bluuebunny/crossref_metadata_2025 huggingface dataset:
RD Lawrence Lecture 2009 Old genes, new tricks: learning about blood glucose regulation from naturally occurring genetic variation in humans
Authors: Gloyn A. L.
Published: October 2009

The study of rare monogenic forms of diabetes and pancreatic B‐cell dysfunction provides an unrivalled opportunity to link a specific change in gene function with precise cellular consequences and clinical phenotype in humans. Over the past 20 years there has been considerable success in determining the genetic aetiology of a number of rare monogenic forms of diabetes, which has had a significant impact on both our understanding of normal physiology and on translational medicine. The impact of these discoveries has been substantial, with insights into both developmental biology and normal physiology. There are clear examples where determining the genetic aetiology for individuals with rare monogenic subtypes of diabetes has led to improved treatment. Although formerly in the shadow of the monogenic diabetes field, over the past 3 years there has been staggering progress in our understanding of the genetic basis of Type 2 diabetes. This has been largely as a result of genome‐wide association studies and has seen the list of ‘diabetes susceptibility genes’ increase from three to close to 20. There is now encouraging evidence to support a potential role for genetics in determining the response of individuals with Type 2 diabetes to different therapeutic options. One of the challenges that lies ahead is determining how the non‐coding genetic variants exert their pathogenicity. It is possible that parallels can be drawn from functional work on rare regulatory mutations causing monogenic forms of diabetes. However, it is more likely that comprehensive approaches will be necessary.
Mitigating sea turtle by‐catch in coastal passive net fisheries
Authors: Gilman Eric , Gearhart Jeff , Price Blake , Eckert Scott , Milliken Henry , Wang John , Swimmer Yonat , Shiode Daisuke , Abe Osamu , Hoyt Peckham S. , Chaloupka Milani , Hall Martin , Mangel Jeff , Alfaro‐Shigueto Joanna , Dalzell Paul , Ishizaki Asuka
Published: October 2009

There is growing evidence that small‐scale, coastal, passive net fisheries may be the largest single threat to some sea turtle populations. We review assessments of turtle interactions in these fisheries, and experiments on gear‐technology approaches (modifying gear designs, materials and fishing methods) to mitigate turtle by‐catch, available from a small number of studies and fisheries. Additional assessments are needed to improve the limited understanding of the relative degree of risk coastal net fisheries pose to turtle populations, to prioritize limited conservation resources and identify suitable mitigation opportunities. Whether gear technology provides effective and commercially viable solutions, alone or in combination with other approaches, is not well‐understood. Fishery‐specific assessments and trials are needed, as differences between fisheries, including in gear designs; turtle and target species, sizes and abundance; socioeconomic context; and practicality affect efficacy and suitability of by‐catch mitigation methods. Promising gear‐technology approaches for gillnets and trammel nets include: increasing gear visibility to turtles but not target species, through illumination and line materials; reducing net vertical height; increasing tiedown length or eliminating tiedowns; incorporating shark‐shaped silhouettes; and modifying float characteristics, the number of floats or eliminating floats. Promising gear‐technology approaches for pound nets and other trap gear include: replacing mesh with ropes in the upper portion of leaders; incorporating a turtle releasing device into traps; modifying the shape of the trap roof to direct turtles towards the location of an escapement device; using an open trap; and incorporating a device to prevent sea turtle entrance into traps.
The Self-Organization of Explicit Attitudes
Authors: Wojnowicz Michael T. , Ferguson Melissa J. , Dale Rick , Spivey Michael J.
Published: October 2009

How do minds produce explicit attitudes over several hundred milliseconds? Speeded evaluative measures have revealed implicit biases beyond cognitive control and subjective awareness, yet mental processing may culminate in an explicit attitude that feels personally endorsed and corroborates voluntary intentions. We argue that self-reported explicit attitudes derive from a continuous, temporally dynamic process, whereby multiple simultaneously conflicting sources of information self-organize into a meaningful mental representation. While our participants reported their explicit (like vs. dislike) attitudes toward White versus Black people by moving a cursor to a “like” or “dislike” response box, we recorded streaming x- and y-coordinates from their hand-movement trajectories. We found that participants' hand-movement paths exhibited greater curvature toward the “dislike” response when they reported positive explicit attitudes toward Black people than when they reported positive explicit attitudes toward White people. Moreover, these trajectories were characterized by movement disorder and competitive velocity profiles that were predicted under the assumption that the deliberate attitudes emerged from continuous interactions between multiple simultaneously conflicting constraints.
When the Boss Feels Inadequate
Authors: Fast Nathanael J. , Chen Serena
Published: October 2009

When and why do power holders seek to harm other people? The present research examined the idea that aggression among the powerful is often the result of a threatened ego. Four studies demonstrated that individuals with power become aggressive when they feel incompetent in the domain of power. Regardless of whether power was measured in the workplace (Studies 1 and 4), manipulated via role recall (Study 2), or assigned in the laboratory (Study 3), it was associated with heightened aggression when paired with a lack of self-perceived competence. As hypothesized, this aggression appeared to be driven by ego threat: Aggressiveness was eliminated among participants whose sense of self-worth was boosted (Studies 3 and 4). Taken together, these findings suggest that (a) power paired with self-perceived incompetence leads to aggression, and (b) this aggressive response is driven by feelings of ego defensiveness. Implications for research on power, competence, and aggression are discussed.
WOMEN AND GIRLS AS UPPER PALAEOLITHIC CAVE ‘ARTISTS’: DECIPHERING THE SEXES OF FINGER FLUTERS IN ROUFFIGNAC CAVE
Authors: VAN GELDER LESLIE , SHARPE KEVIN
Published: October 2009

