Effect of rufinamide on gating properties of voltage-gated sodium channel Na(v)1.7

Background: Voltage-gated sodium channels (Nav1.x) are important players in chronic pain. A particular interest has grown in Nav1.7, expressed in nociceptors, since mutations in its gene are associated to two inherited pain syndromes or insensitivity to pain. Rufinamide, a drug used to treat refractory epilepsy such as the Lennox-Gastaut syndrome, has been shown to reduce the number of action potentials in cortical neurons without completely blocking Na channels. Aim: The goal of this study was to investigate the effect of rufinamide on Nav1.7 current. Methods and results: Whole-cell patch clamp experiments were performed using HEK293 cells stably expressing Nav1.7. Rufinamide significantly decreased peak sodium current by 28.3, 21.2 and 12.5% at concentrations of 500, 100 and 50μM respectively (precise EC50 could not be calculated since higher rufinamide concentrations could not be achieved in physiological buffer solution). No significant difference on the V1/2 of voltage-dependence of activation was seen; however a shift in the steady-state inactivation curve was observed (-82.6 mV to -88.8 mV and -81.8 to -87.6 mV for 50 and 100 μM rufinamide respectively, p <0.005). Frequency-dependent inhibition of Nav1.7 was also influenced by the drug. One hundred μM rufinamide reduced the peak sodium current (in % of the peak current taken at the first sweep of a train of 50) from 90.8 to 80.8% (5Hz), 88.7 to 71.8% (10 Hz), 69.1 to 49.2% (25 Hz) and 22.3 to 9.8% (50 Hz) (all p <0.05). Onset of fast inactivation was not influenced by the drug since no difference in the time constant of current decay was observed. Conclusion: In the concentration range of plasma level in human treated for epilepsy, 15 μM, rufinamide only minimally blocks Nav1.7. However, it stabilizes the inactivated state and exerts frequencydependent inhibition of Nav1.7. These pharmacological properties may be of use in reducing ectopic discharges as a causal and symptom related contributor of neuropathic pain syndrome.

Cluster algebras, quiver representations and triangulated categories

This is an introduction to some aspects of Fomin-Zelevinsky’s cluster algebras and their links with the representation theory of quivers and with Calabi-Yau triangulated categories. It is based on lectures given by the author at summer schools held in 2006 (Bavaria)and 2008 (Jerusalem). In addition to by now classical material, we present the outline of a proof of the periodicity conjecture for pairs of Dynkin diagrams (details will appear elsewhere) and recent results on the interpretation of mutations as derived equivalences.

Evolució del poblament i organització del territori a la Catalunya interior durant l'Antiguitat Tardana i l'Alta Edat Mitjana: els casos de la Catalunya Central (Bages, Berguedà i Solsonès) i la Garrotxa (segles V-X)

Projecte de recerca elaborat a partir d’una estada a la Université de Toulouse 2 – Le Mirail entre gener i juny del 2007. En concret, l’estada efectuada ha suposat la integració de qui signa aquesta memòria dins l’equip al-Andalus/Hispaniae, dirigit pel professor Philippe Sénac, una de les diverses branques que conformen el grup FRAMESPA d’aquella universitat, unitat de recerca adscrita al CNRS (UMR 5136). El títol proposat per al contingut de la recerca en la sol•licitud presentada, Evolució del poblament i organització del territori a la Catalunya interior a l’Alta Edat Mitjana, encapçalava un pla de treball que tenia per objectiu la recopilació i l’anàlisi de dades arqueològiques i textuals que oferissin un escenari a partir del qual establir una seqüència evolutiva en relació a les diferents tendències pel que fa al poblament tardoantic i altmedieval en dues zones diferenciades com són les conques mitjanes dels rius Llobregat i Cardener, a la Catalunya Central, i la capçalera del riu Fluvià, a la Garrotxa. Així, s’han pogut detectar, a partir de la contrastació de les diferents dades, fenòmens diversos que reflecteixen la incidència dels successius canvis històrics a nivell territorial i de poblament.

