Mycobacterium tuberculosis-specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease.

Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8(+) T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8(+) T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb-specific CD8(+) T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8(+) T cells in LTBI subjects were mostly T EMRA cells (CD45RA(+) CCR7(-)), coexpressing 2B4 and CD160, and in TB patients were mostly TEM cells (CD45RA(-) CCR7(-)), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8(+) T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8(+) T cells expressed perforin and granulysin. Finally, Mtb-specific CD8(+) T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8(+) T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8(+) T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response.

Longitudinal and cross-sectional changes in active commuting to school among Brazilian schoolchildren.

OBJECTIVE: The objective of the study is to evaluate cross-sectional and longitudinal changes in children's commuting to school in a representative sample of a Brazilian city. METHODS: Two school-based studies were carried out in 2002 (n=2936; 7-10years old) and 2007 (n=1232; 7-15years old) in Florianopolis, Brazil. Cross-sectional data were collected from children aged 7 to 10years in 2002 and 2007. Longitudinal analyses were performed with data from 733 children participating in both surveys. Children self-reported their mode of transportation to school using a validated illustrated questionnaire. Changes were tested with chi square statistics and McNemar's test. RESULTS: Cross-sectional data showed a 17% decline in active commuting; a decrease from 49% in 2002 to 41% in 2007. On the other hand, active commuting among the 733 children increased as they entered adolescence 5years later, rising from 40% to 49%. CONCLUSION: Active commuting to school decreased in Brazilian children aged 7-10years over a five year period; whereas, it increased among children entering adolescence. Policies should focus on safety and environmental determinants to increase active commuting.

A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.

Identification of active oxalotrophic bacteria by Bromodeoxyuridine DNA labeling in a microcosm soil experiments

The oxalate-carbonate pathway (OCP) leads to a potential carbon sink in terrestrial environments. This process is linked to the activity of oxalotrophic bacteria. Although isolation and molecular characterizations are used to study oxalotrophic bacteria, these approaches do not give information on the active oxalotrophs present in soil undergoing the OCP. The aim of this study was to assess the diversity of active oxalotrophic bacteria in soil microcosms using the Bromodeoxyuridine (BrdU) DNA labeling technique. Soil was collected near an oxalogenic tree (Milicia excelsa). Different concentrations of calcium oxalate (0.5%, 1%, and 4% w/w) were added to the soil microcosms and compared with an untreated control. After 12days of incubation, a maximal pH of 7.7 was measured for microcosms with oxalate (initial pH 6.4). At this time point, a DGGE profile of the frc gene was performed from BrdU-labeled soil DNA and unlabeled soil DNA. Actinobacteria (Streptomyces- and Kribbella-like sequences), Gammaproteobacteria and Betaproteobacteria were found as the main active oxalotrophic bacterial groups. This study highlights the relevance of Actinobacteria as members of the active bacterial community and the identification of novel uncultured oxalotrophic groups (i.e. Kribbella) active in soils.

Prévention de la violence commise par les spectateurs lors de manifestations sportives : étude des mesures préventives et de la responsabilité de l'organisateur à la lumière du droit comparé, du droit suisse et du droit associatif