Popular and scholarly literature usually assumes that prehistoric artists were adult men. We show in other publications that young children from the Palaeolithic fluted in Rouffignac Cave, France, and hence the incorrectness at least here of the usual assumption. Our research also shows that females as well as males fluted in Rouffignac. Our methods for demonstrating this are forensic based on physiological research of relative finger lengths of males and females. We examine the profiles of the flutings of seven individuals and show that two are probably male whereas the remaining five are probably female. This type of study leading to where we identify individuals can produce responses to social questions about the fluters both as a group and as individuals.
VISUAL AFFORDANCE, LANDSCAPE, AND THE MEGALITHS OF ALDERNEY
Authors: GILLINGS MARK
Published: October 2009

The core of this paper seeks to make a methodological contribution to the GIS‐based analysis of visibility as a potential locational factor in past landscape placement, an area of study whose utility and value have been hotly debated by archaeologists keen to promote more experiential approaches to the interpretation of past landscapes. In doing so it seeks to break with recent discussions on the topic by not show‐casing new or technically more sophisticated sets of approaches. Instead it backtracks to reclaim a methodology introduced over a decade ago, yet rarely applied in routine archaeological practice – a case of taking one step back to advance two steps forward. An important subtext is that for the utility of GIS‐based work to be appreciated, it has to be driven by a clear archaeological research programme. To this end the study is fully embedded in a current research initiative exploring the megalithic monuments of prehistoric Alderney, the northernmost of the Channel Islands.
SIMULATING THE WESTERN SEAWAYS
Authors: CALLAGHAN RICHARD , SCARRE CHRIS
Published: October 2009

Recent debates on the introduction of Neolithic features to Britain have emphasized the role of the western maritime routes and the possibility of direct or indirect connections from Brittany to Ireland and Argyll. Here we present the results of simulation modelling of maritime voyaging by paddled or sail‐powered boat, indicating the likely lengths of the journeys that would have been required. The issue of direct travel vs. short crossings and coasting is explored, and the implications for specific connections, such as those posited to account for cattle remains in a pre‐Neolithic context in Ireland, are considered.
LEGACIES OF CHANGE: THE SHAPING OF CULTURAL LANDSCAPES IN A MARGINAL MEDITERRANEAN MOUNTAIN RANGE, THE GARRAF MASSIF, NORTH‐EASTERN SPAIN
Authors: EJARQUE ANA , ORENGO HECTOR A.
Published: October 2009

Human conceptions of landscape have influenced the shaping of landscapes as much as landscape configurations have modelled human perceptions. In this article a new theoretical approach to long‐term cumulative landscape change is tested on the Garraf Massif (Baix Llobregat, north‐eastern Spain). Thanks to its ancient occupation, physical character and location near to the city of Barcelona, the area provides a good illustration of how human‐induced landscape change has shaped new, and sometimes conflicting, landscape perceptions. These perceptions then play an equally active role in altering the previously ‘inherited landscape’ in a long‐term cyclical process that can be studied through the combined use of historical, palaeoenvironmental and archaeological records.
When divergent life histories hybridize: insights into adaptive life‐history traits in an annual weed
Authors: Campbell Lesley G. , Snow Allison A. , Sweeney Patricia M.
Published: October 2009

DOI: 10.1111/j.1469-8137.2009.03077.xFeatured paper: See Commentary, p741
Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson’s disease
Authors: Carta Anna R. , Kachroo Anil , Schintu Nicoletta , Xu Kui , Schwarzschild Michael A. , Wardas Jadwiga , Morelli Micaela
Published: October 2009

Adenosine A2A receptors antagonists produce neuroprotective effects in animal models of Parkinson’s disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A2A receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A2A receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A2A antagonism. MPTP·HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A2A antagonist SCH58261, or in conditional knockout mice lacking A2A receptors on forebrain neurons (fbnA2AKO mice). MPTP‐induced partial loss of dopamine neurons in substantia nigra pars compacta (SNc) and striatum (Str), associated with increased astroglial and microglial immunoreactivity in these areas. Astroglia was similarly activated 1, 3, and 7 days after MPTP administration, whereas maximal microglial reactivity was detected on day 1, returning to baseline 7 days after MPTP administration. SCH58261 attenuated dopamine cell loss and gliosis in SNc and Str. Selective depletion of A2A receptors in fbnA2AKO mice completely prevented MPTP‐induced dopamine neuron degeneration and gliosis in SNc, and partially counteracted gliosis in Str. Results provide evidence of a primary role played by neuronal A2A receptors in neuroprotective effects of A2A antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A2A receptor antagonists being pursued in clinical trials, this study adds to the rationale for broader clinical benefit and use of these drugs early in the treatment of PD.
Hedgehog signaling maintains hair follicle stem cell phenotype in young and aged human skin
Authors: Rittié Laure , Stoll Stefan W. , Kang Sewon , Voorhees John J. , Fisher Gary J.
Published: October 2009

