Fine structural variations of alphabeta TCRs selected by vaccination with natural versus altered self-antigen in melanoma patients

Immunotherapy of cancer is often performed with altered "analog" peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A26-35-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3 composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR β-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3β amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such "public" motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with "private" CDR3β signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.

Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity.

Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as ABD mutations demonstrated that with only one exception disease-associated substitutions, surrounding hinge 1 demonstrated no tendency to form actin-filamin foci. The exception, a substitution in filamin repeat 6, lies within a region previously implicated in filamin-actin binding. These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.

Use of aggregating brain cell cultures to study developmental effects of organophosphorus insecticides.

Aggregating brain cell cultures of fetal rat telencephalon can be grown in a chemically defined medium for extended periods of time. After a phase of intense mitotic activity, these three-dimensional cell cultures undergo extensive morphological differentiation, including synaptogenesis and myelination. To study the developmental toxicity of organophosphorus compounds (OP), aggregating brain cell cultures were treated with parathion. Protein content and cell type-specific enzyme activities were not affected up to a concentration of 10(5) M. Gliosis, characterized by an increased staining for glial fibrillary acidic protein (GFAP), was observed in immature and in differentiated cells. In contrast, uridine incorporation and myelin basic protein (MBP) immunoreactivity revealed strong differences in sensitivity between these two developmental stages. These results are in agreement with the view that in vivo the development-dependent toxicity is not only due to changes in hepatic detoxification, but also to age-related modifications in the susceptibility of the different populations of brain cells. Furthermore, they underline the usefulness of histotypic culture systems with a high developmental potential, such as aggregating brain cell cultures, and stress the importance of applying a large range of criteria for testing the developmental toxicity of potential neurotoxicants.

Induction of cardiac Angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor beta/delta and protects against fatty acid-induced oxidative stress.

RATIONALE: Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart. OBJECTIVE: To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences. METHODS AND RESULTS: Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)beta/delta(-/-) and not PPARalpha(-/-) mice and was blunted on siRNA-mediated PPARbeta/delta knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPARbeta/delta but not PPARalpha to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding. CONCLUSIONS: Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPARbeta/delta is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid-induced oxidative stress.

Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study.

OBJECTIVE: To define therapeutic strategy for management of patients with ischemic stroke due to a high probability of paradoxical embolism through a Patent Foramen Ovale (PFO). METHODS: Since 1988 all consecutive patients with cerebrovascular events and PFO from the Stroke Registry of our population-based primary-care center are prospectively studied and followed. Since 1992, among 118 patients with cryptogenic embolic brain infarct or transient ischemic attack (TIA) and PFO, 32 consecutive patients younger than 60 years who presented at least two of the following criteria were admitted for surgery: history of Valsalva strain before stroke (11); multiple clinical events (13); multiple infarcts on brain Magnetic Resonance Imaging (MRI) (15); atrial septal aneurysm (ASA) (16); large right-to-left shunt (> 50 microbubbles) (12). RESULTS: Operative time 135' +/- 33'. CPB time 34' +/- 14'. Aortic crossclamping time 16' +/- 6'. Post-operative bleeding 485 +/- 170 ml. No homologous blood transfusion required. No neurological, cardiac or renal complications. All patients were followed-up corresponding to a cumulative time of 601 patient-months. This revealed no recurrent vascular events nor silent new brain lesions on brain MRI. Systematic simultaneous contrast Trans Esophageal Echocardiography (TEE)-Trans Cranial Doppler showed a small residual interatrial shunt in two patients. CONCLUSION: Surgical closure of a patent foramen ovale can be accomplished with very low morbidity and reduce efficiently the risk of stroke recurrence. It seems to be the option of choice in selected patients with a higher (> 1.5%/year) risk of stroke recurrence.

Priming for enhanced defence responses by specific inhibition of the Arabidopsis response to coronatine.

The priming agent β-aminobutyric acid (BABA) is known to enhance Arabidopsis resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 by potentiating salicylic acid (SA) defence signalling, notably PR1 expression. The molecular mechanisms underlying this phenomenon remain unknown. A genome-wide microarray analysis of BABA priming during Pst DC3000 infection revealed direct and primed up-regulation of genes that are responsive to SA, the SA analogue benzothiadiazole and pathogens. In addition, BABA was found to inhibit the Arabidopsis response to the bacterial effector coronatine (COR). COR is known to promote bacterial virulence by inducing the jasmonic acid (JA) response to antagonize SA signalling activation. BABA specifically repressed the JA response induced by COR without affecting other plant JA responses. This repression was largely SA-independent, suggesting that it is not caused by negative cross-talk between SA and JA signalling cascades. Treatment with relatively high concentrations of purified COR counteracted BABA inhibition. Under these conditions, BABA failed to protect Arabidopsis against Pst DC3000. BABA did not induce priming and resistance in plants inoculated with a COR-deficient strain of Pst DC3000 or in the COR-insensitive mutant coi1-16. In addition, BABA blocked the COR-dependent re-opening of stomata during Pst DC3000 infection. Our data suggest that BABA primes for enhanced resistance to Pst DC3000 by interfering with the bacterial suppression of Arabidopsis SA-dependent defences. This study also suggests the existence of a signalling node that distinguishes COR from other JA responses.

