Recognition of hepatitis C virus RNA by toll like receptors 7 and 8 : implications for the initiation of innate immune response

Le virus de l’hépatite C (VHC) est un virus à ARN simple brin positif (ssARN) qui se replique dans le foie. Deux cents millions de personnes sont infectées par le virus dans le monde et environ 80% d’entre elles progresseront vers un stade chronique de l’infection. Les thérapies anti-virales actuelles comme l’interféron (IFN) ou la ribavirin sont de plus en plus utilisées mais ne sont efficaces que dans la moitié des individus traités et sont souvent accompagnées d’une toxicité ou d’effets secondaires indésirables. Le système immunitaire inné est essentiel au contrôle des infections virales. Les réponses immunitaires innées sont activées suite à la reconnaissance par les Pathogen Recognition Receptors (PRRs), de motifs macromoléculaires dérivés du virus appelés Pathogen-Associated Molecular Patterns (PAMPs). Bien que l'activation du système immunitaire par l'ARN ou les protéines du VHC ait été largement étudiée, très peu de choses sont actuellement connues concernant la détection du virus par le système immunitaire inné. Et même si l’on peut très rapidement déceler des réponses immunes in vivo après infection par le VHC, l’augmentation progressive et continue de la charge virale met en évidence une incapacité du système immunitaire à contrôler l’infection virale. Une meilleure compréhension des mécanismes d’activation du système immunitaire par le VHC semble, par conséquent, essentielle au développement de stratégies antivirales plus efficaces. Dans le présent travail nous montrons, dans un modèle de cellule primaire, que le génome ARN du VHC contient des séquences riches en GU capables de stimuler spécifiquement les récepteurs de type Toll (TLR) 7 et 8. Cette stimulation a pour conséquence la maturation des cellules dendritiques plasmacytoïdes (pDCs), le production d’interféron de type I (IFN) ainsi que l’induction de chémokines et cytokines inflammatoires par les différentes types de cellules présentatrices d’antigènes (APCs). Les cytokines produites après stimulation de monocytes ou de pDCs par ces séquences ssARN virales, inhibent la production du virus de façon dépendante de l’IFN. En revanche, les cytokines produites après stimulation de cellules dendritiques myéloïdes (mDCs) ou de macrophages par ces mêmes séquences n’ont pas d’effet inhibiteur sur la production virale car les séquences ssARN virales n’induisent pas la production d’IFN par ces cellules. Les cytokines produites après stimulation des TLR 7/8 ont également pour effet de diminuer, de façon indépendante de l’IFN, l’expression du récepteur au VHC (CD81) sur la lignée cellulaire Huh7.5, ce qui pourrait avoir pour conséquence de restreindre l’infection par le VHC. Quoiqu’il en soit, même si les récepteurs au VHC comme le CD81 sont largement exprimés à la surface de différentes sous populations lymphocytaires, les DCs et les monocytes ne répondent pas aux VHC, Nos résultats indiquent que seuls les macrophages sont capables de reconnaître le VHC et de produire des cytokines inflammatoires en réponse à ce dernier. La reconnaissance du VHC par les macrophages est liée à l’expression membranaire de DC-SIGN et l’engagement des TLR 7/8 qui en résulte. Comme d’autres agonistes du TLR 7/8, le VHC stimule la production de cytokines inflammatoires (TNF-α, IL-8, IL-6 et IL-1b) mais n’induit pas la production d’interféron-beta par les macrophages. De manière attendue, la production de cytokines par des macrophages stimulés par les ligands du TLR 7/8 ou les séquences ssARN virales n’inhibent pas la réplication virale. Nos résultats mettent en évidence la capacité des séquences ssARN dérivées du VHC à stimuler les TLR 7/8 dans différentes populations de DC et à initier une réponse immunitaire innée qui aboutit à la suppression de la réplication virale de façon dépendante de l’IFN. Quoiqu’il en soit, le VHC est capable d’échapper à sa reconnaissance par les monocytes et les DCs qui ont le potentiel pour produire de l’IFN et inhiber la réplication virale après engagement des TLR 7/8. Les macrophages possèdent quant à eux la capacité de reconnaître le VHC grâce en partie à l’expression de DC-SIGN à leur surface, mais n’inhibent pas la réplication du virus car ils ne produisent pas d’IFN. L’échappement du VHC aux défenses antivirales pourrait ainsi expliquer l’échec du système immunitaire inné à contrôler l’infection par le VHC. De plus, la production de cytokines inflammatoires observée après stimulation in vitro des macrophages par le VHC suggère leur potentielle contribution dans l’inflammation que l’on retrouve chez les individus infectés par le VHC.