Skin hair follicles (HF) contain bulge stem cells (SC) that regenerate HFs during hair cycles, and repair skin epithelia following injury. As natural aging is associated with decreased skin repair capacity in humans, we have investigated the impact of age on human scalp HF bulge cell number and function. Here, we isolated human bulge cells, characterized as CD200+/KRT15+/KRT19+ cells of the HF, by dissection‐combined CD200 selection in young and aged human skin. Targeted transcriptional profiling indicates that KRT15, KRT19, Dkk3, Dkk4, Tcf3, S100A4, Gas1, EGFR and CTGF/CCN2 are also preferentially expressed by human bulge cells, compared to differentiated HF keratinocytes (KC). Our results demonstrate that aging does not alter expression or localization of these HF SC markers. In addition, we could not detect significant differences in HF density or bulge cell number between young and aged human scalp skin. Interestingly, hedgehog (Hh) signaling is activated in human bulge cells in vivo, and down‐regulated in differentiated HF KCs, both in young and aged skin. In addition, activation of Hh signaling by lentivirus‐mediated overexpression of transcription factor Gli1 induces transcription of HF SC markers KRT15, KRT19, and Gas1, in cultured KCs. Together with previously reported knock‐out mouse results, these data suggest a role for Hh signaling in maintaining bulge cell phenotype in young and aged human skin.
Visualization of gene expression in the live subject using the Na/I symporter as a reporter gene: applications in biotherapy
Authors: Baril Patrick , Martin‐Duque Pilar , Vassaux Georges
Published: October 2009

Biotherapies involve the utilization of antibodies, genetically modified viruses, bacteria or cells for therapeutic purposes. Molecular imaging has the potential to provide unique information that will guarantee their biosafety in humans and provide a rationale for the future development of new generations of reagents. In this context, non‐invasive imaging of gene expression is an attractive prospect, allowing precise, spacio‐temporal measurements of gene expression in longitudinal studies involving gene transfer vectors. With the emergence of cell therapies in regenerative medicine, it is also possible to track cells injected into subjects. In this context, the Na/I symporter (NIS) has been used in preclinical studies. Associated with a relevant radiotracer (123I‐, 124I‐, 99mTcO4‐), NIS can be used to monitor gene transfer and the spread of selectively replicative viruses in tumours as well as in cells with a therapeutic potential. In addition to its imaging potential, NIS can be used as a therapeutic transgene through its ability to concentrate therapeutic doses of radionuclides in target cells. This dual property has applications in cancer treatment and could also be used to eradicate cells with therapeutic potential in the case of adverse events. Through experience acquired in preclinical studies, we can expect that non‐invasive molecular imaging using NIS as a transgene will be pivotal for monitoring in vivo the exact distribution and pharmacodynamics of gene expression in a precise and quantitative way. This review highlights the applications of NIS in biotherapy, with a particular emphasis on image‐guided radiotherapy, monitoring of gene and vector biodistribution and trafficking of stem cells.

This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00685.x
Irbesartan‐mediated reduction of renal and cardiac damage in insulin resistant JCR : LA‐cprats
Authors: Russell JC , Kelly SE , Vine DF , Proctor SD
Published: October 2009

Background and purpose: Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro‐ and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin‐resistant JCR : LA‐cprat that exhibits micro‐ and macrovascular disease with ischaemic myocardial lesions and renal disease.

Experimental approach: Obese male rats were treated with irbesartan (30 mg·kg−1·day−1, incorporated into chow) from 12 to 25 weeks of age.

Key results: Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA‐cprats was marginally improved, at the expense of increased plasma insulin levels (∼50%). Fasting plasma triglycerides were marginally reduced (∼25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein‐1 and plasminogen activator inhibitor‐1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium‐dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%).

Conclusions and implications: Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end‐stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.
Differential effects of quercetin, apigenin and genistein on signalling pathways of protease‐activated receptors PAR1and PAR4in platelets
Authors: Navarro‐Núñez L , Rivera J , Guerrero JA , Martínez C , Vicente V , Lozano ML
Published: October 2009

Background and purpose: The modulation by flavonoids of platelet responses induced by thrombin has been little investigated, and the antiplatelet activity, as well as possible inhibitory mechanisms of these compounds on thrombin signalling, has not yet been elucidated. We explored whether flavonoids affect platelet signalling pathways triggered by thrombin and by the selective activation of its protease‐activated receptors (PARs) 1 and 4, and analysed the antagonism of these polyphenols at thrombin receptors.

Experimental approach: We investigated the effect of a range of polyphenolic compounds on platelet aggregation, 5‐HT secretion, intracellular calcium mobilization, protein kinase activity and tyrosine phosphorylation, triggered by thrombin and PAR agonist peptides (PAR‐APs). The ability of these flavonoids to bind to thrombin receptors was investigated by competitive radioligand binding assays using125I‐thrombin.