Simultaneous measurement of regional cerebral blood flow by perfusion CT and stable xenon CT: a validation study.

BACKGROUND AND PURPOSE: Knowledge of cerebral blood flow (CBF) alterations in cases of acute stroke could be valuable in the early management of these cases. Among imaging techniques affording evaluation of cerebral perfusion, perfusion CT studies involve sequential acquisition of cerebral CT sections obtained in an axial mode during the IV administration of iodinated contrast material. They are thus very easy to perform in emergency settings. Perfusion CT values of CBF have proved to be accurate in animals, and perfusion CT affords plausible values in humans. The purpose of this study was to validate perfusion CT studies of CBF by comparison with the results provided by stable xenon CT, which have been reported to be accurate, and to evaluate acquisition and processing modalities of CT data, notably the possible deconvolution methods and the selection of the reference artery. METHODS: Twelve stable xenon CT and perfusion CT cerebral examinations were performed within an interval of a few minutes in patients with various cerebrovascular diseases. CBF maps were obtained from perfusion CT data by deconvolution using singular value decomposition and least mean square methods. The CBF were compared with the stable xenon CT results in multiple regions of interest through linear regression analysis and bilateral t tests for matched variables. RESULTS: Linear regression analysis showed good correlation between perfusion CT and stable xenon CT CBF values (singular value decomposition method: R(2) = 0.79, slope = 0.87; least mean square method: R(2) = 0.67, slope = 0.83). Bilateral t tests for matched variables did not identify a significant difference between the two imaging methods (P >.1). Both deconvolution methods were equivalent (P >.1). The choice of the reference artery is a major concern and has a strong influence on the final perfusion CT CBF map. CONCLUSION: Perfusion CT studies of CBF achieved with adequate acquisition parameters and processing lead to accurate and reliable results.

The impact of information on patient preferences in different delivery patterns: a contingent valuation study of prescription versus OTC drugs.

OBJECTIVES: Our analysis assessed the impact of information on patients' preferences in prescription versus over-the-counter (OTC) delivery systems. METHODS: A contingent valuation (CV) study was implemented, randomly assigning 534 lay people into the receipt of limited or extended information concerning new influenza drugs. In each information arm, people answered two questions: the first asked about willingness to pay (WTP) for the new prescription drug; the second asked about WTP for the same drug sold OTC. RESULTS: We show that WTP is higher for the OTC scenario and that the level of information plays a significant role in the evaluation of the OTC scenario, with more information being associated with an increase in the WTP. In contrast, the level of information provided has no impact on WTP for prescription medicine. Thus, for the kind of drug considered here (i.e. safe, not requiring medical supervision), a switch to OTC status can be expected to be all the more beneficial, as the patient is provided with more information concerning the capability of the drug. CONCLUSIONS: Our results shed light on one of the most challenging issues that health policy makers are currently faced with, namely the threat of a bird flu pandemic. Drug delivery is a critical component of pandemic influenza preparedness. Furthermore, the congruence of our results with the agency and demand theories provides an important test of the validity of using WTP based on CV methods.

Prognostic significance of nailfold capillary microscopy in patients with Raynaud's phenomenon and scleroderma-pattern abnormalities. A six-year follow-up study.

The aim of this study was to assess the prognostic significance of scleroderma capillary pattern (SD-pattern) in patients with Raynaud's phenomenon. Thirty patients with a capillaroscopy examination suggestive of scleroderma (megacapillaries and/or avascularity) but without clinical criteria of scleroderma (ARA criteria) were reevaluated 6 years after the initial clinical and capillaroscopy examinations. SD-pattern abnormalities were classified according to a semiquantitative method. Eight out of the 28 evaluated patients (28%) developed a scleroderma spectrum disorder (SDS). The presence of avascularity and/or a mean of more than two megacapillaries digit greatly enhanced the percentage of evolution toward SDS (70%/88% respectively). Most of the patients with few enlarged capillaries and no capillary rarefaction at entry had primary acrocyanosis (11/15). None of them developed SDS. The microangiopathy disappeared during the follow-up period in most of these patients (14/15). These results confirm the prognostic value of SD-pattern capillary abnormalities for SDS. Primary acrocyanosis, a benign clinical entity should be considered in presence of few megacapillaries and without capillary rarefaction.

Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells.

Monocarboxylate transporters (MCTs) are essential for the use of lactate, an energy substrate known to be overproduced in brain during an ischemic episode. The expression of MCT1 and MCT2 was investigated at 48 h of reperfusion from focal ischemia induced by unilateral extradural compression in Wistar rats. Increased MCT1 mRNA expression was detected in the injured cortex and hippocampus of compressed animals compared to sham controls. In the contralateral, uncompressed hemisphere, increases in MCT1 mRNA level in the cortex and MCT2 mRNA level in the hippocampus were noted. Interestingly, strong MCT1 and MCT2 protein expression was found in peri-lesional macrophages/microglia and in an isolectin B4+/S100beta+ cell population in the corpus callosum. In vitro, MCT1 and MCT2 protein expression was observed in the N11 microglial cell line, whereas an enhancement of MCT1 expression by tumor necrosis factor-alpha (TNF-alpha) was shown in these cells. Modulation of MCT expression in microglia suggests that these transporters may help sustain microglial functions during recovery from focal brain ischemia. Overall, our study indicates that changes in MCT expression around and also away from the ischemic area, both at the mRNA and protein levels, are a part of the metabolic adaptations taking place in the brain after ischemia.

Coping is excellent in Swiss Children with inflammatory bowel disease: results from the Swiss IBD cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) starting during childhood has been assumed to impair quality of life (QoL) of affected children. As this aspect is crucial for further personality development, the health-related quality of life (HRQOL) was assessed in a Swiss nationwide cohort to obtain detailed information on the fields of impairment. METHODS: Data were prospectively acquired from pediatric patients included in the Swiss IBD Cohort Study. IBD activity was evaluated by PCDAI and PUCAI. The age adapted KIDSCREEN questionnaire was evaluated for 110 children with IBD (64 with Crohn's disease 46 with ulcerative colitis). Data were analyzed with respect to established reference values of healthy controls. RESULTS: In the KIDSCREEN index a moderate impairment was only found for physical wellbeing due to disease activity. In contrast, mental well-being and social support were even better as compared to control values. A subgroup analysis revealed that this observation was restricted to the children in the German speaking part of Switzerland, whereas there was no difference compared to controls in the French part of Switzerland. Furthermore, autonomy and school variables were significantly higher in the IBD patients as compared to controls. CONCLUSIONS: The social support for children with IBD is excellent in this cohort. Only physical well-being was impaired due to disease activity, whereas all other KIDSCREEN parameters were better as compared to controls. This indicates that effective coping and support strategies may be able to compensate the burden of disease in pediatric IBD patients.

Patterns of neurovascular compression in patients with classic trigeminal neuralgia: A high-resolution MRI-based study.

PURPOSE: To describe the anatomical characteristics and patterns of neurovascular compression in patients suffering classic trigeminal neuralgia (CTN), using high-resolution magnetic resonance imaging (MRI). MATERIALS AND METHODS: The analysis of the anatomy of the trigeminal nerve, brain stem and the vascular structures related to this nerve was made in 100 consecutive patients treated with a Gamma Knife radiosurgery for CTN between December 1999 and September 2004. MRI studies (T1, T1 enhanced and T2-SPIR) with axial, coronal and sagital simultaneous visualization were dynamically assessed using the software GammaPlan?. Three-dimensional reconstructions were also developed in some representative cases. RESULTS: In 93 patients (93%), there were one or several vascular structures in contact, either, with the trigeminal nerve, or close to its origin in the pons. The superior cerebellar artery was involved in 71 cases (76%). Other vessels identified were the antero-inferior cerebellar artery, the basilar artery, the vertebral artery, and some venous structures. Vascular compression was found anywhere along the trigeminal nerve. The mean distance between the nerve compression and the origin of the nerve in the brainstem was 3.76±2.9mm (range 0-9.8mm). In 39 patients (42%), the vascular compression was located proximally and in 42 (45%) the compression was located distally. Nerve dislocation or distortion by the vessel was observed in 30 cases (32%). CONCLUSIONS: The findings of this study are similar to those reported in surgical and autopsy series. This non-invasive MRI-based approach could be useful for diagnostic and therapeutic decisions in CTN, and it could help to understand its pathogenesis.

