Maladaptive exploratory behavior and neuropathology of the PS-1 P117L Alzheimer transgenic mice.

Patients with the early-onset Alzheimer's disease P117L mutation in the presenilin-1 gene (PS-1) present pathological hallmarks in the hippocampus, the frontal cortex and the basal ganglia. In the present work we determined by immunohistochemistry which brain regions were injured in the transgenic PS-1 P117L mice, in comparison to their littermates, the B6D2 mice. Furthermore, as these regions are involved in novelty detection, we investigated the behavior of these mice in tests for object and place novelty recognition. Limited numbers of senile plaques and neurofibrillary tangles were detected in aged PS-1 P117L mice in the CA1 only, indicating that the disease is restrained to an initial neuropathological stage. Western blots showed a change in PSD-95 expression (p=0.03), not in NR2A subunit, NR2B subunit and synaptophysin expressions in the frontal cortex, suggesting specific synaptic alterations. The behavioral tests repeatedly revealed, despite a non-significant preference for object or place novelty, maladaptive exploratory behavior of the PS-1 P117L mice in novel environmental conditions, not due to locomotor problems. These mice, unlike the B6D2 mice, were less inhibited to visit the center of the cages (p=0.01) and they continued to move excessively in the presence of a displaced object (p=0.021). Overall, the PS-1 P117L mice appear to be in an initial Alzheimer's disease-like neuropathological stage, and they showed a lack of reaction toward novel environmental conditions.

Lipoxygenase activities during development of root and nodule of soybean

The objective of this work was to evaluate root and nodule soybean lipoxygenases in Doko cultivar and in a near isogenic line lacking seed lipoxygenases, inoculated and uninoculated with Bradyrhizobium elkanii. The lipoxygenase activities from roots collected at 3, 5, 9, 13, 18 and 28 days post-inoculation and from nodules collected at 13, 18 and 28 days post-inoculation were measured. The pH-activity profiles from root and nodules suggested that the lipoxygenases pool expressed in these organs from Doko cultivar and triple-null near isogenic lines are similar. The root lipoxygenase activity of Doko and triple-null lines, inoculated and uninoculated, reduced over time. The highest lipoxygenase activity observed at the beginning of root formation suggests the involvement of this enzyme in growth and development of this organ. However, for nodules an expressive increase of lipoxygenase activity was noticed 28 days post-inoculation. Root and nodule showed, at least, two mobility groups for lipoxygenases in immunoblottings, with approximately 94 and 97 kDa.

Use of the Cognitive Performance Scale (CPS) to detect cognitive impairment in the acute care setting: concurrent and predictive validity.

The Cognitive Performance Scale (CPS) was initially designed to assess cognition in long term care residents. Subsequently, the CPS has also been used among in-home, post-acute, and acute care populations even though CPS' clinimetric performance has not been studied in these settings. This study aimed to determine CPS agreement with the Mini Mental Status Exam (MMSE) and its predictive validity for institutionalization and death in a cohort (N=401) of elderly medical inpatients aged 75 years and over. Medical, physical and mental status were assessed upon admission. The same day, the patient's nurse completed the CPS by interview. Follow-up data were gathered from the central billing system (nursing home stay) and proxies (death). Cognitive impairment was present in 92 (23%) patients according to CPS (score >or= 2). Agreement with MMSE was moderate (kappa 0.52, P<.001). Analysis of discordant results suggested that cognitive impairment was overestimated by the CPS in dependent patients with comorbidities and depressive symptoms, and underestimated in older ones. During follow-up, subjects with abnormal CPS had increased risks of death (adjusted hazard ratio (adjHR) 1.7, 95% CI 1.0-2.8, P=.035) and institutionalization (adjHR 2.7, 95% CI 1.3-5.3, P=.006), independent of demographic, health and functional status. Interestingly, subjects with abnormal CPS were at increased risk of death only if they also had abnormal MMSE. The CPS predicted death and institutionalization during follow-up, but correlated moderately well with the MMSE. Combining CPS and MMSE provided additional predictive information, suggesting that domains other than cognition are assessed by professionals when using the CPS in elderly medical inpatients.