Key results: Quercetin, apigenin and genistein impaired platelet aggregation, as well as 5‐HT release and calcium mobilization, induced by thrombin and PAR‐APs. Quercetin and apigenin were inhibitors of protein kinases, but genistein exhibited a minimal ability to suppress platelet phosphorylation. Binding assays did not establish any kind of interaction between thrombin receptors and any of the flavonoids tested.

Conclusions and implications: Quercetin, apigenin and genistein did not inhibit thrombin responses by interacting with thrombin receptors, but by interfering with intracellular signalling. While inhibition by genistein may be a consequence of affecting calcium mobilization, subsequent platelet secretion and aggregation, for quercetin and apigenin, inhibition of kinase activation may also be involved in the impairment of platelet responses.
Long‐term effects of losartan on structure and function of the thoracic aorta in a mouse model of Marfan syndrome
Authors: Yang HH Clarice , Kim Jong Moo , Chum Elliott , van Breemen Cornelis , Chung Ada WY
Published: October 2009

Background and purpose:  During development of thoracic aortic aneurysms in a mouse model of Marfan syndrome, upregulation of matrix metalloproteinase (MMP)‐2 and ‐9 was accompanied by compromised aortic constriction and endothelium‐dependent relaxation. Losartan has been proposed for the prevention of thoracic aortic aneurysm. We hypothesized that losartan would suppress MMP‐2/‐9 activation and improve aortic vasomotor function in this model.

Experimental approach:  A well‐characterized mouse model of Marfan syndrome (Fbn1C1039G/+) was used. Starting at 6 weeks old, Marfan mice were untreated or given losartan (0.6 g·L−1 in drinking water, n= 30). The littermate Fbn1+/+ mice served as control. Thoracic aortas were studied at 3, 6 and 9 months by histology and by contractility assays in isolated segments in vitro.

Key results:  Losartan improved elastic fibre organization and increased aortic breaking stress. Losartan reduced the activity and protein expression of MMP‐2 and MMP‐9 at all ages. Aortic constriction in response to membrane depolarization or phenylephrine was increased by losartan at 3 and 9 months by 100–200%. Active force of aortic smooth muscle was also increased at 6 and 9 months. Acetylcholine‐induced endothelium‐dependent relaxation was improved by 30% after 3 months of losartan treatment, but such improvement disappeared with longer duration of treatment, accompanied by reduced phosphorylation of endothelial nitric oxide (NO) synthaseSer1177, AktThr308 and AktSer473, compared with the control.

Conclusions and implications:  Losartan improved the contractile function of aorta and reduced MMP activation. However, the endothelial NO pathway remained suppressed in the thoracic aorta during losartan treatment, which might limit its long‐term benefits in Marfan syndrome.
HIT‐6 and MIDAS as Measures of Headache Disability in a Headache Referral Population
Authors: Sauro Khara M. , Rose Marianne S. , Becker Werner J. , Christie Suzanne N. , Giammarco Rose , Mackie Gordon F. , Eloff Arnoldas G. , Gawel Marek J.
Published: October 2009

(Headache 2010;50:383‐395)

Objective.— The objective of this study was to compare the headache impact test (HIT‐6) and the migraine disability assessment scale (MIDAS) as clinical measures of headache‐related disability.

Background.— The degree of headache‐related disability is an important factor in treatment planning. Many quality of life and headache disability measures exist but it is unclear which of the available disability measures is the most helpful in planning and measuring headache management.

Methods.— We compared HIT‐6 and MIDAS scores from 798 patients from the Canadian Headache Outpatient Registry and Database (CHORD). Correlation and regression analyses were used to examine the relationships between the HIT‐6 and MIDAS total scores, headache frequency and intensity, and Beck Depression Inventory (BDI‐II) scores.

Results.— A positive correlation was found between HIT‐6 and MIDAS scores (r = 0.52). The BDI‐II scores correlated equally with the HIT‐6 and the MIDAS (r = 0.42). There was a non‐monotonic relationship between headache frequency and the MIDAS, and a non‐linear monotonic relationship between headache frequency and the HIT‐6 (r = 0.24). The correlation was higher between the intensity and the HIT‐6 scores (r = 0.46), than MIDAS (r = 0.26) scores. Seventy‐nine percent of patients fell into the most severe HIT‐6 disability category, compared with the 57% of patients that fell into the most severe MIDAS disability category. Significantly more patients were placed in a more severe category with the HIT‐6 than with the MIDAS (McNemar chi‐square = 191 on 6 d.f., P < .0001).

Conclusions.— The HIT‐6 and MIDAS appear to measure headache‐related disability in a similar fashion. However, some important differences may exist. Headache intensity appears to influence HIT‐6 score more than the MIDAS, whereas the MIDAS was influenced more by headache frequency. Using the HIT‐6 and MIDAS together may give a more accurate assessment of a patient's headache‐related disability.
Noxious Inhibition of Temporal Summation is Impaired in Chronic Tension‐Type Headache
Authors: Cathcart Stuart , Winefield Anthony H. , Lushington Kurt , Rolan Paul
Published: October 2009

(Headache 2010;50:403‐412)

Objective.— To examine effects of stress on noxious inhibition and temporal summation (TS) in tension‐type headache.

