Long-term cognitive profile and incidence of dementia after STN-DBS in Parkinson's disease

An effect of subthalamic nucleus deep brain stimulation (STN-DBS) on cognition has been suspected but long-term observations are lacking. The aim of this study was to evaluate the long-term cognitive profile and the incidence of dementia in a cohort of Parkinson's disease (PD) patients treated by STN-DBS. 57 consecutive patients were prospectively assessed by the mean of a neuropsychological battery over 3 years after surgery. Dementia (DSM-IV) and UPDRS I to IV were recorded. 24.5% of patients converted to dementia over 3 years (incidence of 89 of 1,000 per year). This group of patients cognitively continuously worsened over 3 years up to fulfilling dementia criteria (PDD). The rest of the cohort remained cognitively stable (PD) over the whole follow-up. Preoperative differences between PDD and PD included older age (69.2 +/- 5.8 years; 62.6 +/- 8 years), presence of hallucinations and poorer executive score (10.1 +/- 5.9; 5.5 +/- 4.4). The incidence of dementia over 3 years after STN-DBS is similar to the one reported in medically treated patients. The PDD presented preoperative risk factors of developing dementia similar to those described in medically treated patients. These observations suggest dementia being secondary to the natural evolution of PD rather than a direct effect of STN-DBS.

Analyse de l'activité de match chez l'arbitre de football par accéléromètre et critique des tests de sélection FIFA

Introduction : Depuis 2005, le « Test FIFA » est utilisé chez les arbitres de football, comme critère de sélection pour monter dans les échelons de l'arbitrage et chaque arbitre base son entraînement dans cet objectif. Ce test a été développé grâce aux nombreux travaux scientifiques, ayant utilisé l'analyse vidéo, afin de quantifier les activités de match des arbitres et analyser leur performance en cours de match. Objectifs : Le but de ce travail a été d'évaluer la performance de l'arbitre, lors d'un match de football, au moyen d'un accéléromètre en raison de sa facilité d'utilisation et en particulier d'évaluer si au cours du match, il existe une éventuelle diminution de la capacité de performance engendrée par la fatigue. Enfin, à la lumière des résultats, nous avons pu discuter du bien fondé du «test par intervalle proposé par la FIFA» comme moyen d'estimation de la capacité physique d'un arbitre. Méthode : Il s'agit d'une étude prospective basée sur une analyse descriptive. Les données ont été récoltées dans des stades de football suisses ≥1ère Ligue, du 01.12.2011 au 01.12.2012. Le groupe étudié était composé de 5 arbitres de football de sexe masculin, dont deux officiant en 1ère Ligue et faisant partie des talents de l'Association Cantonale Vaudoise de Football (ACVF) et trois en Super League et Challenge League. Les 5 arbitres ont été équipés d'un iPhone 3GS®, muni d'une application, capable d'enregistrer les déplacements sur le terrain (arrêt, marche et course). Le traitement des données a été effectué par un programme Matlab®, élaboré par le Laboratoire des Mesures d'Analyse du Mouvement (LMAM) de l'EPFL, tout comme l'application en question. Pour ce travail ont été considérées les phases et les fréquences d'arrêt, de marche et de course tout au long de l'évolution de la partie. Résultats : Durant les 90 minutes du match, la répartition se fait de la manière suivante : 13,74% du temps total où l'accéléromètre ne mesure aucune activité, 33,70% concernent une activité de course alors que le reste, 52,48% est de la marche. Avec l'avancement dans le match, il est constaté une augmentation des phases d'arrêt et une diminution du temps de course. Une intensité d'effort plus importante est observée lors des 15 premières minutes du match (environ  41,7% de course), alors qu'en fin de la partie, il y a une alternance de marche et de course avec des efforts de plus en plus brefs. La détermination de la médiane de durée des différents efforts a montré qu'un épisode de marche ou de course étaient de 5-6 secondes. De plus, les épisodes de marche ou de course étaient rarement >20 secondes. Discussion : Les résultats montrent que l'accéléromètre est un système de mesure facile d'utilisation, permettant un gain de temps dans l'analyse des données pour évaluer la performance sportive. Les principaux résultats de cette étude, ont mis en évidence une diminution de l'intensité des activités physiques de l'arbitre avec l'avancement du match, résultant soit de sa propre fatigue, soit de celle des joueurs dictant le rythme du jeu. Cette diminution se traduit par des déplacements de plus en plus brefs au fil du temps. La mesure de médiane du temps de course et de marche (5-6 sec) correspond à une activité aérobie pour la marche et anaérobie alactique pour la course. Par conséquent, le « test par intervalle » de la FIFA actuel ne nous semble pas adéquat en raison de sa filière énergétique de type anaérobique lactique. Conclusion : Cette étude pilote apporte un nouveau type d'instrumentation efficace et simple, jamais employé auparavant dans l'analyse des activités de match des arbitres de football. Il permet d'explorer des mouvements avec précision au fil du match et apporte un nouvel aspect sur la quantification de performance des arbitres non exploré jusqu'ici. Après analyse de l'ensemble des paramètres, il semble que le test FIFA ne soit pas adapté à la performance exigée par l'arbitrage.