Behavioural queueing : cellular automata and a laboratory experiment

Dans cette thèse, nous étudions les aspects comportementaux d'agents qui interagissent dans des systèmes de files d'attente à l'aide de modèles de simulation et de méthodologies expérimentales. Chaque période les clients doivent choisir un prestataire de servivce. L'objectif est d'analyser l'impact des décisions des clients et des prestataires sur la formation des files d'attente. Dans un premier cas nous considérons des clients ayant un certain degré d'aversion au risque. Sur la base de leur perception de l'attente moyenne et de la variabilité de cette attente, ils forment une estimation de la limite supérieure de l'attente chez chacun des prestataires. Chaque période, ils choisissent le prestataire pour lequel cette estimation est la plus basse. Nos résultats indiquent qu'il n'y a pas de relation monotone entre le degré d'aversion au risque et la performance globale. En effet, une population de clients ayant un degré d'aversion au risque intermédiaire encoure généralement une attente moyenne plus élevée qu'une population d'agents indifférents au risque ou très averses au risque. Ensuite, nous incorporons les décisions des prestataires en leur permettant d'ajuster leur capacité de service sur la base de leur perception de la fréquence moyenne d'arrivées. Les résultats montrent que le comportement des clients et les décisions des prestataires présentent une forte "dépendance au sentier". En outre, nous montrons que les décisions des prestataires font converger l'attente moyenne pondérée vers l'attente de référence du marché. Finalement, une expérience de laboratoire dans laquelle des sujets jouent le rôle de prestataire de service nous a permis de conclure que les délais d'installation et de démantèlement de capacité affectent de manière significative la performance et les décisions des sujets. En particulier, les décisions du prestataire, sont influencées par ses commandes en carnet, sa capacité de service actuellement disponible et les décisions d'ajustement de capacité qu'il a prises, mais pas encore implémentées. - Queuing is a fact of life that we witness daily. We all have had the experience of waiting in line for some reason and we also know that it is an annoying situation. As the adage says "time is money"; this is perhaps the best way of stating what queuing problems mean for customers. Human beings are not very tolerant, but they are even less so when having to wait in line for service. Banks, roads, post offices and restaurants are just some examples where people must wait for service. Studies of queuing phenomena have typically addressed the optimisation of performance measures (e.g. average waiting time, queue length and server utilisation rates) and the analysis of equilibrium solutions. The individual behaviour of the agents involved in queueing systems and their decision making process have received little attention. Although this work has been useful to improve the efficiency of many queueing systems, or to design new processes in social and physical systems, it has only provided us with a limited ability to explain the behaviour observed in many real queues. In this dissertation we differ from this traditional research by analysing how the agents involved in the system make decisions instead of focusing on optimising performance measures or analysing an equilibrium solution. This dissertation builds on and extends the framework proposed by van Ackere and Larsen (2004) and van Ackere et al. (2010). We focus on studying behavioural aspects in queueing systems and incorporate this still underdeveloped framework into the operations management field. In the first chapter of this thesis we provide a general introduction to the area, as well as an overview of the results. In Chapters 2 and 3, we use Cellular Automata (CA) to model service systems where captive interacting customers must decide each period which facility to join for service. They base this decision on their expectations of sojourn times. Each period, customers use new information (their most recent experience and that of their best performing neighbour) to form expectations of sojourn time at the different facilities. Customers update their expectations using an adaptive expectations process to combine their memory and their new information. We label "conservative" those customers who give more weight to their memory than to the xiv Summary new information. In contrast, when they give more weight to new information, we call them "reactive". In Chapter 2, we consider customers with different degree of risk-aversion who take into account uncertainty. They choose which facility to join based on an estimated upper-bound of the sojourn time which they compute using their perceptions of the average sojourn time and the level of uncertainty. We assume the same exogenous service capacity for all facilities, which remains constant throughout. We first analyse the collective behaviour generated by the customers' decisions. We show that the system achieves low weighted average sojourn times when the collective behaviour results in neighbourhoods of customers loyal to a facility and the customers are approximately equally split among all facilities. The lowest weighted average sojourn time is achieved when exactly the same number of customers patronises each facility, implying that they do not wish to switch facility. In this case, the system has achieved the Nash equilibrium. We show that there is a non-monotonic relationship between the degree of risk-aversion and system performance. Customers with an intermediate degree of riskaversion typically achieve higher sojourn times; in particular they rarely achieve the Nash equilibrium. Risk-neutral customers have the highest probability of achieving the Nash Equilibrium. Chapter 3 considers a service system similar to the previous one but with risk-neutral customers, and relaxes the assumption of exogenous service rates. In this sense, we model a queueing system with endogenous service rates by enabling managers to adjust the service capacity of the facilities. We assume that managers do so based on their perceptions of the arrival rates and use the same principle of adaptive expectations to model these perceptions. We consider service systems in which the managers' decisions take time to be implemented. Managers are characterised by a profile which is determined by the speed at which they update their perceptions, the speed at which they take decisions, and how coherent they are when accounting for their previous decisions still to be implemented when taking their next decision. We find that the managers' decisions exhibit a strong path-dependence: owing to the initial conditions of the model, the facilities of managers with identical profiles can evolve completely differently. In some cases the system becomes "locked-in" into a monopoly or duopoly situation. The competition between managers causes the weighted average sojourn time of the system to converge to the exogenous benchmark value which they use to estimate their desired capacity. Concerning the managers' profile, we found that the more conservative Summary xv a manager is regarding new information, the larger the market share his facility achieves. Additionally, the faster he takes decisions, the higher the probability that he achieves a monopoly position. In Chapter 4 we consider a one-server queueing system with non-captive customers. We carry out an experiment aimed at analysing the way human subjects, taking on the role of the manager, take decisions in a laboratory regarding the capacity of a service facility. We adapt the model proposed by van Ackere et al (2010). This model relaxes the assumption of a captive market and allows current customers to decide whether or not to use the facility. Additionally the facility also has potential customers who currently do not patronise it, but might consider doing so in the future. We identify three groups of subjects whose decisions cause similar behavioural patterns. These groups are labelled: gradual investors, lumpy investors, and random investor. Using an autocorrelation analysis of the subjects' decisions, we illustrate that these decisions are positively correlated to the decisions taken one period early. Subsequently we formulate a heuristic to model the decision rule considered by subjects in the laboratory. We found that this decision rule fits very well for those subjects who gradually adjust capacity, but it does not capture the behaviour of the subjects of the other two groups. In Chapter 5 we summarise the results and provide suggestions for further work. Our main contribution is the use of simulation and experimental methodologies to explain the collective behaviour generated by customers' and managers' decisions in queueing systems as well as the analysis of the individual behaviour of these agents. In this way, we differ from the typical literature related to queueing systems which focuses on optimising performance measures and the analysis of equilibrium solutions. Our work can be seen as a first step towards understanding the interaction between customer behaviour and the capacity adjustment process in queueing systems. This framework is still in its early stages and accordingly there is a large potential for further work that spans several research topics. Interesting extensions to this work include incorporating other characteristics of queueing systems which affect the customers' experience (e.g. balking, reneging and jockeying); providing customers and managers with additional information to take their decisions (e.g. service price, quality, customers' profile); analysing different decision rules and studying other characteristics which determine the profile of customers and managers.

