, the Qaddafi regime has not been linked to a single attack against Americans. The s...

Valproic acid (VPA) has a narrow therapeutic range (50-100mg/l) and exhibits nonlinear protein binding. Additionally, VPA pharmacokinetics are dependent on age, induction status, and formulation; so titration and dosing vary between individuals. The aim of these simulations was to determine optimal intravenous (i.v.) loading dose, and i.v. and oral VPA maintenance regimens. A 5-min 15mg/kg loading dose resulted in total and free plasma VPA concentrations of approximately 65 and 7.5mg/l in children, and approximately 80 and 11mg/l in adults, 1h after the infusion; induction status had little effect. For uninduced children and adults, 7.5 and 3.5mg/kg q6h i.v. valproate sodium, initiated 6h after loading dose maintains therapeutic plasma VPA concentrations. The rapid decline of plasma VPA concentrations following an i.v. loading dose in combination with the delayed initial absorption of drug from delayed-release divalproex sodium tablets warrant beginning q12h oral maintenance regimens of delayed-release divalproex sodium within 2h of a loading dose in the uninduced population. Plasma VPA concentrations can be sustained in the therapeutic range using once-daily maintenance regimens of extended-release divalproex sodium tablets if initiated concurrently with i.v. loading dose in the uninduced population. A two-fold higher i.v. and oral maintenance regimen dose may be required in induced patients.

Background: Valproate sodium injection (Depacon®) is an intravenous form of valproate for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. Methods: Subjects with epilepsy were randomized in a 2:1 ratio to receive up to 15 mg/kg of valproate sodium infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma valproate concentrations of 50–100 mcg/ml. Primary safety endpoints were the changes in the 5-min and minimum post-first infusion blood pressures (BPs). Results: One hundred twelve subjects were treated, (3.0 mg/kg/min group: n =72, 1.5 mg/kg/min group: n =40). No significant treatment differences were detected for changes in the primary BP endpoints. Two subjects in the 3.0 mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h following the first infusion. Conclusions: Valproate sodium injection dosages up to 15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population.

We prospectively studied eye movement after rapid intravenous administration of phenytoin. Nineteen healthy young adults participated in a study of i.v. phenytoin pharmacokinetics. Subjects received a standard dose of 15 mg/kg at a rate of 25 mg/min, and were examined neuro-ophthalmologically before and at the end of the infusion. All patients had horizontal gaze-evoked nystagmus (HGN), and impairment of horizontal smooth pursuit (SP). Other signs were present in the following percentages: vertical gaze-evoked nystagmus (16 19 ,84%), and impairment of vertical SP (15 19 , 79%). Total and free phenytoin levels did not directly correlate with the degree of any of the neurological signs tested. By review of the past studies of nystagmus during phenytoin therapy, we propose that nystagmus is present consistently during toxicity with initial phenytoin therapy, but occurs less consistently during ongoing phenytoin use or chronic toxicity.

Context.—The adverse event profile of long-term divalproex therapy for epilepsy is well established, but little is known about the tolerability or safety of divalproex in long-term migraine prophylaxis. Objective.—Evaluate the long-term safety and efficacy of divalproex sodium in migraine prophylaxis. Design.—Open-label, long-term study, of up to 3 years, of patients who completed one of two multicenter, double-blind, randomized, placebo-controlled studies. Setting.—Eighteen headache/neurology centers throughout the United States. Patients.—One hundred sixty-three patients: 46 treated with placebo, 117 treated with divalproex for migraine in previous studies. Intervention.—Divalproex therapy initiated at 500 mg/day (250 mg twice daily), with adjustment in dose and dosing frequency possible after 1 to 3 days. Main Outcome Measures.—Number and proportion of patients reporting treatment-emergent adverse events, prevalence and incidence for each treatment-emergent adverse event, vital signs, body weight, 4-week migraine rates and proportion of patients with 50% or greater reduction in rate over time. Results.—Treatment lasted more than 180 days for 71% of patients and more than 360 days for 48% of patients. Improvements in the 4-week, change-from-baseline migraine rates were seen during each of the 3- and 6-month time intervals. Conclusions.—Divalproex is effective for migraine prophylaxis, and initial benefits are maintained for periods in excess of 1080 days.