Background.— Stress is the most commonly reported trigger of a chronic tension‐type headache (CTH) episode; however, the mechanisms underlying this are unclear. Stress affects pain processing throughout the central nervous system, including, potentially, mechanisms of TS and diffuse noxious inhibitory controls (DNIC), both of which may be abnormal in CTH sufferers (CTH‐S). No studies have examined TS of pressure pain or DNIC of TS in CTH‐S to date. Similarly, effects of stress on TS or DNIC of TS have not been reported in healthy subjects or CTH‐S to date.

Methods.— The present study measured TS and DNIC of TS in CTH‐S and healthy controls (CNT) exposed to an hour‐long stressful mental task, and in CTH‐S exposed to an hour‐long neutral condition. TS was elicited at finger and shoulder via 10 pulses from a pressure algometer, applied before and during stimulation from an occlusion cuff at painful intensity.

Results.— Algometer pain ratings increased more in the CTH compared with the CNT group, and were inhibited during occlusion cuff more in the CNT compared with CTH groups. Task effects on TS or DNIC were not significant.

Conclusions.— The results indicate increased TS to pressure pain and impaired DNIC of TS in CTH‐S. Stress does not appear to aggravate abnormal TS or DNIC mechanisms in CTH‐S.
Urinary 6‐Sulphatoxymelatonin Levels Are Depressed in Chronic Migraine and Several Comorbidities
Authors: Masruha Marcelo R. , Lin Jaime , De Souza Vieira Domingos S. , Minett Thais S.C. , Cipolla‐Neto José , Zukerman Eliova , Vilanova Luiz C.P. , Peres Mario F.P.
Published: October 2009

(Headache 2010;50:413‐419)

Objective.— To assess urinary 6‐sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls.

Background.— Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders.

Methods.— Urine samples were collected into a single plastic container over a 12‐hour period from 8:00 pm to 8:00 am of the next day, and 6‐sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State‐Trait Anxiety Inventory, and the Beck Depression Inventory.

Results.— A total of 220 subjects were evaluated – 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6‐sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6‐sulphatoxymelatonin levels and depression, anxiety, and fatigue.

Conclusions.— To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.
Neocortical seizure foci localization by means of a directed transfer function method
Authors: Wilke Christopher , Van Drongelen Wim , Kohrman Michael , He Bin
Published: October 2009

Purpose:  Determination of the origin of extratemporal neocortical onset seizures is often challenging due to the rapid speed at which they propagate throughout the cortex. Typically, these patients are poor surgical candidates and many times experience recurrences of seizure activity following resection of the assumed seizure focus.

Methods:  We applied a causal measurement technique—the directed transfer function (DTF)—in an effort to determine the cortical location responsible for the propagation of the seizure activity. Intracranial seizure recordings were obtained from a group of 11 pediatric patients with medically intractable neocortical‐onset epilepsy. Time windows were selected from the recordings following onset of the ictal activity. The DTF was applied to the selected time windows, and the frequency‐specific statistically significant source activity arising from each cortical recording site was quantified. The DTF‐estimated source activity was then compared with the seizure‐onset zone(s) identified by the epileptologists.

Results:  In an analysis of the 11 pediatric patients, the DTF was shown to identify estimated ictal sources that were highly correlated with the clinically identified foci. In addition, it was observed that in the patients with multiple ictal foci, the topography of the casual source activity from the analyzed seizures was associated with the separate clinically identified seizure‐onset zones.

Discussion:  Although localization of neocortical‐onset seizures is typically challenging, the causal measures employed in this study—namely the directed transfer function—identified generators of the ictal activity that were highly correlated with the cortical regions identified as the seizure‐onset zones by the epileptologists. This technique could prove useful in the identification of seizure‐specific propagation pathways in the presurgical evaluation of patients with epilepsy.
Pathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: A case–control study
Authors: Surges Rainer , Adjei Patrick , Kallis Constantinos , Erhuero Joy , Scott Catherine A. , Bell Gail S. , Sander Josemir W. , Walker Matthew C.
Published: October 2009

Purpose:  To determine whether abnormal cardiac repolarization and other electrocardiography (ECG) predictors for cardiac mortality occur in epilepsy patients and whether they are associated with an increased risk for sudden unexpected death in epilepsy (SUDEP).

Methods:  In a matched‐pair case–control study, recordings of adult patients with pharmacoresistant focal epilepsies who died from SUDEP and who had previously had presurgical video‐EEG (electroencephalography) telemetry were reviewed. Living controls were matched for age, gender, and date of admission for video‐EEG telemetry. Periictal heart rate (HR), corrected QT interval (QTc), postictal HR recovery, HR variability, and cardiac rhythm were assessed. QT dispersion was analyzed with 12‐lead ECG.

Results:  A total of 38 patients (19 per group) had 91 recorded seizures. QTc was prolonged above pathologic upper limits in 9 of 89 seizures and 5 of 38 patients. Nine of 34 patients displayed pathologic QT dispersion. Presence of neither pathologic cardiac repolarization nor other ECG features were specifically associated with SUDEP. SUDEP patients were, however, more likely to lack pathologic cerebral magnetic resonance imaging (MRI) findings, less likely to experience antiepileptic drug reduction during telemetry, and had more secondarily generalized tonic–clonic seizures (SGTCS) per year.