Macropropagation and micropropagation of Ziziphus spina-christi

Christ's thorn (Ziziphus spina-christi (L.) Desf.) is a cross-pollinated plant with a wide range of genetic variability in nature and, for this reason, vegetative propagation assumes importance for improvement programs. The objective of this work was to evaluate cutting, T budding and tissue culture methods for this species. Shoots of 22-25 cm length were treated by two culture media and three shoot diameters for cutting trial. The T budding treatments consisted of three and five collection dates in spring and autumn, respectively. Tissue culture nodal segments bearing axillary buds were removed from shoots of mature trees at different seasons. Experiments to determine the best disinfectant chemical, appropriate conditions and materials to prevent phenolic compound exudation, explant characteristics, media type and cytokinin-auxin ratios were carried out. Successful rooting happened only on the sand beds and with cuttings greater than 8 mm diameter. The effects of T budding seasons on budtake percentage were significantly different. The best time for explant harvesting was mid of summer. Amount of rooting on media containing IBA as well as activated charcoal and disinfection with Ca(OCl)2 at concentration of 5% for 20 minutes were the best treatments.

Forensic imaging: New challenges for radiographers : B-588

Purpose: Cross-sectional imaging techniques have pioneered forensic medicine. The involvement of a radiographer and formation of "forensic radiographers" allows an improvement of the quality of radiological examinations and facilitates the implementation of techniques, such as sample collections, and the performance of post-mortem angiography. Methods and Materials: During a period of three months, five radiographers with clinical experience have undergone a special training in order to learn procedures dedicated to forensic imaging. These procedures involved: I). acquisition of MDCT data, II). sample collection for toxicological or histological analyses by performing CT-guided biopsies and liquid sampling, III). post-mortem angiography and IV). post-processing of all data acquired. To perform the post-mortem angiography, radiographers were in charge of the preparation of the perfusion device and the investigated body. Therefore, cannulas were inserted into the femoral vessels and connected to the machine. For angiography, the radiographers had to synchronize the perfusion with the CT-acquisitions. Results: All five radiographers have acquired new skills to become "forensic radiographers". They were able to perform post-mortem MDCT, sample collection, post-mortem angiography and post-processing of the acquired data all by themselves. Most problems have been observed concerning the preparation of the body for post-mortem angiography. Conclusion: Our experience shows that radiographers are able to perform high quality examinations after a short period of training. Their collaboration is well accepted by the forensic team and regarding the increase of radiological exams in forensic department, it would be nonsense to exclude radiographers from the forensic-radiological team.

Beyond Conditionality versus Cooperation: Power and Resistance in the Case of EU Mobility Partnerships and Swiss Migration Partnerships

Migration partnerships (MPs) have become a key instrument in global migration governance. In contrast to traditional unilateral approaches, MPs emphasize a more comprehensive and inclusive tackling of migration issues between countries of origin, transit, and destination. Due to this cooperation-oriented concept, most of the existing studies on MPs neglect power questions within partnerships in line with the official discourse, reflecting a broader trend in the international migration governance literature. Others take an instrumentalist view in analysing the power of partnerships or focus on soft power. Illustrated with the examples of the European Mobility Partnerships (EU MPs) and the Swiss Migration Partnerships (CH MPs), we conduct an analysis based on a concept of productive power drawing on post-structural and post-colonial insights. Our main argument is that in contrast to their seemingly consent-oriented and technical character, MPs are sites of intense (discursive) struggles, and (re-)produce meanings, subjects, and resistances. A productive power analysis allows us to move beyond the dichotomy in the literature between coercion and cooperation, as well as between power and resistance more broadly.

