bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of stereoselective anticonvulsant, teratogenic, and pharmacokinetic profile of valnoctylurea (capuride): A chiral stereoisomer of valproic acid urea derivative
Authors: Shimshoni Jakob A. , Yagen Boris , Wlodarczyk Bogdan , Finnell Richard H. , Schurig Volker , Bialer Meir
Published: August 2009

Purpose: The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)–active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA).

Methods: VCU stereoisomers (2S,3S)‐VCU and (2R,3S)‐VCU were synthesized. Their anticonvulsant activity was determined and compared to VPA and racemic‐VCU in rats utilizing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scMet) tests. Neurotoxicity was determined in rats using the positional sense test, muscle tone test, and gait and stance test. The induction of neural tube defects (NTDs) by VCU stereoisomers was evaluated in a mouse strain highly susceptible to VPA‐induced teratogenicity. The pharmacokinetics of VCU was studied in a stereoselective manner following intraperitoneal (i.p.) administration to rats.

Results: (2S,3S)‐VCU and (2R,3S)‐VCU median effective dose ED50values were 29 mg/kg [95% confidence interval (CI) = 8–60 mg/kg] and 42 mg/kg (95% CI = 36–51 mg/kg) (MES) and 22 mg/kg (95% CI = 13–51 mg/kg) and 12 mg/kg (95%CI = 7–21 mg/kg) (scMet), respectively. (2S,3S)‐VCU was more potent and had a wider safety margin (p < 0.05), defined as the protective index (PI = TD50/ED50), at both the MES (PI > 17) and scMet (PI > 23) tests than racemic‐VCU or (R,S)‐VCU (PI = 2.8 and 9.9, respectively). VCU stereoisomers caused NTDs at doses >4 times that of their anticonvulsant ED50values. At a dose of 112 mg/kg, (2R,3S)‐VCU was nonteratogenic and less embryotoxic than its stereoisomer (2S,3S)‐VCU. No stereoselective pharmacokinetics was observed following intraperitoneal dosing of racemic‐VCU to rats. VCU was mainly eliminated by metabolism with a half‐life of 2 h.

Conclusions: VCU anticonvulsant activity and wide PI values make it a potential candidate for development as a new, potent antiepileptic drug (AED).
Seizures increase cell proliferation in the dentate gyrus by shortening progenitor cell‐cycle length
Authors: Varodayan Florence P. , Zhu Xin‐Jian , Cui Xiao‐Nan , Porter Brenda E.
Published: August 2009

Purpose:  A prolonged seizure, status epileptics (SE), is a potent stimulus for increased neurogenesis in the dentate gyrus of the hippocampus. Molecular mechanisms that regulate normal and pathologic cell birth in the dentate gyrus are poorly understood.

Methods:  Lithium–pilocarpine was used to induce SE in immature postnatal day 20 rats. Newborn cells in the dentate were labeled with bromo‐deoxyuridine to determine a time‐course of cell proliferation, and measure cell‐cycle length. In addition, we studied expression by Western blot and immunohistochemistry of two known inhibitors of G1–S cell‐cycle progression P27/Kip1 and P15/Ink4b following SE.

Results:  Cell proliferation in the dentate gyrus increases starting 2 h after SE and is sustained for 40 days. Increased cell proliferation following SE is associated with a shortened dentate gyrus progenitor’s cell cycle, 15 h in control to 12 h in the SE animals. To identify molecules responsible for the shortened progenitor cell cycle we studied inhibitors of cell‐cycle progression P27/Kip1, and P15/Ink4b. We find decreased phosphorylation at P27/Kip1 Serine 10 and Threonine 187 following SE. Although total P27/Kip1 and P15/Ink4b levels were not altered after SE, P27/Kip1 immunoreactivity was minimal in newborn but increased with maturation of the dentate granule neurons.

Discussion:  The sustained increase in dentate gyrus cell proliferation following SE provides a large pool of immature dentate granule cells prior to development of spontaneous seizures. A decrease in cell‐cycle length of dentate gyrus progenitors is at least partially responsible for increased numbers of newborn cells following SE.
Bitemporal form of partial reading epilepsy: Further evidence for an idiopathic localization‐related syndrome
Authors: Maillard Louis , Vignal Jean‐Pierre , Raffo Emmanuel , Vespignani Hervé
Published: August 2009

Idiopathic partial reading epilepsy (RE) is a rare syndrome. We report the clinical and electroencephalographic characteristics of two right‐handed patients with the following: reading‐induced independent bilateral temporal lobe seizures, accompanied by alexia in left (dominant) sided seizures recorded on video‐EEG (electroencephalography); subclinical activation over left posterior temporal and occipital electrodes during reading; no spontaneous seizure and no other trigger than reading; onset in adolescence; and history of varying resistance to treatment. Bilateral independent temporal lobe reflex seizures are part of the clinical spectrum of RE. It may result from hyperexcitability of bilateral cortical networks involved in the early steps of the reading process.
A novel mouse model for sudden unexpected death in epilepsy (SUDEP): Role of impaired adenosine clearance
Authors: Shen Hai‐Ying , Li Tianfu , Boison Detlev
Published: August 2009

Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in people with epilepsy. Two postulated causes for SUDEP, cardiac and respiratory depression, can both be explained by overstimulation of adenosine receptors. We hypothesized that SUDEP is a consequence of a surge in adenosine as a result of prolonged seizures combined with deficient adenosine clearance; consequently, blockade of adenosine receptors should prevent SUDEP. Here we induced impaired adenosine clearance in adult mice by pharmacologic inhibition of the adenosine‐removing enzymes, adenosine kinase and deaminase. Combination of impaired adenosine clearance with kainic acid–induced seizures triggered sudden death in all animals. Most importantly, the adenosine receptor antagonist caffeine, when given after seizure onset, increased survival from 23.75 ± 1.35 min to 54.86 ± 6.59 min (p < 0.01). Our data indicate that SUDEP is due to overactivation of adenosine receptors and that caffeine treatment after seizure onset might be beneficial.
Reevaluating the mechanisms of focal ictogenesis: The role of low‐voltage fast activity
Authors: De Curtis Marco , Gnatkovsky Vadym
Published: August 2009

The mechanisms that control the transition into a focal seizure are still uncertain. The introduction of presurgical intracranial recordings to localize the epileptogenic zone in patients with drug‐resistant focal epilepsies opened a new window to the interpretation of seizure generation (ictogenesis). One of the most frequent focal patterns observed with intracranial electrodes at seizure onset is characterized by low‐voltage fast activity in the beta‐gamma range that may or may not be preceded by changes of ongoing interictal activities. In the present commentary, the mechanisms of generation of focal seizures are reconsidered, focusing on low‐voltage fast activity patterns. Experimental findings on models of temporal lobe seizures support the view that the low‐voltage fast activity observed at seizure onset is associated with reinforcement and synchronization of inhibitory networks. A minor role for the initiation of the ictal pattern is played by principal neurons that are progressively recruited with a delay, when inhibition declines and synchronous high‐voltage discharges ensue. The transition from inhibition into excitatory recruitment is probably mediated by local increase in potassium concentration associated with synchronized interneuronal firing. These findings challenge the classical theory that proposes an increment of excitation and/or a reduction of inhibition as a cause for the transition to seizure in focal epilepsies. A new definition of ictogenesis mechanisms, as herewith hypothesized, might possibly help to develop new therapeutic strategies for focal epilepsies.
Protective effects of naloxone in two‐hit seizure model
Authors: Yang Lu , Li Fuhai , Ge Wei , Mi Changrui , Wang Rong , Sun Ruopeng
Published: August 2009

Purpose: Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two‐hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose‐dependent protective effects of naloxone in kainic acid (KA)–induced two‐hit seizure model.

Methods: After KA‐induced SE at postnatal day 15 (P15), Sprague‐Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin‐1β [IL‐1β], S100B) was assessed by real‐time polymerase chain reaction (PCR) and enzyme‐linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT‐mediated dUTP nick end labeling (TUNEL) assays.

Results: Naloxone reduced IL‐1β synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE.

Conclusions: Naloxone treatment immediately after early life SE could dose‐dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood.
Incidence of newly diagnosed epileptic seizures in a French South Indian Ocean Island, La Réunion (EPIREUN)
Authors: Mignard Claude , Tchalla Edem , Marin Benoît , Tabailloux Emmanuel , Mignard Didier , Jallon Pierre , Preux Pierre‐Marie
Published: August 2009

Purpose:  To assess the incidence of newly diagnosed epileptic seizures in the population of La Réunion.

Methods:  From July 1, 2004 to June 30, 2005, we conducted a prospective, observational, and multicenter epidemiologic study to identify patients with newly diagnosed epileptic seizures. Febrile and neonatal seizures were excluded.

Results:  Seven hundred sixty‐six patients were included. The standardized (2000 U.S. population) incidence rate of all suspected cases of newly diagnosed (provoked and unprovoked) epileptic seizures was 115.4/100.000 person‐years [95% confidence interval (CI) 106.7–124.0]. We observed a bimodal distribution: The crude incidence was 99.5/100,000 in the group aged 0–14 years and 330.8/100,000 in those older than 65 years. One hundred thirty‐five cases were classified as provoked seizures (17.6%; incidence 17.7/100,000). Alcohol consumption, cranial trauma, and cerebrovascular disease were the most frequent causes (27.4%, 11.1%, and 10.4%, respectively). Six hundred twenty cases were classified as unprovoked seizures (single and recurrent) (80.9%; incidence, 81.2/100,000). Two hundred sixty cases of seizures were due to stable neurologic conditions (incidence, 34.1/100,000) and the most common causes were cerebrovascular disease (46.2%), alcoholism (20.4%), and cranial trauma (5.4%). Evolutive neurologic conditions contributed to 23 cases (incidence, 3.0/100,000). Lastly, unprovoked seizures with unknown etiology were 337 (incidence, 44.2/100,000).

Conclusions:  The global incidence rate of newly diagnosed epileptic seizures in La Réunion was clearly higher than those observed in industrialized countries and similar to those observed in developing countries. The major risk factors were represented by cerebrovascular disease, alcohol consumption, and cranial trauma. Surprisingly, there were few infections.
Optical suppression of experimental seizures in rat brain slices
Authors: Yang Xiao‐Feng , Schmidt Brigitte F. , Rode Daniel L. , Rothman Steven M.
Published: August 2009

Purpose:  To determine if a small ultraviolet emitting diode (UV LED) could release sufficient γ‐aminobutyric acid (GABA) from a caged precursor to suppress paroxysmal activity in rat brain slices.