Discussion:  Our study did not reveal a clear‐cut ECG predictor for SUDEP. Pathologic cardiac repolarization is not uncommon in adult patients with pharmacoresistant focal epilepsy and could favor occurrence of fatal tachyarrhythmia as one plausible cause for SUDEP. SGTCS are a risk factor for SUDEP, have, as compared to complex‐partial seizures, a greater, unfavorable impact on heart activity, and may thereby additionally compromise cardiac function.
Comparison of antiepileptic drug prescribing in children in three European countries
Authors: Hsia Yingfen , Neubert Antje , Sturkenboom Miriam C.J.M. , Murray Macey L. , Verhamme Katia M.C. , Sen Fatma , Giaquinto Carlo , Ceci Adriana , Wong Ian C.K. ,   on behalf of the TEDDY Network of Excellence
Published: October 2009

Purpose:  Antiepileptic drug (AED) use in young people is increasing. However, evidence of its use at a multinational level is limited. This study aims to characterize AED prescribing in the young in three European countries and to assess the capacity of drug safety surveillance.

Methods:  A retrospective cohort study was conducted in 2001–2005 using primary care databases: PEDIANET (Italy, 0–11 years), IPCI (The Netherlands, 0–18 years), and IMS Disease Analyzer (United Kingdom, 0–18 years). Prescribing prevalence was calculated by country, patient age, and drug type.

Results:  In 2005, AED prevalence in children (0–11 years) was highest in Italy [3.9 subjects/1,000 person‐years (PY)] followed by the United Kingdom (3.0 subjects/1,000 PY) and The Netherlands (2.2 subjects/1,000 PY). Over the study period, prescribing prevalence in 0–11 year olds was stable in all countries. In contrast, a steady rise of AED prevalence was observed in adolescents (12–18 years) in the United Kingdom (p = 0.0003) but not in The Netherlands (p = 0.88). All countries showed a slight increase in prevalence for newer AEDs. Simultaneously, the prevalence of conventional AEDs decreased in The Netherlands and Italy, but not in the United Kingdom. In 2005, lamotrigine use was highest in The Netherlands and the United Kingdom, whereas topiramate was favored in Italy.

Discussion:  In Europe, conventional AEDs are still the main treatment choice for children with epilepsy, and the use of newer AEDs remains low. Our study highlights a lack of research capacity to conduct multinational AED safety studies in children. Further work should explore large databases and other health care settings to meet these research needs.
Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy
Authors: Romigi Andrea , Bari Monica , Placidi Fabio , Marciani M. Grazia , Malaponti Marilena , Torelli Federico , Izzi Francesca , Prosperetti Chiara , Zannino Silvana , Corte Francesca , Chiaramonte Carlo , Maccarrone Mauro
Published: October 2009

Purpose:  The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug‐naive patients affected by temporal lobe epilepsy (TLE).

Methods:  We measured the levels of both AEA and the other endocannabinoid, 2‐arachidonoylglycerol (2‐AG), in the CSF of drug‐naive patients with TLE.

Results:  A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 ± 1.78 pmol/ml; healthy controls = 11.65 ± 7.53 pmol/ml; n = 9 for both groups, p < 0.01). 2‐AG levels, however, were not affected (epileptic patients = 209.5 ± 146.56; healthy controls = 159.6 ± 110.2) (n = 6 for both groups, p = 0.48).

Discussion:  Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.
Contralateral MRI abnormalities in candidates for hemispherectomy for refractory epilepsy
Authors: Hallbook Tove , Ruggieri Paul , Adina Chirla , Lachhwani Deepak K. , Gupta Ayaj , Kotagal Prakash , Bingaman William E. , Wyllie Elaine
Published: October 2009

Purpose:  To assess the impact of contralateral magnetic resonance imaging (MRI) findings on seizure outcome after hemispherectomy for refractory epilepsy.

Methods:  We retrospectively reviewed 110 children, 0.4–18 (median 5.9) years of age, who underwent hemispherectomy for severe refractory epilepsy at Cleveland Clinic Children’s Hospital. In children with contralateral (as well as ipsilateral) MRI findings appreciated preoperatively, the decision to proceed to surgery was based on other features concordant with the side with the most severe MRI abnormality, including ipsilateral epileptiform discharges, lateralizing seizure semiology, and side of hemiparesis.

Results:  We retrospectively observed contralateral MRI abnormalities (predominantly small hemisphere, white matter loss or abnormal signal, or sulcation abnormalities) in 81 patients (74%), including 31 of 43 (72%) with malformations of cortical development (MCD), 31 of 42 (73%) with perinatal injury from infarction or hypoxia, and 15 of 25 (60%) with Rasmussen’s encephalitis, Sturge‐Weber syndrome, or posttraumatic encephalomalacia. Among 84 children (76%) with lesions that were congenital or acquired pre‐ or perinatally, 67 (83%) had contralateral MRI abnormalities (p = 0.02). Contralateral findings were subjectively judged to be mild or moderate in 70 (86%). At follow‐up 12–84 (median 24) months after surgery, 79% of patients with contralateral MRI abnormalities were seizure‐free compared to 83% of patients without contralateral MRI findings, with no differences based on etiology group or type or severity of contralateral MRI abnormality.