Reduced genetic diversity, increased isolation and multiple introductions of invasive giant hogweed in the western Swiss Alps.

Abstract The giant hogweed (Heracleum mantegazzianum) has successfully invaded 19 European countries as well as parts of North America. It has become a problematic species due to its ability to displace native flora and to cause public health hazards. Applying population genetics to species invasion can help reconstruct invasion history and may promote more efficient management practice. We thus analysed levels of genetic variation and population genetic structure of H. mantegazzianum in an invaded area of the western Swiss Alps as well as in its native range (the Caucasus), using eight nuclear microsatellite loci together with plastid DNA markers and sequences. On both nuclear and plastid genomes, native populations exhibited significantly higher levels of genetic diversity compared to invasive populations, confirming an important founder event during the invasion process. Invasive populations were also significantly more differentiated than native populations. Bayesian clustering analysis identified five clusters in the native range that corresponded to geographically and ecologically separated groups. In the invaded range, 10 clusters occurred. Unlike native populations, invasive clusters were characterized by a mosaic pattern in the landscape, possibly caused by anthropogenic dispersal of the species via roads and direct collection for ornamental purposes. Lastly, our analyses revealed four main divergent groups in the western Swiss Alps, likely as a consequence of multiple independent establishments of H. mantegazzianum.

Selection of shrimp breeders free of white spot syndrome and infectious hypodermal and hematopoietic necrosis

The objective of this work was to select surviving breeders of Litopenaeus vannamei from white spot syndrome virus (WSSV) outbreak, adapted to local climatic conditions and negatively diagnosed for WSSV and infectious hypodermal and hematopoietic necrosis virus (IHHNV), and to evaluate if this strategy is a viable alternative for production in Santa Catarina, Brazil. A total of 800 males and 800 females were phenotypically selected in a farm pond. Nested-PCR analyses of 487 sexually mature females and 231 sexually mature males showed that 63% of the females and 55% of the males were infected with IHHNV. Animals free of IHHNV were tested for WSSV, and those considered double negative were used for breeding. The post-larvae produced were stocked in nine nursery tanks for analysis. From the 45 samples, with 50 post-larvae each, only two were positive for IHHNV and none for WSSV. Batches of larvae diagnosed free of virus by nested-PCR were sent to six farms. A comparative analysis was carried out in growth ponds, between local post-larvae and post-larvae from Northeast Brazil. Crabs (Chasmagnathus granulata), blue crabs (Callinectes sapidus), and sea hares (Aplysia brasiliana), which are possible vectors of these viruses, were also evaluated. The mean survival was 55% for local post-larvae against 23.4% for post-larvae from the Northeast. Sea hares showed prevalence of 50% and crabs of 67% of WSSV.

Sensitivity of Spring Phenology to Warming Across Temporal and Spatial Climate Gradients in Two Independent Databases

Disparate ecological datasets are often organized into databases post hoc and then analyzed and interpreted in ways that may diverge from the purposes of the original data collections. Few studies, however, have attempted to quantify how biases inherent in these data (for example, species richness, replication, climate) affect their suitability for addressing broad scientific questions, especially in under-represented systems (for example, deserts, tropical forests) and wild communities. Here, we quantitatively compare the sensitivity of species first flowering and leafing dates to spring warmth in two phenological databases from the Northern Hemisphere. One-PEP725-has high replication within and across sites, but has low species diversity and spans a limited climate gradient. The other-NECTAR-includes many more species and a wider range of climates, but has fewer sites and low replication of species across sites. PEP725, despite low species diversity and relatively low seasonality, accurately captures the magnitude and seasonality of warming responses at climatically similar NECTAR sites, with most species showing earlier phenological events in response to warming. In NECTAR, the prevalence of temperature responders significantly declines with increasing mean annual temperature, a pattern that cannot be detected across the limited climate gradient spanned by the PEP725 flowering and leafing data. Our results showcase broad areas of agreement between the two databases, despite significant differences in species richness and geographic coverage, while also noting areas where including data across broader climate gradients may provide added value. Such comparisons help to identify gaps in our observations and knowledge base that can be addressed by ongoing monitoring and research efforts. Resolving these issues will be critical for improving predictions in understudied and under-sampled systems outside of the temperature seasonal mid-latitudes.