Compendium of projects in the European nanosafety cluster

This is the third edition of the compendium. It documents the status of important projects on nanomaterial toxicity and exposure monitoring, integrated risk management, research infrstructure and coordination and support activities. The compendium is not intended to be a guidance document for human health and environmental safety management of nanotechnologies, as such guidance documents already exist and are widely available. Neither is the compendium intended to be a medium for the publication of scientific papers and research results, as this task is covered by scientific conferences and the reviewed press. The compendium aims to bring researchers closer together and show them the potential for synergy in their work. It is a means to establish links and communication between them during the actual research phase and well before the publication of their results. It thus focuses on the communication of projects' strategic aims, extensively covers specific work objectives and the methods used in research, and documents human capacities and available laboratory infrastructure. As such, the compendium supports collaboration on common goals and the joint elaboration of future plans, whilst compromising neither the potential for scientific publication, nor intellectual property rights. [Auteurs]

The Economics of CO2-EOR Cluster Developments in the UK Central North Sea/ Outer Moray Firth

NORTH SEA STUDY OCCASIONAL PAPER No. 123

Risc cardiovascular dels fitoesterols

Els fitoesterols són components importants de la dieta Mediterrània. La seva ingesta augmenta les concentracions en sang i les concentracions elevades s’han relacionat amb un augment de risc cardiovascular. Però el síndrome metabòlic (SMet) s’associa a concentracions baixes de fitoesterols. S’ha investigat la relació entre fitoesterols del plasma i la dieta amb la presència de factors de risc cardiovascular, incloent el SMet, i malaltia cardiovascular. També s’han avaluat factors socioeconòmics que influencien els hàbits dietètics. Per dur-ho a terme s’ha realitzat un anàlisi retrospectiu en l’estudi Prevención con Dieta Mediterránea (PREDIMED) amb dades basals i a l’any d’una intervenció dietètica per avaluar la influència dels fitosterols de la dieta en el perfil lipídic dels participants. En l’estudi European Prospective Investigation into Cancer and Nutrition (EPIC) d’Espanya s’ha realitzat una anàlisi transversal per analitzar factors socials i dieta, i un estudi cas-control per avaluar el risc de desenvolupar malaltia cardiovascular segons les concentracions plasmàtiques de fitoesterols. Resultats: el consum de fitoesterols amb la dieta habitual s’ha relacionat amb la ingesta d’aliments saludables, amb una millora del perfil lipídic en els participants del PREDIMED i amb un increment dels fitoesterols plasmàtics. Aquest increment es va associar en l’estudi EPIC amb una millora dels factors de risc cardiovascular, una disminució del risc de patir malaltia cardiovascular o qualsevol component del SMet o el propi síndrome. Fa 10 anys la població espanyola seguia un patró de dieta mediterrània i era accessible a tothom independentment de la posició socioeconòmica. Conclusions. Les concentracions de fitoesterols plasmàtics semblen ser marcadors fiables d’un risc cardiometabòlic menor i un menor risc de patir malaltia cardiovascular. Ja que aquests elements són abundants en els aliments que característicament es consumeixen a Espanya, és necessari evitar que siguin difícils d’aconseguir per un encariment en el mercat i es generin desigualtats en salut a causa de l’alimentació.

A morphological, isoenzymatic and behavioural study of ten populations of Anopheles(Nyssorhynchus) albitarsis Lynch-Arribalzaga, 1878 (Diptera: culicidae) including from the type-locality - Baradero, Argentina

Anopheles (Nyssorhynchus) albitarsis Lynch-Arribalzaga, 1878 shows morphological and behavioural variations which results in it being sometimes considered as a major malaria vector and at other times as playing no important role in epidemiology. With the aim of clarifying the taxonomy of the species, comparative morphological and isoenzymatic studies were made in populations from the type-locality, Baradero, Argentina and from 9 different localities inBrazil. Morphological studies consisted of the observation of eggs in scanning electron microscopy, of complete chaetotaxy of larvae and pupae and of the detailed drawing of male and female adults. Only Guajara-Mirim and Rio Branco populations, described previously as Anopheles deaneorum sp.n., showed morphological differences. Isoenzymes were studied using 4th instar larvae homogenate and agarosegel electrophoresis. Eleven enzymatic loci were analyzed. By calculation of Nei's Genetic Distance (D), the populations could be separated into 5 groups: i)Baradero, ii)Marajo, iii)Boa Vista, iv)Angra, Itaguai and Paraipaba and v)Guajara-Mirim and Rio Branco. These groups belong to 2 major clusters called I and II, separated by D = 0.345. In the I cluster are groups i, ii and iii and in II clusteriv and v. In I, D=0.246 separates i and ii from iii, while i is separated by D =0.181 from ii. In II, D = 0.223 between iv and v. Only the population of group vcould be distinguished morphologically from the others, leading to the description of an independent species An. deaneorum.

Long-term effect of a school-based physical activity program (KISS) on fitness and adiposity in children: a cluster-randomized controlled trial.