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic beta-cells, liver, skeletal muscle, and adipocytes. This study investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIF-/-) mice. Compared with wild-type (WT) mice, MIF-/- mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIF-/- mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIF-/- mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIF-/- mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIF-/- mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIF-/- mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIF-/- mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis.

Performance of an automated multiplex immunofluorescence assay for detection of Chlamydia trachomatis immunoglobulin G.

Chlamydia serology is indicated to investigate etiology of miscarriage, infertility, pelvic inflammatory disease, and ectopic pregnancy. Here, we assessed the reliability of a new automated-multiplex immunofluorescence assay (InoDiag test) to detect specific anti-C. trachomatis immunoglobulin G. Considering immunofluorescence assay (IF) as gold standard, InoDiag tests exhibited similar sensitivities (65.5%) but better specificities (95.1%-98%) than enzyme-linked immunosorbent assays (ELISAs). InoDiag tests demonstrated similar or lower cross-reactivity rates when compared to ELISA or IF.

Penicillin-binding protein gene alterations in Streptococcus uberis isolates presenting decreased susceptibility to penicillin.

Streptococcus uberis is an environmental pathogen commonly causing bovine mastitis, an infection that is generally treated with penicillin G. No field case of true penicillin-resistant S. uberis (MIC > 16 mg/liter) has been described yet, but isolates presenting decreased susceptibility (MIC of 0.25 to 0.5 mg/liter) to this drug are regularly reported to our laboratory. In this study, we demonstrated that S. uberis can readily develop penicillin resistance in laboratory-evolved mutants. The molecular mechanism of resistance (acquisition of mutations in penicillin-binding protein 1A [PBP1A], PBP2B, and PBP2X) was generally similar to that of all other penicillin-resistant streptococci described so far. In addition, it was also specific to S. uberis in that independent resistant mutants carried a unique set of seven consensus mutations, of which only one (Q(554)E in PBP2X) was commonly found in other streptococci. In parallel, independent isolates from bovine mastitis with different geographical origins (France, Holland, and Switzerland) and presenting a decreased susceptibility to penicillin were characterized. No mosaic PBPs were detected, but they all presented mutations identical to the one found in the laboratory-evolved mutants. This indicates that penicillin resistance development in S. uberis might follow a stringent pathway that would explain, in addition to the ecological niche of this pathogen, why naturally occurring resistances are still rare. In addition, this study shows that there is a reservoir of mutated PBPs in animals, which might be exchanged with other streptococci, such as Streptococcus agalactiae, that could potentially be transmitted to humans.

Testing for hysteresis in unemployment in OECD countries: new evidence using stationarity panel tests with breaks

This paper tests hysteresis effects in unemployment using panel data for 19 OECD countries covering the period 1956-2001. The tests exploit the cross-section variations of the series, and additionally, allow for a diferent number of endogenous breakpoints in the unemployment series. The critical values are simulated based on our specific panel sizes and time periods. The findings stress the importance of accounting for exogenous shocks in the series and give support to the natural-rate hypothesis of unemployment for the majority of the countries analyzed

New evidence of the real interest rate parity for OECD countries using panel unit root tests with breaks

This paper tests for real interest parity (RIRP) among the nineteen major OECD countries over the period 1978:Q2-1998:Q4. The econometric methods applied consist of combining the use of several unit root or stationarity tests designed for panels valid under cross-section dependence and presence of multiple structural breaks. Our results strongly support the fulfilment of the weak version of the RIRP for the studied period once dependence and structural breaks are accounted for.