Comparison of quality of life after stereotactic body radiotherapy and surgery for early-stage prostate cancer

Background: As the long-term efficacy of stereotactic body radiation therapy (SBRT) becomes established and other prostate cancer treatment approaches are refined and improved, examination of quality of life (QOL) following prostate cancer treatment is critical in driving both patient and clinical treatment decisions. We present the first study to compare QOL after SBRT and radical prostatectomy, with QOL assessed at approximately the same times pre- and post-treatment and using the same validated QOL instrument. Methods: Patients with clinically localized prostate cancer were treated with either radical prostatectomy (n = 123 Spanish patients) or SBRT (n = 216 American patients). QOL was assessed using the Expanded Prostate Cancer Index Composite (EPIC) grouped into urinary, sexual, and bowel domains. For comparison purposes, SBRT EPIC data at baseline, 3 weeks, 5, 11, 24, and 36 months were compared to surgery data at baseline, 1, 6, 12, 24,and 36 months. Differences in patient characteristics between the two groups were assessed using Chi-squared tests for categorical variables and t-tests for continuous variables. Generalized estimating equation (GEE) models were constructed for each EPIC scale to account for correlation among repeated measures and used to assess the effect of treatment on QOL. Results: The largest differences in QOL occurred in the first 16 months after treatment, with larger declines following surgery in urinary and sexual QOL as compared to SBRT, and a larger decline in bowel QOL following SBRT as compared to surgery. Long-term urinary and sexual QOL declines remained clinically significantly lower for surgery patients but not for SBRT patients. Conclusions: Overall, these results may have implications for patient and physician clinical decision making which are often influenced by QOL. These differences in sexual, urinary and bowel QOL should be closely considered in selecting the right treatment, especially in evaluating the value of non-invasive treatments, such as SBRT.

Prepregnancy body mass index and resting metabolic rate during pregnancy.

AIM: The resting metabolic rate (RMR) varies among pregnant women. The factors responsible for this variability are unknown. This study aimed to assess the influence of the prepregnancy body mass index (BMI) on the RMR during late pregnancy. METHODS: RMR, height, weight, and total (TEE) and activity (AEE) energy expenditures were measured in 46 healthy women aged 31 ± 5 years (mean ± SD) with low (<19.8), normal (19.8-26.0), and high (>26.0) prepregnancy BMI at 38.2 ± 1.5 weeks of gestation (t(gest)) and 40 ± 7 weeks postpartum (t(post)) (n = 27). RESULTS: The mean t(gest) RMR for the low-, normal-, and high-BMI groups was 1,373, 1,807, and 2,191 kcal/day, respectively (p = 0.001). The overall mean t(gest) RMR was 316 ± 183 kcal/day (21%), higher than the overall mean t(post) value and this difference was correlated with gestational weight gain (r = 0.78, p < 0.001). The scaled metabolic rate by allometry (RMR/kilograms⁰·⁷³) was similar in the low-, normal-, and high-BMI groups, respectively (p = 0.45). Changes in t(gest) TEE closely paralleled changes in t(gest) RMR (r = 0.84, p < 0.001). AEE was similar among the BMI groups. CONCLUSION: The RMR is significantly increased in the third trimester of pregnancy. The absolute gestational RMR is higher in women with high prepregnancy BMI due to increased body weight. The scaled metabolic rate (RMR/kilograms⁰·⁷³) is similar among the BMI groups of pregnant women.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer.

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.

Growth mechanisms and timing of emplacement of a vertically layered mafic intrusion in the feeder zone of an ocean island volcano (Fuerteventura, Canary islands)