Methods:  Electrophysiologic recordings were obtained from rat brain slices bathed with caged GABA: 4‐[[(2H‐benzopyran‐2‐one‐7‐amino‐4‐methoxy)carbonyl]amino]butanoic acid (BC204), at concentrations between 3 and 30 μm. Seizure‐like activity was induced by perfusing slices with extracellular medium lacking magnesium and containing 4‐aminopyridine (4‐AP; 100 μm). A small, high‐power UV LED was used to uncage BC204 and determine whether an increase in ambient GABA could alter normal or paroxysmal activity in the slice.

Results:  UV LED illumination, in the absence of BC204, had no effect on CA1 population spikes or seizure‐like activity. The light did induce a small temperature elevation (<0.15°C) over the current intensities and exposure durations used in these experiments. In the presence of BC204, UV light decreased the CA1 population spike and seizure‐like activity. The BC204 effect can be best accounted for by release of GABA: The reduction of population spikes and seizure‐like activity was blocked by the GABA antagonist picrotoxin, and BC204 illumination produced a membrane polarization that reversed at the expected potential for GABAA receptors.

Discussion:  These experiments establish that illumination of a low concentration of caged GABA with a tiny UV LED can release sufficient GABA to attenuate seizure‐like activity in brain slices. Because our seizure model is very severe, it is probable that this technique would have a robust effect in human focal epilepsy.
Balance impairment in chronic antiepileptic drug users: A twin and sibling study
Authors: Petty Sandra J. , Hill Keith D. , Haber Natalie E. , Paton Lynda M. , Lawrence Kate M. , Berkovic Samuel F. , Seibel Markus J. , O’Brien Terence J. , Wark John D.
Published: August 2009

Purpose:  Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED‐discordant, twin and sibling matched‐pair approach, and assessed clinically relevant subgroups: AED polytherapy; longer‐duration AED; and falls history.

Methods:  Twenty‐nine same‐sex (mean age 44.9 years, 59% female), ambulatory, community‐dwelling twin and sibling pairs, discordant for AED exposure (and AED‐indication), were recruited. Validated clinical and laboratory tests of strength, gait, and balance were performed. Relevant AED levels, and fasting serum samples for 25‐hydroxyvitamin D (25OHD), 1,25‐dihydroxyvitamin D [1,25(OH)2D], and immunoreactive parathyroid hormone (iPTH) levels were taken.

Results:  There were significant mean within‐pair differences in tests of static and dynamic balance, with the AED user having poorer balance function than the AED nonuser. No difference was seen in lower limb strength or gait measures. Increased duration of AED therapy and AED polytherapy were independent predictors of increased sway. No significant within‐pair differences were seen in fasting serum levels of 1,25(OH)2D, 25OHD and iPTH after Bonferroni correction.

Discussion:  Balance performance is impaired in AED users compared to their matched nonuser siblings. Pairs where the AED users took AED polytherapy, or had a longer duration of AED use, had more impaired balance performance. These balance deficits may contribute to the increased rate of fractures in this population.
Parkinsonism induced by VNS in a child with double‐cortex syndrome
Authors: Cukiert Arthur , Mariani Pedro Paulo , Burattini Jose Augusto , Cukiert Cristine Mella , Forster Cassio , Baise Carla , Argentoni‐Baldochi Meire , Mello Valeria
Published: August 2009

We describe a child with epilepsy associated with double‐cortex syndrome in whom vagus nerve stimulation (VNS) generated parkinsonian symptoms. A 13‐year‐old girl presented with refractory secondary generalized epilepsy from the age of 6 years and mental retardation. Her electroencephalography (EEG) showed diffuse polyspike and wave discharges. Magnetic resonance imaging (MRI) showed double‐cortex syndrome. She was submitted to extended callosal section at the age of 10 years, which yielded 50% seizure frequency reduction. She was submitted to VNS by the age of 12 years. As stimulation intensity was increased, there was appearance of extrapyramidal symptoms: She developed bilateral tremor and rigidity, and gait and postural disturbance. All symptoms disappeared 7–10 days after VNS was turned off. Several attempts to reactivate VNS led to the same results. During the periods when VNS was on she presented with marked seizure frequency reduction. This is the first report of a clinically evident direct effect of VNS on the basal ganglia.
Successful treatment for refractory convulsive status epilepticus by non‐parenteral lacosamide
Authors: Tilz Christian , Resch Roland , Hofer Thomas , Eggers Christian
Published: August 2009

Lacosamide (Vimpat) is a newly licensed novel antiepileptic drug. We report a case of refractory convulsive status epilepticus (CSE) that was successfully controlled with lacosamide. The 38‐year‐old male patient was admitted for a series of complex partial seizures with secondary generalization leading to refractory CSE. During the transport to the hospital the patient was given 22.5 mg diazepam, 12.5 mg etomidate, and 5 mg midazolam without success. An additional dose of 4 mg lorazepam and a dose of 1,500 mg levetiracetam after admission were yet without clinical effect. A further treatment with lacosamide (300 mg via percutaneous gastric fistula) resulted in complete clinical remission of the epileptic activity within 30 min. The application of lacosamide resulted in cessation of CSE and was well tolerated. To our knowledge, this is the first case of successful treatment of refractory CSE with lacosamide. Further studies are needed to evaluate the safety and efficacy of lacosamide in treatment of SE.
Spatial distribution of intracranially recorded spikes in medial and lateral temporal epilepsies
Authors: Goncharova Irina I. , Zaveri Hitten P. , Duckrow Robert B. , Novotny Edward J. , Spencer Susan S.
Published: August 2009

Purpose:  Although seizures and interictal spikes are not always colocalized, there may be valuable localizing information in the spatial distribution of spikes. To test this hypothesis, we studied the spatial distribution of intracranially recorded interictal spikes in patients with medial temporal (MT) and lateral temporal (LT) neocortical seizure onset.