Introduction 1. Généralités : Le sport occupe une place importante dans notre société, de manière active par la pratique d'une ou de plusieurs activités sportives, ou de manière passive, au travers de la presse, de la radio et de la télévision. Le sport est ainsi un acte de participation, d'appartenance, de revendication et d'intégration à la société en général ou à un groupe. Il stimule l'imagination et permet de rêver aux héros sportifs. Enfin, non seulement il améliore la santé de ceux qui le pratique, mais il a une dimension éducative et joue un rôle social, culturel et récréatif. Toutefois, le sport est également un spectacle qui provoque des passions et engendre des émotions de la part des supporters, dont certains s'exaltent pour leur équipe fétiche. Il arrive que ce supportérisme soit à tel point exacerbé qu'il mène à des dérives pouvant aboutir à des actes de violence dans et en dehors des stades, ceci tant avant, pendant qu'après le match. A titre d'exemple tragique, les téléspectateurs garderont longtemps en mémoire les scènes auxquelles ils ont assisté le 29 mai 1985, en direct, lorsque, avant le début de la rencontre, des hooligans anglais ont attaqué des supporters italiens dans les gradins du bloc Z du stade du Heysel à Bruxelles, lors de la finale de la Coupe d'Europe des champions, opposant le FC Liverpool à la Juventus de Turin; 39 personnes en sont mortes et 600 ont été blessées. La Suisse, longtemps épargnée par le phénomène, en regard de la situation qui a prévalu dans d'autres Etats européens, ne peut échapper, depuis quelques années, au triste constat selon lequel les stades constituent désormais des environnements propices à des actions de violence, de racisme et, plus rarement, d'extrémisme. Le cas le plus révélateur a eu lieu le 13 mai 2006, lorsque des fauteurs de trouble ont envahi le terrain du Parc Saint-Jacques de Bâle après le coup de sifflet final du match de championnat opposant le FC Bâle au FC Zurich, match dont l'enjeu était la première place du classement du championnat de Super League, pour attaquer à coups de pied et à coups de poing des joueurs, des accompagnants et des personnes chargées de la sécurité. Les affrontements ont continué dans la rue jusque tard dans la soirée. Il s'en est suivi une centaine de blessés et des dégâts d'un demi million de francs. De tels débordements mettent en danger la sécurité du public, des équipes et des arbitres. Il s'agit de tout mettre en oeuvre afin que les spectateurs qui assistent à une manifestation sportive puissent prendre du plaisir aux performances des sportifs sans devoir craindre pour leur sécurité. De même, les acteurs sur le terrain doivent pouvoir exercer leur sport sans craindre un envahissement de l'aire de jeu. Ainsi, les Etats et les associations sportives ont élaboré des textes juridiques afin d'éviter des débordements ou tout autre événement qui pourraient mettre en danger des personnes ou des biens matériels lors de manifestations sportives. Sous l'angle du droit étatique helvétique, cela s'est traduit, notamment en vue du déroulement en Suisse du Championnat d'Europe de football de l'UEFA en 2008 (EURO 2008) et du Championnat du monde de hockey sur glace en 2009, par l'adoption de mesures préventives permettant de lutter contre les actes de violence lors de manifestations sportives, introduites dans la Loi fédérale du 21 mars 1997 instituant des mesures visant au maintien de la sûreté intérieure (LMSI). Elles se concrétisent par l'inscription d'individus ayant commis des actes de violence dans une banque de données nationale, ainsi que par le recours au périmètre d'exclusion, à l'interdiction de sortie du territoire, à l'obligation de s'annoncer à la police et, en dernier ressort, à la garde à vue; enfin, il est également possible de saisir, séquestrer ou confisquer du matériel de propagande5. La mise en place de telles mesures relève de l'Etat, garant de la sécurité et de l'ordre publics à l'extérieur des enceintes sportives. L'organisateur, chargé quant à lui d'assurer la sécurité à l'intérieur du stade, n'est toutefois pas en marge, puisque les fédérations et associations sportives ont édicté des règlements dont il est le destinataire. Ces textes prévoient, à sa charge, notamment les mesures suivantes: le prononcé d'interdictions de stade à l'encontre de supporters violents, la fouille accrue des spectateurs, l'engagement d'un service de sécurité privé, l'obligation de désigner un responsable de la sécurité, la séparation des différents groupes de supporters, etc.. Il appartient ainsi aux associations sportives, aux organisateurs, aux chargés de la sécurité au sein des clubs et aux forces de l'ordre public d'appliquer de la meilleure façon que ce soit les mesures proposées et de collaborer afin de combattre les débordements des spectateurs de manière effective. Prévenir et supprimer la violence dans les manifestations sportives exige ainsi la mobilisation et la collaboration de tous les protagonistes concernés.

Predicting the evolution of Kaposi sarcoma, in the highly active antiretroviral therapy era.

BACKGROUND: The outcome of Kaposi sarcoma varies. While many patients do well on highly active antiretroviral therapy, others have progressive disease and need chemotherapy. In order to predict which patients are at risk of unfavorable evolution, we established a prognostic score. METHOD: The survival analysis (Kaplan-Meier method; Cox proportional hazards models) of 144 patients with Kaposi sarcoma prospectively included in the Swiss HIV Cohort Study, from January 1996 to December 2004, was conducted. OUTCOME ANALYZED: use of chemotherapy or death. VARIABLES ANALYZED: demographics, tumor staging [T0 or T1 (16)], CD4 cell counts and HIV-1 RNA concentration, human herpesvirus 8 (HHV8) DNA in plasma and serological titers to latent and lytic antigens. RESULTS: Of 144 patients, 54 needed chemotherapy or died. In the univariate analysis, tumor stage T1, CD4 cell count below 200 cells/microl, positive HHV8 DNA and absence of antibodies against the HHV8 lytic antigen at the time of diagnosis were significantly associated with a bad outcome.Using multivariate analysis, the following variables were associated with an increased risk of unfavorable outcome: T1 [hazard ratio (HR) 5.22; 95% confidence interval (CI) 2.97-9.18], CD4 cell count below 200 cells/microl (HR 2.33; 95% CI 1.22-4.45) and positive HHV8 DNA (HR 2.14; 95% CI 1.79-2.85).We created a score with these variables ranging from 0 to 4: T1 stage counted for two points, CD4 cell count below 200 cells/microl for one point, and positive HHV8 viral load for one point. Each point increase was associated with a HR of 2.26 (95% CI 1.79-2.85). CONCLUSION: In the multivariate analysis, staging (T1), CD4 cell count (<200 cells/microl), positive HHV8 DNA in plasma, at the time of diagnosis, predict evolution towards death or the need of chemotherapy.