Résumé pour le grand public L'île de Fuerteventura (Canaries) offre l'occasion rare d'observer les racines d'un volcan océanique édifié il y a 25 à 30 millions d'années et complètement érodé. On y voit de nombreux petits plutons de forme et composition variées, témoignant d'autant d'épisodes de l'activité magmatique. L'un de ces plutons, appelé PX1, présente une structure inhabituelle formée d'une alternance de bandes verticales d'épaisseur métrique à hectométrique de roches sombres de composition pyroxénilique ou gabbroïque. Les pyroxénites résultent clairement de l'accumulation de cristaux de pyroxènes et non de la simple solidification d'un magma? Se pose dès lors la question de la nature du processus qui a conduit à l'accumulation verticale de niveaux concentrés en pyroxènes. En effet, les litages pyroxénitiques classiques sont subhorizontaux, car ils résultent de l'accumulation gravitaire des cristaux séparés du magma dont ils cristalli¬sent par sédimentation. Cette étude vise à identifier et comprendre les mécanismes qui ont engendré ce Iitage minéralogique vertical et l'im¬portant volume de ces faciès cumulatifs. Nous nous sommes également intéressés aux conditions de pression et de température régnant au moment de la mise en place du pluton, ainsi qu'à sa durée de vie et à sa vitesse de refroidis¬sement. Enfin une approche géochimique nous a permis de préciser la nature de la source mantellique des magmas liés à cette activité magmatique. PX1 est en réalité un complexe filonien formé à des conditions de pression et de température de 1-2 kbar et 1050- 1100°C; sa construction a nécessité au moins 150 km3 de magma. L'alternance d'horizons gabbroïques et pyroxéniti¬ques représente des injections successives de magma sous la forme de filons verticaux, mis en place dans un contexte régional en extension. L'étude des orientations des minéraux dans ces faciès révèle que les horizons gabbroïques enregistrent l'extension régionale, alors que les pyroxénites sont générées par une compaction au sein du pluton. Ceci suggère que le régime des contraintes, qui était extensif lors de l'initiation de la mise en place de PX1, est pério¬diquement devenu compressif au sein même du pluton. Cette compression serait liée à des cycles de mise en place où la vitesse de croissance du pluton dépassait celle de l'extension régionale. La différenciation observée au sein de chaque horizon, depuis des pyroxénites riches en olivine jusqu'à des pyroxé¬nites à plagioclase interstitiel et des gabbros, ainsi que la composition géochimique des minéraux qui les constituent suggèrent que chaque filon vertical s'est mis en place à partir d'un magma de composition identique, puis a évolué indépendamment des autres en fonction du régime thermique et du régime des contraintes local. Lorsque le magma en train de cristalliser s'est trouvé en compression, le liquide résiduel a été séparé des cristaux déjà formés et extrait du système, laissant derrière lui une accumulation de cristaux dont la nature et les proportions dépendaient du stade de cristallisation atteint par le magma au moment de l'extraction. Ainsi, les niveaux de pyroxénites à olivine (premier minéral à cristalliser) ont été formés lorsque le magma correspondant était encore peu cristallisé; à l'inverse, les py¬roxénites riches en plagioclase (minéral plus tardif dans la séquence de cristallisation) et certains gabbros à caractère cumulatif résultent d'une compression tardive dans le processus de cristallisation du filon concerné. Les liquides résiduels extraits des niveaux pyroxénitiques sont rarement observés dans PX1, certaines poches et filonets de com¬position anorthositique pourraient en être les témoins. L'essentiel de ces liquides a probablement gagné des niveaux supérieurs du pluton, voire la surface du volcan. L'origine du régime compressif périodique affectant les filons en voie de cristallisation est attribuée aux injections suivantes de magma au sein du pluton, qui se sont succédées à un rythme plus rapide que la vitesse de consolidation des filons. Des datations U/Pb de haute précision sur des cristaux de zircon et de baddeleyite ainsi que40Ar/39Ar sur des cris¬taux d'amphibole révèlent une initiation de la mise en place de PX1 il y a 22.1 ± 0,7 Ma; celle-ci a duré quelque 0,48 ± 0,22 à 0,52 ± 0,29 Ma. Ce laps de temps est compatible avec celui nécessaire à la cristallisation des filons individuels, qui va de moins d'une année lors de l'initiation du magmatisme à 5 ans lors du maximum d'activité de PX1. La présence de cristaux résorbés enregistrant une cristallisation complexe suggère l'existence d'une chambre mag¬matique convective sous-jacente à PX1 et périodiquement rechargée. Les compositions isotopiques des roches étu¬diées révèlent une source mantellique profonde de type point chaud avec une contribution du manteau lithosphéri- que métasomatisé présent sous les îles Canaries. Résumé L'intrusion mafique Miocène PX1 fait partie du soubassement superficiel (0.15-0.2 GPa, 1100 °Q d'un volcan d'île océanique. La particularité de ce pluton est l'existence d'alternances d'unités de gabbros et de pyroxénites qui met¬tent en évidence un litage magmatique vertical (NNE-SSW). Les horizons gabbroiques et pyroxénitiques sont constitués d'unités de différenciation métriques qui suggèrent tine mise en place par injections périodiques de filons verticaux de magma formant un complexe filonien. Chaque filon vertical a subi une différenciation parallèle à un front de solidification sub-vertical parallèle aux bords du filon. Les pyroxénites résultent du fractionnement et de l'accumulation d'olivine ± clinopyroxene ± plagioclase à partir d'un magma basaltique faiblement alcalin et sont interprétées comme étant des imités de différenciation tronquées dont le liquide interstitiel a été extrait par compaction. L'orientation préférentielle des clinopyroxènes dans ces pyroxe- nites (obtenues par analyse EBSD et micro-tomographique) révèle une composante de cisaillement simple dans la genèse de ces roches, ce qui confirme cette interprétation. La compaction des pyroxénites est probablement causée par a mise en place de filons de magma suivants. Le liquide interstitiel expulsé est probablement par ces derniers. Les clinopyroxènes des gabbros, montrent une composante de cisaillement pure suggérant qu'ils sont affectés par une déformation syn-magmatique parallèle aux zones de cisaillement NNE-SSW observées autour de PX1 et liées au contexte tectonique Miocène d'extension régionale. Ceci suggère que les gabbros sont liés à des taux de mise en place faibles à la fin de cycles d'activité magmatique et sont peu ou pas affectés par la compaction. L'initiation et la géométrie de PX1 sont donc contrôlées par le contexte tectonique régional d'extension alors que les taux et les volumes de magma dépendent de facteurs liés à la source. Des taux d'injection élevés résultent probable¬ment en une croissance du pluton supérieure à la place crée par cette extension. Dans ce cas de figure, la propagation des nouveaux dykes et l'inaptitude du magma à circuler à travers les anciens dykes cristallisés pourrait causer une augmentation de la pression non-lithostatique sur ces derniers, exprimée par un cisaillement simple et l'expulsion du liquide interstitiel qu'ils contiennent (documenté par les zones de collecte anorthositiques). Les compositions en éléments majeurs et traces des gabbros et pyroxenites de PX1 sont globalement homogènes et dépendent de la nature cumulative des échantillons. Cependant, de petites variations des concentrations en éléments traces ainsi que les teneurs en éléments traces des bordures de clinopyroxenes suggèrent que ces derniers ont subi un processus de rééquilibrage