Methods:  A total of 21 patients (MT n = 12, LT n = 9) who completed intracranial monitoring were selected for this study. Two 4‐h intracranial electroencephalography (icEEG) epochs were analyzed, one during wake and one during sleep, both at least 6 h removed from seizures. Spikes detected automatically in medial temporal structures [hippocampal formation (H) and entorhinal cortex (EC)], and in five cortical areas (occipital, frontal, parietal, lateral temporal, and inferior temporal) were tabulated.

Results:  Interictal spikes occurred broadly over medial temporal structures and cortical areas in MT and LT patients. The patients differed with a greater number of spikes in medial temporal structures in the MT group (p < 0.05 for H and p < 0.001 for EC) and a greater number of spikes in parietal (p < 0.01) and frontal (p < 0.001) areas in the LT group. There were sleep‐related increases in spike rates in inferomedial temporal structures in both groups. The two groups could be separated with a classifier based on medial temporal and parietal and frontal spikes (p < 0.0001).

Discussion:  MT and LT patients have different spatial distributions of interictal spikes and can be distinguished by the relative spike rates in medial temporal and extratemporal areas during sleep and wake.
Histologic and morphologic effects of valproic acid and oxcarbazepine on rat uterine and ovarian cells
Authors: Cansu Ali , Erdogan Deniz , Serdaroglu Ayse , Take Gülnur , Coskun Zafer K. , Gurgen Seren G.
Published: August 2009

Purpose:  To determine the histologic and morphologic effects of valproic acid (VPA) and oxcarbazepine (OXC) on rat uterine and ovarian cells.

Methods:  Fifty‐six female prepubertal Wistar rats (21–24 days old and weighing between 47.5 and 58.1 g) were divided equally into four groups, which were given drinking water (controls), 300 mg/kg/day of VPA, 100 mg/kg/day of OXC or VPA + OXC via gavage, for 90 days. Ovaries and uteri of rats on proestrous and diestrous phases of estrous cycle were extirpated and placed in a fixation solution. The tissue specimens were assessed with apoptosis (TUNEL) staining protocols, eosinophil counting, and electron microscopic techniques.

Results:  In uteri, apoptosis in stroma, mitochondrial swelling, and cristolysis were observed in the VPA group, and OXC led to negative effects on epithelial cell and intracellular edema. In ovaries, both drugs increased apoptosis and intracytoplasmic edema. Organelle structure disruption was also observed in the OXC group. More conspicuous degenerative modifications were determined in the VPA + OXC group. In uteri, the number of TUNEL‐positive luminal epithelial cells was 7.20 ± 1.32 in controls, and significantly increased to 29.60 ± 1.58, 34.20 ± 2.53, and 54.80 ± 2.04 in VPA, OXC, and VPA + OXC groups, respectively (p < 0.001). The highest number of TUNEL‐positive glandular epithelium cells was observed in the VPA + OXC group; however, the number of TUNEL‐positive stroma cells was highest in the VPA group. The highest number of eosinophils in stroma was in the VPA group.

Conclusion:  VPA and OXC trigger apoptotic and degenerative effects on rat uterine and ovarian cells. VPA also prevents implantation of embryo to the uterus and causes abortion via endometrial eosinophil infiltration.
Spike–wave discharges are necessary for the expression of behavioral depression‐like symptoms
Authors: Sarkisova Karine Yu , Kuznetsova Galina D. , Kulikov Michael A. , Van Luijtelaar Gilles
Published: August 2009

Purpose: The WAG/Rij strain of rats, a well‐established model for absence epilepsy, has comorbidity for depression. These rats exhibit depression‐like behavioral symptoms such as increased immobility in the forced swimming test and decreased sucrose intake and preference (anhedonia). These depression‐like behavioral symptoms are evident in WAG/Rij rats, both at 3–4 and 5–6 months of age, with a tendency to aggravate in parallel with an increase in seizure duration. Here we investigated whether the behavioral symptoms of depression could be prevented by the suppression of absence seizures.

Methods: Ethosuximide (ETX; 300 mg/kg/day, in the drinking water) was chronically applied to WAG/Rij rats from postnatal day 21 until 5 months. Behavioral tests were done before the cessation of the treatment. Electroencephalography (EEG) recordings were made before and after cessation of treatment to measure seizure severity at serial time‐points.

Results: ETX‐treated WAG/Rij rats exhibited no symptoms of depression‐like behavior in contrast to untreated WAG/Rij rats of the same age. Moreover, treated WAG/Rij rats did not differ from control age‐matched Wistar rats. ETX treatment led to almost complete suppression of spike‐wave discharges (SWDs) in 5–6 month old WAG/Rij rats. Discontinuation of chronic treatment was accompanied by a gradual emergence of SWDs; however, a persistent reduction in seizure activity was still present 47 days after discontinuation of the chronic treatment.