Tiagabine HCl [(R]-N-[4,4-bis(3-methyl-2-thienyl]-3-butenyl] nipecotic acid hydrochloride], a potent and selective GABA uptake inhibitor, was evaluated for potential anti-allodynic effects in a rodent model of neuropathic pain and for antinociceptive activity in rodent models of acute and persistent pain. The effect of tiagabine on neuropathic pain was evaluated in rats that developed allodynia after tight ligation of L5 and L6 spinal nerves. The anti-allodynic effects of tiagabine were dose-dependent, with significant increases in response threshold to tactile stimulation occurring at 72.8 μmoles/kg, ip, but not at lower doses of 7.2 and 24.3 μmoles/kg, ip. In the hot-plate test in mice, tiagabine significantly increased foot-licking latency at 7.2 and 24.3 μmoles/kg, ip, and jump latency at 24.3 μmoles/kg, ip. After twice daily dosing with 72.8 μmoles/kg, ip, of tiagabine for 4 days, mice showed a tolerance to the antinociceptive effect of the 7.2 μmoles/kg, ip, dose of tiagabine in the hot-plate test. Tolerance did not occur after twice daily dosing of the 7.2 μmoles/kg, ip, dose of tiagabine. Tiagabine did not have significant effects on the tail-flick latency of rats at doses of 0.7 to 72.8 μmoles/kg, ip. Doses of 7.2 and 24.3 μmoles/kg, ip, of tiagabine significantly reduced the number of acetic acid-induced stretches in mice. In rats, tiagabine significantly decreased the number of paw flinches in the early phase of the formalin test at 24.3 and 72.8 μmoles/kg, ip, and in the late phase of the test at 72.8 μmoles/kg, ip. Tiagabine had no significant effects on carrageenan-induced paw edema at doses of 0.7 to 72.8 μmoles/kg, ip. Taken together, the results of these experiments revealed the potential anti-allodynic and antinociceptive pharmacology of tiagabine. Drug Dev. Res. 44:106–113, 1998. © 1998 Wiley-Liss, Inc.

In preparation for winter low temperatures, larvae of the gall fly, Eurosta solidaginis, accumulate the cryoprotectants glycerol, sorbitol, and trehalose. The fat body cells of these freeze-tolerant larvae can survive intracellular freezing to −80°C for 48 h even though no whole larvae survive this treatment. We hypothesized that some other tissue was more susceptible to freezing and therefore may be responsible for larval death. This paper compares the ultrastructure of brain, muscle, and Malpighian tubules between non-lethally frozen and lethally frozen freeze-tolerant larvae. The nuclei of cortical brain cells from lethally frozen larvae exhibited clumped chromatin and nuclear membranes with occasional expansions or `blebs' of the intermembranous space, while the cytoplasm contained swollen spheres of endoplasmic reticulum. In contrast, non-lethally frozen brain contained nuclei with evenly dispersed chromatin, smooth nuclear membranes and a cytoplasm free of swollen endoplasmic reticulum. Muscle tissue of lethally frozen larvae contained disrupted myofilaments surrounding the Z-line in comparison to non-lethally frozen muscle which had myofilaments extending all the way to the Z-line. Alterations of Malpighian tubule cells from lethally frozen larvae included an extracted cytoplasm with swollen and rounded mitochondria. In contrast, Malpighian tubule cells from non-lethally frozen larvae had a more concentrated cytoplasm with many rod-shaped mitochondria. Results show alterations to all three tissue types due to lethal freezing. The brain tissue contained the most observable alterations and therefore may be the most susceptible to lethal freeze damage.

Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS).Medical records and 332 cranial MRIs from 205 infants (agedor=24 months) with IS treated at 10 sites in the United States and Canada were collected. Similarly, 2,074 images from 668 children (aged 2-16 years) and adults (aged16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated.Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects.Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.

Refractory epilepsies such as infantile spasms (IS) and complex partial seizures (CPS) can have a severe negative impact on the neurological integrity and quality of life of affected patients, in addition to drastically increasing their risk of premature mortality. Early identification of potentially effective pharmacotherapy agents is important. Vigabatrin has been shown to be a generally well tolerated and effective antiepileptic drug (AED) in a wide variety of seizure types affecting both children and adults, particularly those with IS and CPS. A bilateral, concentric constriction of the peripheral visual field characterizes the visual field defect (VFD) associated with vigabatrin, well characterized by numerous studies. This peripheral VFD presents in 30-50% of patients with exposure of several years; however, most of these patients are asymptomatic. In well-controlled studies, the earliest onset in patients with CPS is 11 months and at 5 months in infants, with average onsets being more than 5 years and 1 year, respectively. Patients with a peripheral VFD retain an average 65 degrees of lateral vision (normal, 90 degrees). The fact that many patients never develop the vigabatrin-related peripheral VFD, despite long-term exposure at high doses, may support the hypothesis that the injury is an idiosyncratic adverse drug reaction (as opposed to a strict dose- or duration-dependent toxicity). Effective testing methods are available to aid in the early detection and management of the peripheral VFD. This article discusses issues of importance to clinical decision-making in the use of vigabatrin to assist the physician and patient in assessing the benefits of vigabatrin therapy and understanding the potential risks of the VFD and uncontrolled seizures.