Elastic scattering and total reaction cross sections for the (8)Li+(12)C system

The elastic-scattering angular distribution for (8)Li on (12)C has been measured at E(LAB) = 23.9 MeV with (8)Li radioactive nuclear beam produced by the Radioactive Ion Beams in Brazil facility. This angular distribution was analyzed in terms of optical-model with Woods-Saxon and double-folding Sao Paulo potential. The roles of the breakup and inelastic channels were also investigated with cluster folding and deformed potentials, respectively, through coupled-channels calculations. The angular distribution for the proton-transfer (12)C((8)Li, (9)Be)(11)B reaction was also measured at the same energy. The spectroscopic factor for the <(9)Be|(8)Li + p > bound system was obtained and compared with shell-model calculations and with other experimental values. Total reaction cross sections for the present system were also extracted from the elastic-scattering analysis. A systematic of the reduced reaction cross sections obtained from the present and published data on (6,7,8)Li isotopes on (12)C was performed as a function of energy.

Estudo sorológico sobre a cepa A/New Jersey/8/76 em grupos populacionais brasileiros: nota prévia

O estudo sorológico de vários grupos populacionais brasileiros, pela pesquisa de anticorpos inibidores da hemaglutinação para a cepa de vírus da influenza A/New Jersey/8/76, deu os seguintes resultados preliminares: 7,8% do total de crianças normais e 75% do total de indivíduos adultos normais já estudados mostraram possuir títulos de anticorpos inibidores da hemaglutinação para aquela cepa > 80; num grupo de índios da região do Xingu, todos os soros testados apresentaram título < 40.

Development of a high throughput PCR to detect Coxiella burnetii and its application in a diagnostic laboratory over a 7-year period.

Q fever is a worldwide zoonotic infectious disease due to Coxiella burnetii. The clinical presentation may be acute (pneumonia and/or hepatitis) or chronic (most commonly endocarditis). Diagnosis mainly relies on serology and PCR. We therefore developed a quantitative real-time PCR. We first tested blindly its performance on various clinical samples and then, when thoroughly validated, we applied it during a 7-year period for the diagnosis of both acute and persistent C. burnetii infection. Analytical sensitivity (< 10 copies/PCR) was excellent. When tested blindly on 183 samples, the specificity of the PCR was 100% (142/142) and the sensitivity was 71% (29/41). The sensitivity was 88% (7/8) on valvular samples, 69% (20/29) on blood samples and 50% (2/4) on urine samples. This new quantitative PCR was then successfully applied for the diagnosis of acute Q fever and endovascular infection due to C. burnetii, allowing the diagnosis of Q fever in six patients over a 7-year period. During a local small cluster of cases, the PCR was also applied to blood from 1355 blood donors; all were negative confirming the high specificity of this test. In conclusion, we developed a highly specific method with excellent sensitivity, which may be used on sera for the diagnosis of acute Q fever and on various samples such as sera, valvular samples, aortic specimens, bone and liver, for the diagnosis of persistent C. burnetii infection.

Síntese e avaliação da atividade fitotóxica de lactonas derivadas do 2,4-dimetil-8-oxabiciclo[3.2.1]-oct-6-en-3-ona

The alkene 2,4-dimethyl-8-oxabicyclo[3.2.1]-oct-6-en-3-one (3) was converted to 1,3,10-trimethyl-8-oxabicyclo[5.3.0]-dec-3-ene-2,9-dione (7) and 1,3-dimethyl-8-oxabicyclo[5.3.0]-dec-3-ene-2,9-dione (8) with a 55% overall yield in both cases. Lactones (7) and (8) were converted in two steps to 1,3,4-trimethyl-13-methylene-6-oxatricyclo[8.3.0.0(3,7)]-trideca-2,5,12-trione (12) (63%) and 1,3-dimethyl-13-methylene-6-oxatricycle[8.3.0.0(3,7)]-trideca-2,5,12-trione (13) (45% from 8). The effect of lactones (7), (8), (12), (13) and the intermediates (5) and (6), at the concentration of 250 mug mL-1, on the growth of Cucumis sativus L. and Sorghum bicolor L. was evaluated. The best results were observed for lactone (13) that caused 100% inhibition on the root growth of C. sativus and lactone (12) that inhibited 90% of the root growth for S. bicolor.