Discussion: The results suggest that seizure activity is necessary for the expression of depression‐like behavioral symptoms and confirm that epileptogenesis can be prevented by early and chronic treatment.
Improved seizure control by alternating therapy of levetiracetam and valproate in epileptic rats
Authors: Van Vliet Erwin A. , Edelbroek Peter M. , Gorter Jan A.
Published: August 2009

Purpose: Tolerance to drug treatment is a serious problem in the treatment of epilepsy. We previously showed that tolerance to levetiracetam (LEV) developed within 4 days after the start of the treatment in a rat model for spontaneous seizures after electrically induced status epilepticus. In the current study we tested whether the development of tolerance to LEV could be prevented by alternating between LEV and valproate (VPA) treatment.

Methods: Before starting the alternating therapy with LEV and VPA (3 day LEV–3 day VPA, two cycles), we assessed the efficacy of VPA monotherapy by administering VPA to chronic epileptic rats via osmotic minipumps during 7 days. The anticonvulsive effects were determined by continuous video‐EEG (electroencephalography) monitoring, and the concentration of VPA and LEV was measured in plasma using gas chromatography.

Results: VPA significantly suppressed spontaneous seizures in chronic epileptic rats for 5 days. Hereafter, seizure frequency increased to pretreatment values despite adequate VPA blood levels. Seizure duration was reduced for 6 days during treatment. Seizure severity was reduced throughout the 7‐day treatment period. Alternating treatment of LEV and VPA did not prevent development of tolerance; however, seizures were suppressed significantly longer compared to VPA and LEV monotherapy.

Conclusions: Because alternating treatment with LEV and VPA led to a prolonged effective seizure control in the animal model, it would be worthwhile to explore the possibilities of using an alternating treatment protocol in pharmacoresistant patients in whom an effective treatment is hampered by tolerance to antiepileptic drugs.
Precipitous induction of audiogenic kindling by activation of adenylyl cyclase in the amygdala
Authors: Tupal Srinivasan , Faingold Carl L.
Published: August 2009

Purpose: Kindling of audiogenic seizure (AGS) involves ≥14 AGS over 1–2 weeks in genetically epilepsy‐prone rats (GEPR‐9s) and induces gradual seizure duration increases, epileptiform electroencephalography (EEG), and emergence of post tonic clonus (PTC), which are long‐lasting.N‐methyl‐d‐aspartate (NMDA)–receptor activation in lateral amygdala (LA) is implicated in AGS kindling initiation. However, the persistence of AGS kindling appears to be dependent on molecular mechanisms initiated by NMDA‐receptor activation, which may involve adenylyl cyclase (AC). This study attempted to mimic AGS kindling persistently in nonkindled GEPR‐9s by one‐time activation of AC in LA.

Methods: The effects of a single focal bilateral microinjection into LA of an AC activator, MPB forskolin {7‐Deacetyl‐7‐[O‐(N‐methylpiperazino)‐γ‐butyryl]‐forskolin dihydrochloride} (25–100 pmol/side), on seizure behavior in GEPR‐9s were evaluated.

Results: One‐time bilateral microinjection of MPB forskolin in GEPR‐9s precipitously induced an AGS kindling–like effect, which involved significant increases in seizure duration and long‐lasting susceptibility to AGS that culminates in PTC. This effect occurred at 24 h after MPB forskolin microinjection and lasted ≥5 weeks. The effect was seen when AGS was initiated at 1 and 12 h after microinjection, but not if AGS was induced only at 24 h, indicating the importance of the temporal proximity of AGS induction to the MPB forskolin microinjection.

Discussion: These findings indicate that one‐time activation of AC within the NMDA receptor–mediated molecular cascade results in precipitous induction of AGS kindling. These data further suggest that AC activation in the LA may be an important epileptogenic mechanism that subserves the long‐lasting persistence of AGS kindling.
Language development before and after temporal surgery in children with intractable epilepsy
Authors: De Koning Trudi , Versnel Huib , Jennekens‐Schinkel Aag , Van Schooneveld Monique M. J. , Dejonckere Philippe H. , Van Rijen Peter C. , Van Nieuwenhuizen Onno ,   on behalf of the Dutch Collaborative Epilepsy Surgery Programme (DuCESP)
Published: August 2009

Purpose:  To obtain systematic knowledge of language development before and after epilepsy surgery in regions that, if damaged, are known to entail language impairment in adults.

Methods:  Twenty‐four children (mean age 11 years; range 5.8–15.7 years) with pharmacologically intractable epilepsy participated prior to (the majority) anterior temporal lobectomy and 6, 12, and 24 months thereafter. Reception and production of lexicon (vocabulary) and syntax (sentence structure including grammar) were examined using developmental language tests that provide normative data.

Results:  Prior to surgery the mean language delay varied from 1.7 years (productive syntax) to 3.5 years (productive lexicon). For lexicon, language delay was larger, the older the children; for syntax it was smaller in children with mothers with higher education. Over the 2 years following surgery, the children developed in all four language components. Development was, however, slower than normal, that is, language delay increased, in three of the four components: in productive lexicon it continued to increase, and in receptive lexicon and productive syntax it appeared to stabilize during the second year. Receptive syntax developed at a normal pace. The development of productive lexicon was remarkably slow when surgery and language mediation were both in the left hemisphere.