et de cristallisation in situ. L'homogénéité des compositions chimiques des échantillons, ainsi que la présence de grains de clinopyroxene résorbés suggère que le complexe filonien PX1 s'est mis en place au dessus d'une chambre magmatique périodiquement rechargée dans laquelle la convection est efficace. Chaque filon est donc issu d'un même magma, mais a subi une différenciation par cristallisation in situ (jusqu'à 70% de fraction¬nement) indépendamment des autres. Dans ces filons cristallisés, les minéraux cumulatifs subissent un rééquilibrage partiel avec les liquide interstitiel avant que ce dernier ne soit expulsé lors de la compaction (mettant ainsi un terme à la différenciation). Ce modèle de mise en place signifie qu'un minimum de 150Km3 de magma est nécessaire à la genèse de PX1, une partie de ce volume ayant été émis par le 'Central Volcanic Complex' de Fuerteventura. Les rapports isotopiques radiogéniques mesurés révèlent la contribution de trois pôles mantelliques dans la genèse du magma formant PX1. Le mélange de ces pôles HIMU, DMM et EM1 refléterai l'interaction du point chaud Cana¬rien avec un manteau lithosphérique hétérogène métasomatisé. Les petites variations de ces rapports et des teneurs en éléments traces au sein des faciès pourrait refléter des taux de fusion partielle variable de la source, résultant en un échantillonnage variable du manteau lithosphérique métasomatisé lors de son interaction avec le point chaud. Des datations U/Pb de haute précision (TIMS) sur des cristaux de zircon et de baddeleyite extraits de gabbros de PX1 révèlent que l'initiation de la cristallisation du magma a eu lieu il y a 22.10±0.07 Ma et que l'activité magmatique a duré un minimum de 0.48 à 0.52 Ma. Des âges 40Ar/39Ar obtenus sur amphibole sont de 21.9 ± 0.6 à 21.8 ± 0.3 Ma, identiques aux âges U/Pb. La combinaison de ces méthodes de datations, suggère que le temps maximum nécessaire à PX1 pour se refroidir en dessous de la température de fermeture de l'amphibole est de 0.8Ma. Ceci signifie que la durée de vie de PX1 est de 520 000 à 800 000 ans. La coexistence de cristaux de baddeleyite et de zircon dans un gabbro est attribuée à son interaction avec un fluide riche en C02 relâché par les carbonatites encaissantes lors du métamorphisme de contact généré par la mise en place de PX1 environ 160 000 ans après le début de sa mise en place. Les durées de vie obtenue sont en accord avec le modèle de mise en place suggérant une durée de cristallisation poux chaque filon allant de 1 an à 5 ans. Abstract The Miocene PX1 gabbro-pyroxenite intrusion (Fuerteventura, Canary Islands), is interpreted as the shallow-level feeder-zone (0.15-0.2 GPa and 1100-1120°C), to an ocean island volcano. The particularity of PX1 is that it displays a NNE-SSW trending vertical magmatic banding expressed by alternating gabbro and pyroxeriite sequences. The gabbro and pyroxenite sequences consist of metre-thick differentiation units, which suggest emplacement by pe¬riodic injection of magma pulses as vertical dykes that amalgamated, similarly to a sub-volcanic sheeted dyke com¬plex. Individual dykes underwent internal differentiation following a solidification front (favoured by a significant lateral/horizontal thermal gradient) parallel to the dyke edges. Pyroxenitic layers result from the fractionation and accumulation of clinopyroxene ± olivine ± plagioclase crystals from a mildly alkaline basaltic liquid and are interpre¬ted as truncated differentiation sequences, from which residual melts were extracted by compaction. Clinopyroxene mineral orientation in pyroxenites (evidenced by EBSD and micro X-ray tomography analysis) display a marked pure shear component, supporting this interpretation. Compaction and squeezing of the crystal mush is ascribed to the incoming and inflating magma pulses. The resulting expelled interstitial liquid was likely collected and erupted along with the magma flowing through the newly injected dykes. Gabbro sequences represent crystallised coalesced magma batches, emplaced at lower rates at the end of eruptive cycles, and underwent minor melt extraction as evi¬denced by clinopyroxene orientations that record a simple shear component suggesting syn-magmatic deformation parallel to observed NNF.-SSW trending shear-zones induced by the regional tensional Miocene stress-field. The initiation and geometry of PX1 is controlled by the regional extensional tectonic regime whereas rates and vo¬lumes of magma depend on source-related factors. High injection rates are likely to induce intrusion growth rates larger than could be accommodated by the regional extension. In this case, dyke tip geometry and the inability of magma to circulate through previously emplaced and crystallised dykes could result in an increase of non-lithostatic pressure on previously emplaced mushy dyke walls; generating strong pure-shear compaction and interstitial melt expulsion within the feeder-zone as recorded by the cumulitic pyroxenite bands and anorthositic collection zones. The whole-rock major and trace-element chemistry of PX1 gabbros and pyroxenites is globally homogeneous and controlled by the cumulate nature of the samples (i.e. on the modal proportions of olivine, pyroxene, plagioclase and oxides). However, small variations of whole-rock trace-element contents as well as trace-element contents of clinopyroxene rims suggest that in-situ re-equilibration and crystallisation has occurred. Additionally, the global homogeneity and presence of complex zoning of rare resorbed clinopyroxene crystals suggest that the PX1 feeder- zone overlies a periodically replenished and efficiently mixed magma chamber. Each individual dyke of magma thus originated from a compositionally constant mildly alkaline magma and differentiated independently from the others reaching up to 70% fractionation. Following dyke arrest these are affected by interaction with the trapped interstitial liquid prior to its compaction-linked expulsion (thus stopping the differentiation process). This emplacement model implies that minimum amount of approximately 150 km3 of magma is needed to generate PX1, part of it having been erupted through the overlying Central Volcanic Complex of Fuerteventura. The radiogenic isotope ratios of PX1 samples reveal the contribution on three end-members during magma genesis. This mixing of the H1MU, EMI and DMM end-members could reflect the interaction of the deep-seated Canarian mantle plume with a heterogeneous metasomatic and sepentininsed lithospheric mantle. Additionally, the observed trace-element and isotopic variations within the same fades groups could reflect varying degrees of partial melting of the source region, thus tapping more or less large areas of the metasomatised lithospheric mantle during interac¬tion with the plume. High precision ID-TIMS U/Pb zircon and baddeleyite ages from the PX1 gabbro samples, indicate initiation of magma crystallisation at 22.10 ± 0.07 Ma. The magmatic activity lasted a minimum of 0.48 to 0.52 Ma. 40Ar/39Ar amphibole ages are of 21.9 ± 0.6 to 21.8 ± 0.3, identical within errors to the U/Pb ages. The combination of the 40Ar/39Ar and U/Pb datasets imply that the maximum amount of time PX1 took to cool below amphibole Tc is 0.8 Ma, suggesting PX1 lifetime of 520 000 to 800 000 years. On top of this, the coexistence of baddeleyite and zircon in a single sample is ascribed to the interaction of PX1 with C02-rich carbonatite-derived fluids released from the host-rock carbonatites during contact metamorphism 160 000 years after PX1 initiation. These ages are in agreement with the emplacement model, implying a crystallisation time of less than 1 to 5 years for individual dykes.