Testing for hysteresis in unemployment in OECD countries: new evidence using stationarity panel tests with breaks

This paper tests hysteresis effects in unemployment using panel data for 19 OECD countries covering the period 1956-2001. The tests exploit the cross-section variations of the series, and additionally, allow for a diferent number of endogenous breakpoints in the unemployment series. The critical values are simulated based on our specific panel sizes and time periods. The findings stress the importance of accounting for exogenous shocks in the series and give support to the natural-rate hypothesis of unemployment for the majority of the countries analyzed

New evidence of the real interest rate parity for OECD countries using panel unit root tests with breaks

This paper tests for real interest parity (RIRP) among the nineteen major OECD countries over the period 1978:Q2-1998:Q4. The econometric methods applied consist of combining the use of several unit root or stationarity tests designed for panels valid under cross-section dependence and presence of multiple structural breaks. Our results strongly support the fulfilment of the weak version of the RIRP for the studied period once dependence and structural breaks are accounted for.

The daily energy expenditure in stable chronic obstructive pulmonary disease.

Resting energy expenditure is frequently increased in chronic obstructive pulmonary disease (COPD), but it is unknown if this hypermetabolism holds true over 24 h. The aim of this study was to measure the actual 24-h energy expenditure (24-h EE) in patients with stable COPD. Energy expenditure was measured by indirect calorimetry, using a metabolic chamber for 24-h EE and a canopy for basal metabolic rate (BMR). Physical activity was detected in the chamber by a radar system, and its duration was quantified. Two groups matched for age and height were studied: 16 male ambulatory patients with stable COPD and 12 male normal subjects. Body weight was 92 +/- 12% of ideal body weight in the group with COPD and 108 +/- 11% in the control group (p = 0.01). BMR was 120 +/- 7% of predicted in the group with COPD and 108 +/- 12% in the control group (p < 0.01). However, 24-h EE was similar in the two groups, amounting to 1,935 +/- 259 kcal in patients with COPD and 2,046 +/- 253 kcal in the control group (NS). This corresponded to 145% and 137% of predicted BMR, and to 121% and 126% of measured BMR in patients with COPD and the control group, respectively (NS). Patients were allowed to pursue their usual treatment within the chamber, and a positive correlation existed between 24-h EE and the daily dose of inhaled beta 2-agonists (p < 0.03). During daytime, physical activity was lower in patients with COPD. This study shows that patients with stable COPD are characterized by a normal daily energy expenditure in controlled conditions in spite of an increased basal metabolic rate. They appear to save energy by reducing their spontaneous level of physical activity.