Discussion:  Pharmacologically intractable epilepsy of the temporal lobe, or the underlying condition, is a significant risk factor for delayed language development. Temporal epilepsy surgery does not result in acceleration of language development. If language is still mediated in the operated left hemisphere, development of particular language components may slow down after surgery.
Black and White Adult Family Members' Attitudes Toward a Dementia Diagnosis
Authors: Connell Cathleen M , Roberts J. Scott , McLaughlin Sara J. , Carpenter Brian D.
Published: August 2009

OBJECTIVES: To examine potential benefits of and barriers to diagnosis from the perspective of black and white adults directly affected by Alzheimer's disease (AD).

DESIGN: Telephone survey.

SETTING: Convenience sample recruited from two U.S. metropolitan areas.

PARTICIPANTS: One hundred seventy‐eight family members of people with AD, including current and former AD caregivers and immediate blood relatives of someone with AD.

MEASUREMENTS: Respondents were asked to rate the importance of eight benefits of and 16 barriers to obtaining a diagnosis.

RESULTS: Family members strongly endorse several benefits of obtaining a diagnosis, including getting information, finding out what is wrong with their relative, and prompting future planning. A majority of survey respondents did not endorse any barriers examined. Lack of a cure for AD and the belief that little can be done for someone with AD were the most frequently endorsed barriers. Black respondents endorsed five of the eight benefits more frequently than white respondents.

CONCLUSION: Black and white adults with a family member who has received an diagnosis of AD perceive a range of benefits and few barriers to the diagnostic process examined in this study. Their positive experiences might be instructive to families considering pursuing a diagnosis and to physicians who may be reluctant to offer screening or referral because of the belief that families have little to gain.
Clinical Features, Treatment Practices, and Hospital and Long‐Term Outcomes of Older Patients Hospitalized with Decompensated Heart Failure: The Worcester Heart Failure Study
Authors: Saczynski Jane S. , Darling Chad E. , Spencer Frederick A. , Lessard Darleen , Gore Joel M. , Goldberg Robert J.
Published: August 2009

OBJECTIVES: To examine age‐specific differences in clinical presentation, receipt of therapeutic practices and lifestyle recommendations, and hospital and long‐term survival in patients hospitalized for acute heart failure HF.

DESIGN: Population‐based study.

SETTING: The Worcester Heart Failure Study, a population‐based study of residents of the a large Central New England metropolitan area hospitalized for decompensated HF at 11 greater‐Worcester medical centers.

PARTICIPANTS: Four thousand five hundred thirty‐four patients hospitalized for decompensated HF during 1995 and 2000.

MEASUREMENTS: Medical records were reviewed for demographic, clinical, and treatment characteristics and hospital survival status. Long‐term follow‐up of discharged hospital patients was conducted through 2005. Patients were compared according to four age groups (<65, 65–74, 75–84, and ≥85).

RESULTS: Mean age was 76; 24.0% were aged 85 and older. Patients aged 75 and older were more likely to be female and to have multiple comorbidities, a lower body mass index at the time of hospitalization, and higher ejection fraction findings. Older patients were significantly more likely to receive symptom‐modifying medications and less likely to receive disease‐modifying medications than younger patients. Older age was directly associated with higher in‐hospital, 30‐day, and 1‐year death rates in crude and multivariable‐adjusted analyses.

CONCLUSION: The results of this community‐wide study suggest that clinical, treatment, and prognostic factors differ according to age in patients hospitalized for decompensated HF. These high‐risk patients warrant special attention in future studies to improve their management and long‐term survival.
Mortality Risk Associated with Physical and Verbal Abuse in Women Aged 50 to 79
Authors: Baker Margaret W. , LaCroix Andrea Z. , Wu Chunyuan , Cochrane Barbara B. , Wallace Robert , Woods Nancy F.
Published: August 2009

OBJECTIVES: To investigate whether midlife and older women who reported prior‐year physical abuse, verbal abuse, or both abuse types had higher mortality risk than peers who did not report prior‐year abuse.

DESIGN: Retrospective analysis.

SETTING: Community.

PARTICIPANTS: One hundred sixty‐thousand six hundred seventy‐six community‐dwelling women ages 50 to 79 at baseline enrolled in one of two major Women's Health Initiative (WHI) study components who responded to baseline abuse questions. Observational study enrollment was N=93,676 (1994–1998; 90 months average follow‐up). Clinical trial enrollment was N=68,132 (1993–1998; 96 months average follow‐up).

MEASUREMENTS: Total mortality was measured from 1993 to 2005 using all available data sources. Blinded physician adjudicators measured cause‐specific mortality. Ninety‐six percent of death records were adjudicated.

RESULTS: Prior‐year self‐reported abuse prevalence was 11.3%. Women who reported physical abuse had the highest age‐adjusted mortality rate, followed by women who reported both abuse types. Abuse independently predicted mortality risk after controlling for age, education, ethnicity, and WHI component. High mortality risk remained for physically abused women (hazard ratio (HR)=1.54, 95% confidence interval (CI)=1.09–2.18) after adjusting for demographic and health‐related factors. Further adjustment for psychosocial variables diminished this association (HR=1.40, 95% CI=0.93–2.11), but high risk remained.