Hypotensive effect of the active fragment derived from factor XII is mediated by an activation of the plasma kallikrein-kinin system.

Plasma protein fraction (PPF) contaminated by factor XII active fragment (XIIf) may cause hypotensive reactions when infused to patients. This study was planned to assess in conscious normotensive rats whether the blood pressure response to the factor XIIf is mediated by an activation of the plasma kallikrein-kinin system or by stimulation of prostaglandin synthesis. To test whether the factor XIIf-induced blood pressure fall is due partially to an enhanced generation of vasodilating prostaglandins, the blood pressure effect of XIIf (1 microgram i.v.) was investigated 15 min after treatment with indomethacin (5 mg i.v.), an inhibitor of cyclo-oxygenase. Factor XIIf reduced mean blood pressure similarly in indomethacin- and vehicle-treated rats (-23 +/- 4 mmHg, n = 5, and -23 +/- 5 mmHg, n = 4, respectively). Other rats received factor XIIf 15 min after depletion of circulating prekallikrein by the administration of dextran sulfate. Thirty minutes after a 0.25 mg i.v. dose of this agent, plasma prekallikrein activity averaged 0.12 +/- 0.015 mumol/min/ml (n = 6) as compared to 2.48 +/- 0.31 mumol/min/ml in control rats (n = 4, P less than .001). Factor XIIf decreased mean blood pressure by only 4 +/- 2 mm Hg in rats pretreated with dextran sulfate. Thus, it was possible to blunt the acute hypotensive effect of factor XIIf by depleting circulating prekallikrein, but not by inhibiting prostaglandin production. This strongly suggests that the blood pressure effects of factor XIIf is mediated by a stimulation of the plasma kallikrein-kinin system.

Pi*-pi* bonding interactions generated by halogen oxidation of zirconium(IV) redox-active ligand complexes.

The new complex, [Zr(pda)2]n (1, pda2- = N,N'-bis(neo-pentyl)-ortho-phenylenediamide, n = 1 or 2), prepared by the reaction of 2 equiv of pdaLi2 with ZrCl4, reacts rapidly with halogen oxidants to afford the new product ZrX2(disq)2 (3, X = Cl, Br, I; disq- = N,N'-bis(neo-pentyl)-ortho-diiminosemiquinonate) in which each redox-active ligand has been oxidized by one electron. The oxidation products 3a-c have been structurally characterized and display an unusual parallel stacked arrangement of the disq- ligands in the solid state, with a separation of approximately 3 A. Density functional calculations show a bonding-type interaction between the SOMOs of the disq- ligands to form a unique HOMO while the antibonding linear combination forms a unique LUMO. This orbital configuration leads to a closed-shell-singlet ground-state electron configuration (S = 0). Temperature-dependent magnetism measurements indicate a low-lying triplet excited state at approximately 750 cm-1. In solution, 3a-c show strong disq--based absorption bands that are invariant across the halide series. Taken together these spectroscopic measurements provide experimental values for the one- and two-electron energies that characterize the pi-stacked bonding interaction between the two disq- ligands.

Participation de la population au dépistage du cancer du sein : déterminants et enjeux

Cet article présente le résumé de l'atelier consacré au dépistage du cancer du sein organisé dans le cadre de la 70e Assemblée annuelle de la Société suisse de médecine interne qui s'est tenue à Genève du 25 au 27 avril 2002. L'objectif de cet atelier était d'identifier, sur la base des programmes pilotes conduits en Suisse ainsi que dans le Bas-Rhin (France), les modalités d'organisation les mieux adaptées au contexte sanitaire et culturel local afin d'optimiser la participation de la population aux programmes de dépistage du cancer susceptibles d'être mis en oeuvre dans les prochaines années. En effet, une participation élevée constitue, avec l'exigence de qualité, la condition nécessaire pour que ces programmes soient efficaces.