Fatores perinatais associados a recém-nascidos de termo com pH<7,1 na artéria umbilical e índice de Apgar <7,0 no 5º minuto

OBJETIVO: Avaliar os fatores perinatais associados a recém-nascidos de termo com pH<7,1 na artéria umbilical e índice de Apgar no 5º min<7,0. MÉTODOS: Estudo retrospectivo com delineamento caso-controle, realizado após revisão dos prontuários de todos os nascimentos ocorridos entre setembro/1998 e março/2008, no Hospital Geral de Caxias do Sul. Foi considerado fator de inclusão os recém-nascidos de termo que apresentaram índice de Apgar no 5º min <7,0 e pH de artéria umbilical <7,1. Na análise univariada foi utilizado o teste t de Student e Mann-Whitney para as variáveis contínuas, o teste do c² para as variáveis dicotômicas e estimativa de risco pelo odds ratio (OR). Foi utilizado um valor de p<0,05 como estatisticamente significativo. RESULTADOS: De um total de 15.495 nascimentos consecutivos observaram-se 25 neonatos (0,16%) de termo com pH<7,1 na artéria umbilical e índice de Apgar no 5º min <7,0. Apresentaram associação significativa com o evento acidótico a apresentação pélvica (OR=12,9; p<0,005), parto cesáreo (OR=3,5; p<0,01) e cardiotocografia intraparto alterada (OR=7,8; p<0,02). Dentre as características fetais, associaram-se o déficit de base (-15,0 versus -4,5; p<0,0001), necessidade de internação em unidade de terapia intensiva neonatal (OR=79,7; p<0,0001) e necessidade de reanimação (OR=12,2; p<0,0001). CONCLUSÃO: Baixo índice de Apgar no 5º min de vida associado a pH<7,1 na artéria umbilical pode predizer desfechos neonatais desfavoráveis.

Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9% NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 ± 0.04 ml/min vs 1.45 ± 0.18 ml/min in vehicle-treated rats, P<0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 ± 0.34 ml/60 min and 3.39 ± 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.

Psychopharmacotherapy of panic disorder: 8-week randomized trial with clonazepam and paroxetine

The objective of the present randomized, open-label, naturalistic 8-week study was to compare the efficacy and safety of treatment with clonazepam (N = 63) and paroxetine (N = 57) in patients with panic disorder with or without agoraphobia. Efficacy assessment included number of panic attacks and clinician ratings of the global severity of panic disorders with the clinical global impression (CGI) improvement (CGI-I) and CGI severity (CGI-S) scales. Most patients were females (69.8 and 68.4% in the clonazepam and paroxetine groups, respectively) and age (mean ± SD) was 35.9 ± 9.6 years for the clonazepam group and 33.7 ± 8.8 years for the paroxetine group. Treatment with clonazepam versus paroxetine resulted in fewer weekly panic attacks at week 4 (0.1 vs 0.5, respectively; P < 0.01), and greater clinical improvements at week 8 (CGI-I: 1.6 vs 2.9; P = 0.04). Anxiety severity was significantly reduced with clonazepam versus paroxetine at weeks 1 and 2, with no difference in panic disorder severity. Patients treated with clonazepam had fewer adverse events than patients treated with paroxetine (73 vs 95%; P = 0.001). The most common adverse events were drowsiness/fatigue (57%), memory/concentration difficulties (24%), and sexual dysfunction (11%) in the clonazepam group and drowsiness/fatigue (81%), sexual dysfunction (70%), and nausea/vomiting (61%) in the paroxetine group. This naturalistic study confirms the efficacy and tolerability of clonazepam and paroxetine in the acute treatment of patients with panic disorder.

[7 lettres d'Augusta Holmès à Jules Massenet, [entre 1892 et 1903]]

f.1-5, 7-8 : lettres, f.6 : carte ; f.1 daté d'après le contenu de la lettre, f.7-8 datés d'après l'année de décès d'Augusta Holmès

Estudio experimental sobre la enseñanza del Inglés a hispanohablantes de 6 a 8 años.