Canakinumab Relieves Symptoms of Acute Flares and Improves Health-Related Quality Of Life (HRQoL) in Difficult-To-Treat Gouty Arthritis Patients by Suppressing Inflammation: Results of a Randomized, Dose-Ranging Study

RATIONALE:We investigated the impact of canakinumab, a fully human anti-interleukin-1b monoclonal antibody on inflammation and HRQoL in gouty arthritis patients.METHODS: In this 8-week, single-blind, dose-ranging study, patients with acute gouty arthritis flares, unresponsive/intolerant or contraindicated to NSAIDs and/or colchicine were randomized to single subcutaneous canakinumab (10, 25, 50, 90, or 150mg, N5143) or single intramuscular triamcinolone acetonide (TA, 40mg, N557). Patients assessed pain (Likert scale), physicians assessed clinical signs of joint inflammation, and HRQoL was recorded using SF-36.RESULTS: At baseline, 98% patients had moderate-to-extreme pain, 85% had moderate/severe joint swelling, 64-79% had elevated inflammatory markers and HRQoL scores indicated impaired physical function. Percentage of patients with no/mild pain was numerically greater in most canakinumab groups vs. TA, 24-72h post-dose; difference significant for 150mg group at these time-points (P<0.05). Canakinumab 150mg was associated with significantly lower Likert scores for tenderness [OR, 3.2; 95% CI, 1.27-7.89; P50.014] and swelling (OR, 2.7; 95% CI, 1.09-6.50, P50.032) at 72h vs. TA; erythema was not different. Median CRP and SAA levels normalized by 7 days post-dose in most canakinumab groups, but remained elevated in TA. Physical function improved at 7 days postdose in all groups, highest improvement for canakinumab 150mg. SF-36 scores for physical functioning and bodily pain with canakinumab 150mg approached US general population scores by 7 days post-dose and exceeded normal values by 8 weeks post-dose.CONCLUSION: Canakinumab 150mg produced significantly greater and rapid pain-relief and improvements in HRQoL vs. TAin acute gouty arthritis patients.