CONCLUSION: Community‐dwelling middle‐aged and older women who reported prior‐year physical, verbal, or both types of abuse had significantly higher adjusted mortality risk than women who did not report abuse. These findings highlight the need for longitudinal research into prevention of abuse in later life and accompanying excess mortality and emphasize the importance of abuse prevention in later life.
Removable Partial Denture in Combination with a Milled Fixed Partial Prosthesis as Interim Restorations in Long‐Term Treatment
Authors: Pellizzer Eduardo Piza , Mazaro José Vitor Quinelli , Verri Fellippo Ramos , Antenucci Rosse Mary Falcón , Goiato Marcelo Coelho
Published: August 2009

Interim restorations are frequently used in prosthodontic treatments. Many complex situations require the combination of fixed and removable partial prostheses. An appropriate interim restoration design that accurately implements the treatment plan is necessary to prepare the oral cavity for the prostheses, and to contribute to the preservation and health of remaining natural teeth, bone support, and gingival tissues. This report describes a modified technique for construction of interim restorations with a combination of fixed and removable partial prostheses. The technique consists of the construction of a milled fixed prosthesis and removable partial denture with metallic framework for use during extensive treatment, improving masticatory function and esthetics and preserving the periodontal health of supporting structures. This interim restoration can also serve as a template for the definitive restoration, allowing patient and dentist to evaluate appearance and function and helping to ensure the success of the definitive restoration.
Tooth Reduction Guide Using Silicone Registration Material Along with Vacuum‐Formed Thermoplastic Matrix
Authors: Oh Won‐suk , Saglik Berna , May Kenneth B.
Published: August 2009

Adequate tooth reduction is a prerequisite for function, esthetics, and longevity of fixed restorations. A tooth reduction guide may be useful for establishing the proper angulation of the tooth and maximizing periodontal health and restorative success. This article describes a simple and versatile technique for an accurate evaluation of tooth reduction for fixed restorations by using a color‐contrasting positive guide of a silicone occlusal registration material processed inside a vacuum‐formed clear thermoplastic matrix.
Foreword
Authors: Fisher George W.
Published: August 2009

Published QUARTERLY in the interest of constructive synthesis in the social sciences, under grants from the Francis Neilson Fund and the Robert Schalkenbach Foundation.

Founded in 1941
Comment on William C. Brainard and Herbert E. Scarf's “How to Compute Equilibrium Prices in 1891”
Authors: Brown Donald , Kubler Felix
Published: August 2009

Abstract.  A comment on Brainard and Scarf's article in this volume.
Comment on Robert Hall's “Controlling the Price Level”
Authors: Tobin James
Published: August 2009

Abstract.  James Tobin discusses Fisher's compensated dollar plan and Robert Hall's proposal for controlling the price level.
Econometric Analysis of Fisher's Equation
Authors: Phillips Peter C. B.
Published: August 2009

Abstract.  Fisher's equation for the determination of the real rate of interest is studied from a fresh econometric perspective. Some new methods of data description for nonstationary time series are introduced. The methods provide a nonparametric mechanism for modelling the spatial densities of a time series that displays random wandering characteristics, like interest rates and inflation. Hazard rate functionals are also constructed, an asymptotic theory is given, and the techniques are illustrated in some empirical applications to real interest rates for the United States. The paper ends by calculating semiparametric estimates of long‐range dependence in U.S. real interest rates, using a new estimation procedure called modified log periodogram regression and new asymptotics that covers the nonstationary case. The empirical results indicate that the real rate of interest in the United States is (fractionally) nonstationary over 1934–1997 and over the more recent subperiods 1961–1985 and 1961–1997. Unit root nonstationarity and short memory stationarity are both strongly rejected for all these periods.
Fisher's Introductory Text
Authors: Tobin James
Published: August 2009

Abstract.  In this essay, James Tobin discusses Fisher's Elementary Principles of Economics (1912). This essay was first published in the American Economic Review: Papers and Proceedings, 87 (May 1997): pp. 430–432. We are grateful to the American Economic Association for permission to republish this essay.
Comments on William D. Nordhaus’s, “Irving Fisher and the Contribution of Improved Longevity to Living Standards”
Authors: Dimand Robert W.
Published: August 2009

Abstract  This essay discusses Fisher's contributions to life extension and to human capital theory.
Does “Health Promotion” Really Promote Health?
Authors: Feinstein Alvan R.
Published: August 2009

Abstract  In his comment on Victor Fuch's essay, the late Alvan Feinstein raised the question of whether government‐sponsored programs of “health promotion” are always good for well‐being.
Dividing the Oils: Dynamic Bargaining as Policy Formation in the Nigerian Petroleum Industry
Authors: Hosman Laura
Published: August 2009

In academic studies of the interface between developing countries and large multinational oil corporations, scholars have noted that over time and through repeated interaction, the developing countries tend to negotiate better outcomes for themselves: they progress along a learning curve by incrementally improving their outcomes through bargaining and strategic interaction. This phenomenon can be demonstrated in a number of oil‐rich developing countries. Nigeria's case, however, is more complex. During the two decades following its independence, the state successfully negotiated for more control over—made strides in the developing of the skills necessary to manage—its petroleum industry, as our model would predict. Then, in a puzzling late‐1970s‐to‐mid‐1980s change of course, the government abruptly gave back concessions, undermined local entrepreneurial endeavors, and repealed indigenization laws. This paper combines, in the analytic narrative tradition, the case study method with an extensive form game; it applies a dynamic bargaining model to Nigeria's historical experience, demonstrating that Nigeria improved its outcomes and ascended along the “bargaining learning curve,” only to reverse policy and “unlearn,” with serious consequences for the Nigerian population. Even so, the demonstration of both successful and improved outcomes in past negotiations give evidence that Nigeria could once again ascend its bargaining learning curve if the government were to re‐commit to such a policy.
Blockade of GRP78 sensitizes breast cancer cells to microtubules‐interfering agents that induce the unfolded protein response
Authors: Wang Jiao , Yin Yancun , Hua Hui , Li Minjing , Luo Ting , Xu Li , Wang Ranran , Liu Dongbo , Zhang You , Jiang Yangfu
Published: August 2009