Role of the inflammasome in murine experimental models of arthritis

Summary : The purpose of this study was to investigate the role of the inflammasome in human and experimental murine models (such as ΑΙΑ and K/BxN) of rheumatoid arthritis (RA)RA, affecting 1% of the population is the most frequent inflammatory disease characterized by synovial hyperplasia and cartilage and bone erosion, leading to joint destruction. In general, women are 3 times more affected by RA suggesting a role of estrogen in this disease. The inflammasome is a multiproteic complex triggering the activation of caspase-1 leading to the activation of IL-1 β, an important pro-inflammatory cytokine implicated in arthritis. The inflammasome has been implicated in several inflammatory diseases and particularly in gout. To highlight a possible role of the inflammasome in murine arthritis, we obtained ASC, caspase-1 and NALP3 +/+ and -/- littermate mice to perform ΑΙΑ and K/BxN arthritis. NALP3 -/- and caspase-1 -/- mice were as arthritic as wild type littermate mice in both ΑΙΑ and K/BxN models implicating that the NALP3 inflammasome is not involved in experimental arthritis. By contrast, ΑΙΑ severity was significantly diminished in ASC- deficient male and female mice, and in the K/BxN model, in ASC-deficient female mice. These results were supported by histological scoring and acute phase protein serum amyloid A (SAA) levels that were equivalent between NALP+/+ and NALP3-/- mice and diminished in ASC -/- mice. In ΑΙΑ and K/BxN murine experimental models, we observed a sexdependent phenotype. We studied the role of estradiol in both the ALA and the K/BxN models. Castrated female or male ASC -/- mice that received estradiol had a decreased arthritis severity. This implies a protective role of estrogen in the absence of ASC. In the ΑΙΑ model, proliferation assay were performed using splenocytes from mBSA- immunized ASC +/+ and -/- mice. The mBSA-induced proliferation was significantly lower in ASC-/- splenocytes. Moreover the CD3-specific proliferation of purified splenic Τ cells was significantly lower in ASC-/- cells. Finally, Τ cells from ASC-/- mice produced significantly decreased levels of IFN-gamma associated with increased levels of IL-10. These results imply a possible role of ASC in the TCR-signaling pathway and Τ cell cytokine production. In parallel the expression of the different inflammasome components were analyzed in biopsies from rheumatoid arthritis (RA) and osteoarthritis (OA) patiens. The expression of the 14 different NALPs, their effector protein ASC, and caspase-1 and -5 was readily measurable by RT-PCR in a similar proportion in RA and OA synovial samples, with the exception of NALP-5 and NALP-13, which weren't found in samples from either disease. The corresponding NALP1, -3, -12 and ASC proteins were expressed at similar levels in both OA and RA biopsies, as determined by immunohistochemistry and Western-blot analysis. By contrast, caspase-1 levels were significantly enhanced in RA synovial tissues compared to those from OA patients. NALP-1, -2, -3, -10, -12 and -14, as well as ASC, caspase-1, and -5 were detected in RNA from unstimulated and stimulated RA synoviocytes. In FLS, only ASC and caspase-1 were expressed at the protein level. NALP1, 3 and 12 were not detected. However, upon stimulation, no secreted IL-Ιβ was detectable in either RA or in OA synoviocytes culture medium. Résumé : Le but de ce projet était d'étudier le rôle de l'inflammasome dans des modèles expérimentaux d'arthrite tels que les modèles ΑΙΑ et K/BxN ainsi que dans la polyarthrite humaine (RA). La polyarthrite est une maladie inflammatoire très fréquente avec 1 % de la population affectée et touche 3 fois plus les femmes que les hommes, suggérant un rôle des hormones sexuelles dans cette pathologie. L'inflammasome est un complexe multiprotéique qui permet l'activation de la caspase-1, une cystéine protéase qui va ensuite cliver et activer rinterleukine-ΐβ (IL-Ιβ). L'inflammasome a été impliqué ces dernières années dans de nombreuses maladies inflammatoires notamment dans la goutte. Pour mettre en évidence un éventuel rôle de l'inflammasome dans l'arthrite expérimentale nous avons obtenu des souris déficientes pour certains des composants de l'inflammasome tels que ASC, NALP3 et caspase-1. Les souris NALP3 déficientes et caspase-1 déficientes sont aussi arthritiques que les souris wild type correspondantes que ce soit dans le modèle ΑΙΑ ou K/BxN. Par contre les souris mâles et femelles ASC-déficientes sont moins arthritiques que les souris +/+ correspondantes dans le modèle ΑΙΑ. Dans le modèle KRN, le même phénotype (diminution de la sévérité de l'arthrite) est observé uniquement chez les femelles ASC-/- Ce phénotype est corrélé avec l'histologie ainsi qu'avec le dosage du serum amyloid A (SAA) qui reflète l'inflammation systémique et qui est diminué chez les souris ASC-déficientes. Nous avons ensuite étudié le rôle de Γ estradiol (une des formes active des estrogènes) dans les modèles K/BxN et ΑΙΑ. Les souris castrées maies ou femelles déficientes pour ASC ayant reçu de l'estradiol ont une arthrite moins sévère ce qui implique que les estradiol ont un effet protecteur en l'absence de ASC. Dans le modèle ΑΙΑ, nous nous sommes aussi intéressés à la réponse immune. Des tests de prolifération ont été effectués sur des splénocytes en présence de mBSA (qui est l'antigène utilisé dans le modèle ΑΙΑ). Les splénocytes ASC -/- ont une proliferation qui est diminuée en présence de l'antigène. De plus la proliferation de cellules Τ spléniques purifiées en présence d'anti-CD3 est diminuée chez les cellules Τ ASC-/-. Ces résultats nous indiquent une éventuelle implication de ASC dans la signalisation par le récépteur des cellules T. En parallèle l'expression des différents composants de l'inflammasome a été analysée dans des biopsies de patients atteints de polyarthrite rhumatoide (RA) et d'arthrose (OA). L'expression des 14 différents NALPs, de l'adaptateur ASC, ainsi que des caspase-1 et -5 était similaires dans les échantillons RA et OA, à l'exception de NALP5 et 13 qui n'étaient pas détéctables. L'expression protéique de NALP1, 3, 12 et ASC effectuée par Western blot et immunohistochimie était similaire dans les biopsies RA et OA. Par contre la quantité de la caspase-1 mesurée par ELISA était augmentée de façon significative dans les extraits protéiques de biopsies RA. NALP-1, -2. -3, -10, -12, and -14 ainsi que ASC, caspase-1 et -5 étaient exprimés de façon similaire par les synoviocytes RA non stimulés et stimulés. Dans les synoviocytes seuls ASC et caspase-1 étaient détéctable au niveau protéique. NALP-1, -3 et -12 n'était pas détéctables. Cependant après stimulation il n'y avait d'IL-Ιβ sécrété que ce soit dans les surnageants de cultures de synoviocytes RA ou OA.