Comprobar el Inglés que pueden aprender los escolares, número de vocablos, dificultades de pronunciación, estructuras gramaticales más adecuadas, extensión de los diálogos, y diseñar un corpus de actividades, recursos, y técnicas de evaluación. En colaboración continuada: 5 colegios nacionales y privados con 1600 alumnos. Con una colaboración parcial: 6 colegios nacionales y privados con 630 alumnos, tanto unos como otros son de Granada capital. Elaboración de materiales didácticos del proyecto Junior English 1976, reformulados cada año. Realización de una evaluación oral continuada y una evaluación escrita con diferentes pruebas cada bimestre. Presentan el material del alumno, las evaluaciones, y los resultados. Aplicación del proyecto Junior English 1976. Pruebas de control para cada actividad, orales y escritas: test de vocabulario, pronunciación ,'Idioms' y estructuras. Media, desviación típica, homogeneidad de los grupos, fiabilidad de la prueba, índices de dificultad y discriminación. Demuestran en cada uno de los tres niveles que, tanto contenidos como objetivos, actividades y evaluaciones, son conseguidas y adecuadas. Los índices de fiabilidad bastante aceptables de algunas pruebas , permiten su estandarización. Desarrollan lo que debe enseñarse a los 6,7,8 y 9 años. Conjunto de material didáctico y juegos originales y motivadores. Presenta ventajas el estudio del idioma en la infancia, siendo beneficioso para las demás áreas educativas, y posteriormente en la segunda etapa de EGB. Podemos iniciar la lectura de una segunda lengua a partir de tercero de EGB.

Essentials : Year 8 KS3 Science

Este es el segundo de los tres cursos de ciencias para estudiantes de secundaria Key Stage 3. Juntos, los cursos para los años 7,8 y 9 suministran un completo cubrimiento del programa de estudio para Key Stage 3 ciencias. Cada curso comprende preguntas y tareas para reforzar el aprendizaje de los estudiantes y ayudarles a mejorar. Este libro del año 8, está dividido en doce temas. Los temas están ilustrados y tratan sobre los procesos de la vida y la supervivencia (la supervivencia en el medio ambiente), elementos, compuestos y rocas (átomos y elementos), calor, luz y el magnetismo de sonido (magnetismo y electromagnetismo).

Number Processing and Calculation in Brazilian Children Aged 7-12 Years

Numerical cognition is based on two components - number processing and calculation. Its development is influenced by biological, cognitive, educational, and cultural factors. The objectives of the present study were to: i) assess number processing and calculation in Brazilian children aged 7-12 years from public schools using the Zareki-R (Battery of neuropsychological tests for number processing and calculation in children, Revised; von Aster & Dellatolas, 2006) in order to obtain normative data for Portuguese speakers; ii) identify how environment, age, and gender influences the development of these mathematical skills; iii) investigate the construct validity of the Zareki-R by the contrast with the Arithmetic subtest of WISC-III. The sample included 172 children, both genders, divided in two groups: urban (N= 119) and rural (N= 53) assessed by the Zareki-R. Rural children presented lower scores in one aspect of number processing; children aged 7-8 years demonstrated an inferior global score than older; boys presented a superior performance in both number processing and calculation. Construct validity of Zareki-R was demonstrated by high to moderate correlations with Arithmetic subtest of WISC-III. The Zareki-R therefore is a suitable instrument to assess the development of mathematical skills, which is influenced by factors such as environment, age, and gender.

Prompt and non-prompt J/ψ production in pp collisions at √s =7 TeV

The production of J/ψ mesons is studied in pp collisions at √s = 7 TeV with the CMS experiment at the LHC. The measurement is based on a dimuon sample corresponding to an integrated luminosity of 314 nb-1. The J/ψ differential cross section is determined, as a function of the J/ψ transverse momentum, in three rapidity ranges. A fit to the decay length distribution is used to separate the prompt from the non-prompt (b hadron to J/ψ) component. Integrated over J/ψ transverse momentum from 6.5 to 30 GeV/c and over rapidity in the range {pipe}y{pipe} < 2.4, the measured cross sections, times the dimuon decay branching fraction, are 70.9 ± 2.1(stat.) ± 3.0(syst.) ± 7.8(luminosity) nb for prompt J/ψ mesons assuming unpolarized production and 26.0 ± 1.4(stat.) ± 1.6(syst.) ± 2.9(luminosity) nb for J/ψ mesons from b-hadron decays. © CERN for the benefit of the CMS collaboration 2011.

Expressão gênica dos fatores de crescimento fibroblástico 7 e 10 (FGF-7 e FGF-10) ao longo do desenvolvimento folicular ovariano bovino

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)