The health promotion model and rare disease patients : a mixed methods study examining adherence to treatment in men with congenital hypogonadotropic hypogonadism

Rare diseases are typically chronic medical conditions of genetic etiology characterized by low prevalence and high complexity. Patients living with rare diseases face numerous physical, psychosocial and economic challenges that place them in the realm of health disparities. Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterized by absent puberty and infertility. Little is known about the psychosocial impact of CHH on patients or their adherence to available treatments. This project aimed to examine the relationship between illness perceptions, depressive symptoms and adherence to treatment in men with CHH using the nursing-sensitive Health Promotion Model (HPM). A community based participatory research (CBPR) framework was employed as a model for empowering patients and overcoming health inequities. The study design used a sequential, explanatory mixed-methods approach. To reach dispersed CHH men, we used web-based recruitment and data collection (online survey). Subsequently, three patient focus groups were conducted to provide explanatory insights into the online survey (i.e. barriers to adherence, challenges of CHH, and coping/support) The online survey (n=101) revealed that CHH men struggle with adherence and often have long gaps in care (40% >1 year). They experience negative psychosocial consequences because of CHH and exhibit significantly increased rates of depression (p<0.001). Focus group participants (n=26) identified healthcare system, interpersonal, and personal factors as barriers to adherence. Further, CHH impacts quality of life and impedes psychosexual development in these men. The CHH men are active internet users who rely on the web forcrowdsourcing solutions and peer-to-peer support. Moreover, they are receptive to web-based interventions to address unmet health needs. This thesis contributes to nursing knowledge in several ways. First, it demonstrates the utility of the HPM as a valuable theoretical construct for understanding medication adherence and for assessing rare disease patients. Second, these data identify a range of unmet health needs that are targets for patient-centered interventions. Third, leveraging technology (high-tech) effectively extended the reach of nursing care while the CBPR approach and focus groups (high-touch) served as concurrent nursing interventions facilitating patient empowerment in overcoming health disparities. Last, these findings hold promise for developing e-health interventions to bridge identified shortfalls in care and activating patients for enhanced self- care and wellness -- Les maladies rares sont généralement de maladies chroniques d'étiologie génétique caractérisées par une faible prévalence et une haute complexité de traitement. Les patients atteints de maladies rares sont confrontés à de nombreux défis physiques, psychosociaux et économiques qui les placent dans une posture de disparité et d'inégalités en santé. L'hypogonadisme hypogonadotrope congénital (CHH) est un trouble endocrinien rare caractérisé par l'absence de puberté et l'infertilité. On sait peu de choses sur l'impact psychosocial du CHH sur les patients ou leur adhésion aux traitements disponibles. Ce projet vise à examiner la relation entre la perception de la maladie, les symptômes dépressifs et l'observance du traitement chez les hommes souffrant de CHH. Cette étude est modélisée à l'aide du modèle de la Promotion de la santé de Pender (HPM). Le cadre de l'approche communautaire de recherche participative (CBPR) a aussi été utilisé. La conception de l'étude a reposé sur une approche mixte séquentielle. Pour atteindre les hommes souffrant de CHH, un recrutement et une collecte de données ont été organisées électroniquement. Par la suite, trois groupes de discussion ont été menées avec des patients experts impliqués au sein d'organisations reliés aux maladies rares. Ils ont été invités à discuter certains éléments additionnels dont, les obstacles à l'adhésion au traitement, les défis généraux de vivre avec un CHH, et l'adaptation à la maladie en tenant compte du soutien disponible. Le sondage en ligne (n = 101) a révélé que les hommes souffrant de CHH ont souvent de longues périodes en rupture de soins (40% > 1 an). Ils vivent des conséquences psychosociales négatives en raison du CHH et présentent une augmentation significative des taux de dépression (p <0,001). Les participants aux groupes de discussion (n = 26) identifient dans l'ordre, les systèmes de soins de santé, les relations interpersonnelles, et des facteurs personnels comme des obstacles à l'adhésion. En outre, selon les participants, le CHH impacte négativement sur leur qualité de vie générale et entrave leur développement psychosexuel. Les hommes souffrant de CHH se considèrent être des utilisateurs actifs d'internet et comptent sur le web pour trouver des solutions pour trouver des ressources et y recherchent le soutien de leurs pairs (peer-to-peer support). En outre, ils se disent réceptifs à des interventions qui sont basées sur le web pour répondre aux besoins de santé non satisfaits. Cette thèse contribue à la connaissance des soins infirmiers de plusieurs façons. Tout d'abord, elle démontre l'utilité de la HPM comme une construction théorique utile pour comprendre l'adhésion aux traitements et pour l'évaluation des éléments de promotion de santé qui concernent les patients atteints de maladies rares. Deuxièmement, ces données identifient une gamme de besoins de santé non satisfaits qui sont des cibles pour des interventions infirmières centrées sur le patient. Troisièmement, méthodologiquement parlant, cette étude démontre que les méthodes mixtes sont appropriées aux études en soins infirmiers car elles allient les nouvelles technologies qui peuvent effectivement étendre la portée des soins infirmiers (« high-tech »), et l'approche CBPR par des groupes de discussion (« high-touch ») qui ont facilité la compréhension des difficultés que doivent surmonter les hommes souffrant de CHH pour diminuer les disparités en santé et augmenter leur responsabilisation dans la gestion de la maladie rare. Enfin, ces résultats sont prometteurs pour développer des interventions e-santé susceptibles de combler les lacunes dans les soins et l'autonomisation de patients pour une meilleure emprise sur les auto-soins et le bien-être.