Distinct sets of alphabeta TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues.

Naturally acquired immune responses against human cancers often include CD8(+) T cells specific for the cancer testis antigen NY-ESO-1. Here, we studied T cell receptor (TCR) primary structure and function of 605 HLA-A*0201/NY-ESO-1(157-165)-specific CD8 T cell clones derived from five melanoma patients. We show that an important proportion of tumor-reactive T cells preferentially use TCR AV3S1/BV8S2 chains, with remarkably conserved CDR3 amino acid motifs and lengths in both chains. All remaining T cell clones belong to two additional sets expressing BV1 or BV13 TCRs, associated with alpha-chains with highly diverse VJ usage, CDR3 amino acid sequence, and length. Yet, all T cell clonotypes recognize tumor antigen with similar functional avidity. Two residues, Met-160 and Trp-161, located in the middle region of the NY-ESO-1(157-165) peptide, are critical for recognition by most of the T cell clonotypes. Collectively, our data show that a large number of alphabeta TCRs, belonging to three distinct sets (AVx/BV1, AV3/BV8, AVx/BV13) bind pMHC with equal antigen sensitivity and recognize the same peptide motif. Finally, this in-depth study of recognition of a self-antigen suggests that in part similar biophysical mechanisms shape TCR repertoires toward foreign and self-antigens.

Genetic association tests: a method for the joint analysis of family and case-control data.

With the trend in molecular epidemiology towards both genome-wide association studies and complex modelling, the need for large sample sizes to detect small effects and to allow for the estimation of many parameters within a model continues to increase. Unfortunately, most methods of association analysis have been restricted to either a family-based or a case-control design, resulting in the lack of synthesis of data from multiple studies. Transmission disequilibrium-type methods for detecting linkage disequilibrium from family data were developed as an effective way of preventing the detection of association due to population stratification. Because these methods condition on parental genotype, however, they have precluded the joint analysis of family and case-control data, although methods for case-control data may not protect against population stratification and do not allow for familial correlations. We present here an extension of a family-based association analysis method for continuous traits that will simultaneously test for, and if necessary control for, population stratification. We further extend this method to analyse binary traits (and therefore family and case-control data together) and accurately to estimate genetic effects in the population, even when using an ascertained family sample. Finally, we present the power of this binary extension for both family-only and joint family and case-control data, and demonstrate the accuracy of the association parameter and variance components in an ascertained family sample.