Taxane and vinblastine represent two classes of microtubules‐targeted agents for cancer chemotherapy. Although taxol and vinblastine are widely used for cancer treatment, resistance to these agents is frequently encountered in the clinic. An ongoing question has been what mechanisms are involved in the resistance of tumour cells to microtubules‐targeted agents or how the clinical effectiveness can be improved. There is increasing evidence that microtubules interact with the endoplasmic reticulum (ER). Here, we have shown that taxol and vinblastine induce multiple arms of the ER stress response, including up‐regulation of glucose‐regulated protein 78 (GRP78) expression, X‐box binding protein 1 splicing and eukaryotic initiation factor 2α phosphorylation. Abrogation of GRP78 induction sensitizes breast cancer cells to taxol and vinblastine. Treatment with (‐)‐epigallocatechin gallate (EGCG), a known GRP78 inhibitor, synergistically promotes taxol‐ and vinblastine‐induced cell death. GRP78 knockdown or EGCG potentiates taxol‐ and vinblastine‐induced activation of pro‐apoptosis arms of the ER stress response, such as JNK phosphorylation, caspase‐7 and PARP cleavage. Inhibition of JNK and caspase‐7 abrogates EGCG sensitization of breast cancer cells to taxol and vinblastine. We conclude that induction of the unfolded protein response represents a novel mechanism underlying the efficacy and resistance to microtubules‐targeted agents. Combination of compounds capable of suppressing GRP78 might be a novel approach for improving the effectiveness of microtubules‐targeted chemotherapy.
Transforming growth factor‐β1 elicits Nrf2‐mediated antioxidant responses in aortic smooth muscle cells
Authors: Churchman Adrian T. , Anwar Anila A. , Li Francois Y.L. , Sato Hideyo , Ishii Tetsuro , Mann Giovanni E. , Siow Richard C.M.
Published: August 2009

The anti‐inflammatory properties of transforming growth factor‐β1 (TGF‐β1) account for its protection against atherosclerotic plaque rupture. This study investigates whether activation of the Nrf2 (nuclear factor erythroid 2 [NF‐E2]‐related factor 2) transcription pathway is involved in TGF‐β1 mediated induction of the antioxidant enzyme heme oxygenase‐1 (HO‐1) in smooth muscle cells (SMC). Human aortic smooth muscle cells (HAoSMC) or wild‐type and Nrf2‐deficient mouse (MAoSMC) aortic SMC were treated with TGF‐β1 (2.5–10 ng/ml, 0–24 hrs). We report the first evidence that TGF‐β1 induces Nrf2 mediated HO‐1 expression and antioxidant response element activity, which was paralleled by enhanced superoxide production and expression of the NAD(P)H oxidase subunit p22phox. TGF‐β1 failed to induce HO‐1 expression in MAoSMC derived from Nrf2‐deficient mice, and HO‐1 induction by TGF‐β1 in HAoSMC was attenuated by inhibition of extracellular signal regulated kinase or c‐jun‐N‐terminal kinase but not p38 mitogen activated protein kinase. Inhibition of NAD(P)H oxidase or scavenging of superoxide diminished HO‐1 induction in response to TGF‐β1. The oxidative stress agents glucose oxidase (GOx) and diethylmaleate enhanced TGF‐β1 generation and HO‐1 expression in HAoSMC, while antagonism of TGF‐β1 signalling by adenoviral Smad7 overexpression attenuated their induction of HO‐1. Pre‐treatment of HAoSMC with TGF‐β1 reduced nuclear translocation of the pro‐apoptotic mediator p53 elicited by GOx. Our findings demonstrate that Nrf2 is a new target of TGF‐β1 signalling in the vasculature which may contribute to the atheroprotective properties attributed to this growth factor.
Surviving hypoxia by modulation of mRNA translation rate
Authors: Fähling Michael
Published: August 2009

Oxygen in eukaryotic metabolism

Oxygen consumption of tissues and processes

Metabolic rate depression

mRNA translation in hypoxia: the down and up and down

Regulation of global mRNA translation in hypoxia

Regulation of specific mRNA translation in hypoxia

Can an alteration of the translational machinery cause a specific change in gene expression?

Cells can survive hypoxia/anoxia by metabolic rate depression, which involves lowering of mRNA translation rates in an ATP‐dependent manner. By activating anaerobic ATP production (glycolysis), the inhibitory influence on mRNA translation in hypoxia can be abolished. In severe hypoxia, glycolysis cannot fully restore the ATP demand, thus causing a long‐lasting inhibition of global protein synthesis. During moderate hypoxia, fermentative ATP production may maintain normal ATP levels. However, an activation of hypoxia tolerance mechanisms, including specific mRNA translation, also takes place. The latter may be attributed to oxygen‐dependent (but not ATP dependent) processes such as the activation of the hypoxia‐inducible factor cascade. In summary, hypoxia‐induced decline in cellular ATP level can be counteracted by suppression of global mRNA translation rate. Sustained protein synthesis seems to be attributed to the activation of specific mRNA translation under long‐term hypoxic conditions.