The availability of an intravenous formulation now makes possible rapid administration of valproate (VPA) loading doses, but estimates of key VPA pharmacokinetic parameters in patients have limited the use of this approach. VPA disposition was characterized in 112 epilepsy patients, with or without enzyme inducing comedications, randomized to either 3.0 or 1.5 mg/kg/min infusions of valproate sodium injection. Maximum dose was ≤15 mg/kg per infusion. Total and unbound plasma VPA concentrations were determined from blood samples obtained prior to and for 6 h following the infusion. Analyses of covariance assessed the effect of induction, weight, age, gender, albumin, creatinine, and infusion rate on pharmacokinetics. Maximum total and unbound VPA concentrations were 94 and 14 mg/l, respectively. Total concentration fell below 50 mg/l within 3 h in induced and 6 h in uninduced patients. VPA unbound fraction decreased from 15% at maximum concentration to 9% at 45 mg/l. The mean (S.D.) distribution volume was 0.21 (0.044) l/kg. Induction status, albumin concentration, and infusion rate significantly affected pharmacokinetics. Measurement of unbound VPA may be useful when alterations in binding are suspected. Infusions up to 3 mg/kg/min produce predictable total VPA concentrations when induction status and albumin levels are considered.

Untrained Pleurobranchaea feed voraciously when presented food and withdraw from electrical shocks. We trained experimental animals in ten trials spaced 1 hour apart to withdraw from food alone by electrically shocking them if they fed or were indifferent to food. The greatest increase in the number of learned withdrawal responses occurred within 12 hours after conditioning, and was accompanied by long-lasting increased in the threshold and latency of feeding responses. Control animals, which received food and shock alternately (unpaired) every half hour, showed considerably weaker changes than experimentals. These control responses quickly returned to initial levels after conditioning.

Intramedullary spinal cord metastases are uncommon in Hodgkin's disease and have a poor prognosis. This prognosis reflects the refractory or widely disseminated status of the disease at the time of development of neurological symptoms and difficulties in diagnosis. Computerized tomography and magnetic resonance imaging have enabled more rapid and specific diagnosis of spinal cord diseases. The authors report a patient who presented with Brown-Sequard syndrome due to intramedullary spinal cord infiltration from Hodgkin's disease. This patient was diagnosed promptly and with rapid initiation of radiation and chemotherapy, she has had neurologic recovery.

In hyperalgesic states, observed commonly as a major symptom of tissue inflammation or after central or peripheral nerve injury, non-noxious stimuli produce pain and noxious stimuli are perceived as more painful than usual. The mechanisms underlying the generation of hyperalgesia are not known. In patients with causalgia (burning pain and severe hyperalgesia after a nerve injury) activation of sympathetic post-ganglionic neurones or application of noradrenaline to painful skin exacerbates pain and hyperalgesia1 while sympathectomy may afford complete relief2. One suggestion is that noradrenaline released from sympathetic post-ganglionic neurones increases the discharge of damaged small-diameter afferents3,4 by a direct action on the primary afferents5,6. Here we present a new model for noradrenaline-sensitive hyperalgesia and demonstrate that the site of action of noradrenaline is not on the primary afferents but rather is presynaptic on the sympathetic post-ganglionic terminals.

This report reviewed 996 emergency room visits and 279 hospital admissions of patients with complications of cocaine abuse seen at the San Francisco General Hospital between 1979 and 1986. In 143 cases, acute neurologic or psychiatric symptoms were the primary complaint, and case-notes provided sufficient detail for analysis. The major neurologic complications included one or more seizures (n = 29), focal neurologic symptoms or signs (12), headache (10), and transient loss of consciousness (six). Psychiatric disturbances included agitation, anxiety, or depression (33), psychosis and paranola (24), and suicidal ideation (18). The most serious consequences were found in patients with prolonged seizures or strokes, those who jumped out of buildings, and those who attempted suicide by overdosing with other drugs. There was no correlaton between the appearance of complications and the reported route of administration, the amount of cocaine used, or prior experience with cocaine. The number of patients who are seeking hospital attention for these or related complaints appears to be rising substantially. Cocaine abuse, regardless of the use pattern, is associated with a variety of potentially severe neurologic and psychiatric complications.