Discussion:  MRI abnormalities, usually mild to moderate in severity, were seen in the contralateral hemisphere in the majority of children who underwent hemispherectomy for refractory epilepsy due to various etiologies, especially those that were congenital or early acquired. The contralateral MRI findings, always much less prominent than those in the ipsilateral hemisphere, did not correlate with seizure outcome and may not contraindicate hemispherectomy in otherwise favorable candidates.
A comparison of two fMRI methods for predicting verbal memory decline after left temporal lobectomy: Language lateralization versus hippocampal activation asymmetry
Authors: Binder Jeffrey R. , Swanson Sara J. , Sabsevitz David S. , Hammeke Thomas A. , Raghavan Manoj , Mueller Wade M.
Published: October 2009

Purpose:  Language lateralization measured by preoperative functional magnetic resonance imaging (fMRI) was shown recently to be predictive of verbal memory outcome in patients undergoing left anterior temporal lobe (L‐ATL) resection. The aim of this study was to determine whether language lateralization or functional lateralization in the hippocampus is a better predictor of outcome in this setting.

Methods:  Thirty L‐ATL patients underwent preoperative language fMRI, preoperative hippocampal fMRI using a scene encoding task, and pre‐ and postoperative neuropsychological testing. A group of 37 right ATL (R‐ATL) surgery patients was included for comparison.

Results:  Verbal memory decline occurred in roughly half of the L‐ATL patients. Preoperative language lateralization was correlated with postoperative verbal memory change. Hippocampal activation asymmetry was strongly related to side of seizure focus and to Wada memory asymmetry but was unrelated to verbal memory outcome.

Discussion:  Preoperative hippocampal activation asymmetry elicited by a scene encoding task is not predictive of verbal memory outcome. Risk of verbal memory decline is likely to be related to lateralization of material‐specific verbal memory networks, which are more closely correlated with language lateralization than with overall asymmetry of episodic memory processes.
Vanoxerine: Cellular Mechanism of a New Antiarrhythmic
Authors: LACERDA ANTONIO E. , KURYSHEV YURI A. , YAN GAN‐XIN , WALDO ALBERT L. , BROWN ARTHUR M.
Published: October 2009

Cellular Electrophysiology of Vanoxerine. Introduction: There remains an unmet need for safe and effective antiarrhythmic drugs, especially for the treatment of atrial fibrillation. Vanoxerine is a drug that is free of adverse cardiac events in normal volunteers, yet is a potent blocker of the hERG (hKv11.1) cardiac potassium channel. Consequently,we hypothesized that vanoxerine might also be a potent blocker of cardiac calcium (Ca) and sodium (Na) currents, and would not affect transmural dispersion of repolarization.

Methods:
The whole cell patch clamp technique was used to measure currents from cloned ion channels overexpressed in stable cell lines and single ventricular myocytes. We measured intracellular action potentials from canine ventricular wedges and Purkinje fibers using sharp microelectrode technique.

Results:
We found that vanoxerine was a potent hKv11.1 blocker, and at submicromolar concentrations, it blocked Ca and Na currents in a strongly frequency‐dependent manner. In the canine ventricular wedge preparation vanoxerine did not significantly affect transmural action potential waveforms, QT interval or transmural dispersion of repolarization.

Conclusions:
Vanoxerine (1) is a potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly frequency‐dependent especially for Na and Ca channels; and (3) transmural dispersion of ventricular repolarization is unaffected. The multichannel block and repolarization uniformity resemble the effects of amiodarone, the exemplar atrial fibrillation drug. Vanoxerine is a completely different chemical and has none of amiodarone's toxic effects. Vanoxerine has characteristics of a potentially effective and safe antiarrhythmic. (J Cardiovasc Electrophysiol, Vol. 21, pp. 301–310, March 2010)
Long‐Term Outcomes of Inducible Very Fast Ventricular Tachycardia (Cycle Length 200–250 ms) in Patients With Ischemic Cardiomyopathy
Authors: KUMAR SAURABH , SIVAGANGABALAN GOPAL , CHOI MAN‐CHUN , EIPPER VICKI , THIAGALINGAM ARAVINDA , KOVOOR PRAMESH
Published: October 2009

Very Fast Ventricular Tachycardia. Background: The long‐term outcomes of patients with inducible very fast ventricular tachycardia (VFVT) of cycle length (CL) 200 to 250 ms have not been well studied.

Methods: Consecutive patients with ischemic cardiomyopathy with a left ventricular ejection fraction (LVEF) of ≤40% (n = 300) underwent programmed ventricular stimulation (PVS) and were divided into 4 groups based on results of the study. Group A were noninducible, had induced ventricular fibrillation (VF), or polymorphic VT (CL < 200 ms); group B had inducible VFVT (200–250 ms); group C had inducible fast ventricular tachycardia (FVT; CL 251–320 ms); and group D had inducible slow VT (CL >320 ms). The primary endpoint was spontaneous ventricular arrhythmia or sudden death.