BACKGROUND: School-based intervention studies promoting a healthy lifestyle have shown favorable immediate health effects. However, there is a striking paucity on long-term follow-ups. The aim of this study was therefore to assess the 3 yr-follow-up of a cluster-randomized controlled school-based physical activity program over nine month with beneficial immediate effects on body fat, aerobic fitness and physical activity. METHODS AND FINDINGS: Initially, 28 classes from 15 elementary schools in Switzerland were grouped into an intervention (16 classes from 9 schools, n = 297 children) and a control arm (12 classes from 6 schools, n = 205 children) after stratification for grade (1st and 5th graders). Three years after the end of the multi-component physical activity program of nine months including daily physical education (i.e. two additional lessons per week on top of three regular lessons), short physical activity breaks during academic lessons, and daily physical activity homework, 289 (58%) participated in the follow-up. Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). After adjustment for grade, gender, baseline value and clustering within classes, children in the intervention arm compared with controls had a significantly higher average level of aerobic fitness at follow-up (0.373 z-score units [95%-CI: 0.157 to 0.59, p = 0.001] corresponding to a shift from the 50th to the 65th percentile between baseline and follow-up), while the immediate beneficial effects on the other primary outcomes were not sustained. CONCLUSIONS: Apart from aerobic fitness, beneficial effects seen after one year were not maintained when the intervention was stopped. A continuous intervention seems necessary to maintain overall beneficial health effects as reached at the end of the intervention. TRIAL REGISTRATION: ControlledTrials.com ISRCTN15360785.

Avaluació del risc ambiental de productes farmacèutics en l'àmbit català

S’ha dut a terme una Avaluació del Risc Ambiental dels productes farmacèutics més consumits en l’àmbit català treballant sobre un model de planta de tractament d’aigües residuals determinat. La Concentració ambiental estimada (PEC) pel medi aquàtic s’ha calculat a partir de dades fisicoquímiques dels fàrmacs tenint en compte una sèrie d’hipòtesis i suposicions prèvies. La Concentració estimada de no-efecte (PNEC) s’ha estimat mitjançant dades d’ecotoxicitat extretes de l’ECOSAR. Es considera que hi ha afecció al medi quan la relació PEC/PNEC excedeix d’1; en aquest estudi s’ha obtingut que l’Ibuprofèn, el Diclofenac i l’Atorvastatina superen aquest valor suposant, per tant, un risc per al medi ambient. D’aquesta manera es mostra que l’eliminació dels fàrmacs durant el procés de la depuració de les aigües residuals no resulta totalment eficient.

Reduced quality of life associated adverse events in intermediate hepatocellular carcinoma patients treated with PRECISION TACE with drug eluting beads: Results from the PRECISION V randomized trial : B-241

Purpose: To evaluate the extent of quality of life (QoL) associated adverse events (AEs) following PRECISION TACE with DC Bead compared with conventional transarterial chemoembolisation (cTACE). Methods and Materials: 201 intermediate HCC patients were treated with DC Bead (PRECISION TACE) or conventional TACE (cTACE) with doxorubicin in the PRECISION V clinical study. 93 patients were treated with DC Bead and 108 Patients with cTACE every 2 months and followed up for 6 months. AEs were classified according to the South West Oncology Group criteria. QoL associated AEs were defined as alopecia, constipation, nausea, vomiting, pyrexia, chills, asthenia, fatigue, and headache. Results: The biggest difference in QoL associated AEs was for alopecia: 2 patients (2.2%) for DC-Bead versus 21 patients (19.4%) for cTACE. For other clinical symptoms, constipation (n=10; 10.8% vs. n=13; 12%), vomiting (n=10; 10.8% vs. n=14; 13.0%), pyrexia (n=16; 17.2% vs. n=26; 24.1%), chills (n=1; 1.1% vs. n=5; 4.6%), and headache (n=2; 2.2% vs. n=8; 7.4%) showed lower incidence in the DC Bead group versus cTACE. Nausea, n= 15; 13.9% (n=15; 16.1%) and fatigue, n=6; 5.6% (n=13; 14.0%) were lower for cTACE. Total dose of doxorubicin was on average 35% higher in the DC Bead group. Conclusion: Although patients in the DC Bead group received a higher doxorubicin dose, less QoL associated AEs were reported for this group. Alopecia, the most obvious outward sign of toxicity, was only reported in a tenth of DC Bead patients. Thus, PRECISION TACE with DC Bead improves quality of life associated adverse events.