Evolutionary Games in Networked Populations: Models and Experiments

Cooperation and coordination are desirable behaviors that are fundamental for the harmonious development of society. People need to rely on cooperation with other individuals in many aspects of everyday life, such as teamwork and economic exchange in anonymous markets. However, cooperation may easily fall prey to exploitation by selfish individuals who only care about short- term gain. For cooperation to evolve, specific conditions and mechanisms are required, such as kinship, direct and indirect reciprocity through repeated interactions, or external interventions such as punishment. In this dissertation we investigate the effect of the network structure of the population on the evolution of cooperation and coordination. We consider several kinds of static and dynamical network topologies, such as Baraba´si-Albert, social network models and spatial networks. We perform numerical simulations and laboratory experiments using the Prisoner's Dilemma and co- ordination games in order to contrast human behavior with theoretical results. We show by numerical simulations that even a moderate amount of random noise on the Baraba´si-Albert scale-free network links causes a significant loss of cooperation, to the point that cooperation almost vanishes altogether in the Prisoner's Dilemma when the noise rate is high enough. Moreover, when we consider fixed social-like networks we find that current models of social networks may allow cooperation to emerge and to be robust at least as much as in scale-free networks. In the framework of spatial networks, we investigate whether cooperation can evolve and be stable when agents move randomly or performing Le´vy flights in a continuous space. We also consider discrete space adopting purposeful mobility and binary birth-death process to dis- cover emergent cooperative patterns. The fundamental result is that cooperation may be enhanced when this migration is opportunistic or even when agents follow very simple heuristics. In the experimental laboratory, we investigate the issue of social coordination between indi- viduals located on networks of contacts. In contrast to simulations, we find that human players dynamics do not converge to the efficient outcome more often in a social-like network than in a random network. In another experiment, we study the behavior of people who play a pure co- ordination game in a spatial environment in which they can move around and when changing convention is costly. We find that each convention forms homogeneous clusters and is adopted by approximately half of the individuals. When we provide them with global information, i.e., the number of subjects currently adopting one of the conventions, global consensus is reached in most, but not all, cases. Our results allow us to extract the heuristics used by the participants and to build a numerical simulation model that agrees very well with the experiments. Our findings have important implications for policymakers intending to promote specific, desired behaviors in a mobile population. Furthermore, we carry out an experiment with human subjects playing the Prisoner's Dilemma game in a diluted grid where people are able to move around. In contrast to previous results on purposeful rewiring in relational networks, we find no noticeable effect of mobility in space on the level of cooperation. Clusters of cooperators form momentarily but in a few rounds they dissolve as cooperators at the boundaries stop tolerating being cheated upon. Our results highlight the difficulties that mobile agents have to establish a cooperative environment in a spatial setting without a device such as reputation or the possibility of retaliation. i.e. punishment. Finally, we test experimentally the evolution of cooperation in social networks taking into ac- count a setting where we allow people to make or break links at their will. In this work we give particular attention to whether information on an individual's actions is freely available to poten- tial partners or not. Studying the role of information is relevant as information on other people's actions is often not available for free: a recruiting firm may need to call a job candidate's refer- ences, a bank may need to find out about the credit history of a new client, etc. We find that people cooperate almost fully when information on their actions is freely available to their potential part- ners. Cooperation is less likely, however, if people have to pay about half of what they gain from cooperating with a cooperator. Cooperation declines even further if people have to pay a cost that is almost equivalent to the gain from cooperating with a cooperator. Thus, costly information on potential neighbors' actions can undermine the incentive to cooperate in dynamical networks.