Results:
The mean age was 63 ± 12 years and mean LVEF was 29 ± 7%. At mean follow‐up of 38 ± 25 months (median 30 months), the primary endpoint rate was 6.6%, 34%, 44%, and 71% in groups A, B C, and D, respectively (P < 0.001). Neither mode of induction of VT nor LVEF altered the observed pattern in the primary endpoint. There was no significant difference in the primary endpoint among implanted cardioverter defibrillator recipients in groups B and C (38% vs 45%, P = 0.43). Adjusted hazard ratios for the primary endpoint compared to group A were 3.2, 3.5, and 7.0 in groups B, C, and D, respectively (P < 0.05).

Conclusions:
Inducible VFVT (200–250 ms) is a clinically significant arrhythmia with adverse long‐term outcomes and should not be considered a nonspecific finding of PVS. (J Cardiovasc Electrophysiol, Vol. 21, pp. 262–269, March 2010)
Hybrid Therapy of Radiofrequency Catheter Ablation and Percutaneous Transvenous Mitral Commissurotomy in Patients With Atrial Fibrillation and Mitral Stenosis
Authors: MACHINO TAKESHI , TADA HIROSHI , SEKIGUCHI YUKIO , TANAKA YASUAKI , NAITO SHIGETO , YAMASAKI HIRO , ARIMOTO TAKANORI , IGARASHI MIYAKO , KUROKI KENJI , SEO YOSHIHIRO , WATANABE SHIGEYUKI , HOSHIZAKI HIROSHI , OSHIMA SHIGERU , TANIGUCHI KOICHI , AONUMA KAZUTAKA
Published: October 2009

AF Ablation and PTMC. Background: The rhythm control of atrial fibrillation (AF) associated with mitral stenosis (MS) is often difficult using antiarrhythmic drugs (AADs), even after a percutaneous transvenous mitral commissurotomy (PTMC). Few studies have examined the efficacy and safety of simultaneously performing radiofrequency catheter ablation (RFCA) and a PTMC in patients with MS and AF.

Methods:
Twenty consecutive patients with drug‐resistant AF and rheumatic MS underwent RFCA combined with a PTMC (n = 10; persistent AF‐8, long‐lasting [>1 year] persistent AF‐2; RFCA group) or transthoracic direct cardioversion (DC) following a PTMC (n = 10; persistent AF‐7, long‐lasting persistent AF‐3; DC group). In all patients, the mitral valve morphology was amenable to a PTMC, and more than 2 AADs had been ineffective in maintaining sinus rhythm (SR). In the RFCA group, a segmental pulmonary vein isolation (PVI) was performed in the initial 5 patients, and an extensive PVI was performed in the remaining 5.

Results:
During a mean follow‐up period of 4.0 ± 2.7 years, 8 patients (80%) in the RFCA group were maintained in SR, as compared to 1 (10%) in the DC group (hazard ratio, 0.16; 95% confidence interval, 0.03 to 0.75; P = 0.008 by the log‐rank test). The prevalence of the concomitant use of class I and/or class III AADs was comparable between the 2 groups (P = 0.70). No complications occurred during the procedure or follow‐up period in either group.

Conclusions:
The hybrid therapy using RFCA and a PTMC was safe and feasible, and significantly improved the AF free survival rate compared to DC following a PTMC. (J Cardiovasc Electrophysiol, Vol. 21, pp. 284–289, March 2010)
Mechanisms of Arrhythmia Recurrence After Video‐Assisted Thoracoscopic Surgery for the Treatment of Atrial Fibrillation: Insights from Electrophysiological Mapping and Ablation
Authors: LIU XINGPENG , DONG JIANZENG , MAVRAKIS HERCULES E. , ZHENG BIN , LONG DEYONG , YU RONGHUI , TANG RIBO , TIAN YING , VARDAS PANOS E. , MA CHANGSHENG
Published: October 2009

Background:
Video‐assisted thoracoscopic bilateral pulmonary vein (PV) isolation with left atrial appendage (LAA) excision is a novel surgical treatment for patients who have atrial fibrillation (AF) but no indication for open heart surgery. However, the electrophysiological mechanisms of the recurrent atrial tachyarrhythmias after this procedure are unknown.

Methods:
Eight consecutive patients with highly symptomatic atrial tachyarrhythmias after failed video‐assisted thoracoscopic surgery were included in this study. A predetermined stepwise ablation protocol, aimed at termination of the arrhythmia and isolation of all PVs, was conducted. The conduction across the remnant of the LAA was also evaluated in 4 patients.

Results:
Three patients had AF, which was converted into AT by complex fractionated atrial electrogram ablation in 2. Eleven sustained ATs in 7 patients were mapped during the procedure. A majority of ATs (10 of 11) were terminated by ablation before PV isolation. In total, 10 PV gaps in 7 patients were identified. All residual PV gaps were distributed exclusively in the roof or the bottom of the PV antrum. The conduction time across the remnant of the LAA was 90.7 ± 11.5 ms. One patient underwent a repeat successful ablation procedure. After a mean follow‐up of 10.1 ± 5.0 months after the last ablation procedure, 7 of 8 patients were free of clinical atrial tachyarrhythmias recurrence.

Conclusion:
PV gaps are present, with a characteristic distribution, in the majority of patients who fail this surgical procedure, but these gaps are not responsible for the arrhythmias identified. Instead, most are macro‐reentrant, isthmus‐dependent arrhythmias related to clamp‐associated or LAA excision‐associated scars.