An agent based simulation of the dynamics in cognitive depressogenic thought

Depression is a common mental disorder. Appropriate support from others can reduce the cognitive distortion that can be caused by subsequent depressions.To increase our understanding of this process, an agent model is presented in this paper in which the positive and negative effects of social support and its relation with cognitive thoughts are modelled. Simulations show the effect of social support on different personality types.A mathematical analysis of the stable situations in the model gives an additional explanation of extreme cases. Finally, a formal verification of expect ed relations between support, risk factors and depressive thoughts is performed on the simulation traces to check whether the simulations describe realistic processes

Identification de nouvelles options thérapeutiques et diagnostiques dans l'hyperaldostéronisme primaire

L hyperaldostéronisme primaire [HAP] résulte d une hypersécrétion d aldostérone d origine surrénale. La compréhension de la pathogénie de cette maladie, dont la prévalence est estimée à 10% de la population hypertendue, est essentielle pour le développement de nouveaux outils diagnostiques et thérapeutiques. Dans ce contexte, ce travail de doctorat avait pour but d identifier de nouvelles orientations thérapeutiques en testant un inhibiteur de l aldostérone synthase et de rechercher de nouveaux marqueurs diagnostiques par l étude du profil d expression des microARN [miRs]. Dans une étude de phase II, 14 patients présentant un HAP ont reçu un inhibiteur de l aldostérone synthase : le LCI699 pendant 4 semaines. Nous avons ainsi pu montrer que le LCI699 permet de diminuer les concentrations d aldostérone de 70 à 80% et de normaliser la kaliémie chez tous les patients. En revanche, il n a qu un effet modéré sur la pression artérielle et sur l élévation des concentrations de rénine, et n est que partiellement sélectif pour l aldostérone synthase. De plus son efficacité est moindre que celle de l éplérénone, antagoniste minéralocorticoide administré aux mêmes patients au décours du LCI699. Nous avons ensuite étudié l expression de 754 miRs dans des adénomes produisant de l aldostérone [APA] et dans des surrénales contrôles. L hypothèse était qu une dérégulation de leur expression pouvait être impliquée dans la tumorigénèse et la surproduction d aldostérone. L objectif secondaire était d identifier des miRs utilisables en tant que biomarqueurs. Cette analyse par carte microfluidique a révélé que 27 miRs sont significativement sous exprimés dans les APA et un seul miR est surexprimé. L expression différentielle de deux de ces miRs : miR 137 et miR 375 a pu être confirmée dans une cohorte de validation de 36 APA: Des résultats préliminaires in vitro indiquent que le miR 375 pourrait induire une diminution de la synthèse d aldostérone. Enfin, l analyse de l expression de ces miRs dans le plasma a permis de mettre en évidence une sous-expression du miR 375 chez les patients atteints d HAP en comparaison à des sujets sains. En conclusion, le blocage de la biosynthèse de l aldostérone représente une nouvelle option thérapeutiques, cependant il est nécessaire de développer une seconde génération de molécules : plus puissantes et plus sélectives. Les analyses effectuées sur les APA ouvrent de nouvelles perspectives pour l identification de nouveaux biomarqueurs tels que les miRs circulantsPrimary aldosteronism [PA] results from the hypersecretion of aldosterone by the adrenals. Understanding the pathogenesis of the disease is essential for identifying new diagnostic and therapeutic tools. In this context the purpose of my PHD was to investigate the effects of an aldosterone synthase inhibitor and second to investigate new diagnostic options by the extensive study of microRNA [miRNA]. In a phase II clinical study, 14 patients with PA were administered an aldosterone synthase inhibitor: LCI699. Four weeks of treatment lead to a 70 to 80% decrease in aldosterone concentration, associated with the cure of hypokalemia. However, there was only a mild effect on blood pressure and volemia (reflected by renin concentration). In addition, these results demonstrated an incomplete selectivity of LCI699 for aldosterone synthase in vivo, and showed that LCI699 is less potent than the blocker of the mineralocorticoid receptor: eplerenone . We also characterized the miRNA profile of Aldosterone producing adenomas [APA]. The hypothesis was that a dysregulation of the expression of miRNA could induce tumorigenesis and increase the production of aldosterone. The secondary aim of the study was to identify miRNA that could be measured in plasma as biomarkers. miRNA profiling of 754 miRNA using quantitative PCR Low Density array, revealed 28 miRNA whose expression was significantly different in APA. The differential expression of two miRNA: miRNA 137 and miRNA 375 was confirmed in a validation cohort of 36 APA. Preliminary in vitro studies showed that up-regulation of intracellular levels of miR 375 may reduce aldosterone secretion in H295R cells. Lastly, circulating plasma levels of miR 375 are differentially expressed between patients with PA and healthy volunteers. In conclusion, the blocking of the aldosterone pathway in hypertensive patients is a novel therapeutic option but second-generation drugs more potent and more selective of aldosterone synthase are required. Profiling miRNA in APA offers new prospect for the development of biomarkers, such as measuring circulating miRNA in plasmaPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Simulating cognitive coping strategies for intelligent support agents

People react differently to stress.According to the Cognitive Motivational Relational Theory by Lazarus and Folkman, the appraisal of stress and the emotions related to it determine whether people cope with stress by focusing on altering the situation (problem focused) or on changing the emotional consequences of the events (emotion focused). These different coping strategies have different effects on the long term.The coping process can be described in a formal dynamic model. Simulations using this model show that problem focused coping leads to better coping skills and higher decrease of long-term stress than emotion focused coping.These results also follow from a mathematical analysis of the model.The presented model can form the basis of an intelligent support system that uses a simulation of cognitive processes in humans in stressful conditions

0272: True antihypertensive efficacy of sequential nephron blockade in patients with resistant hypertension and confirmed medication adherence

ObjectiveWe previously showed (Bobrie et al. J Hypertens 2012) that sequential-nephron blockade (SNB) was more effective than combined renin angiotensin system blockade (RB) for controlling BP in patients with resistant hypertension (RH). In this post-hoc analysis, we assessed medication adherence (MA) and its influence on the antihypertensive response to SNB/RB with a new combined scoring system.Design and MethodPts with daytime ambulatory SBP/DBP (dASBP/dADBP) >135 and/or 85mmHg, despite 4 week-treatment with irbesartan 300mg+HCTZ 12.5mg+amlodipine 5mg, were randomised either to SNB (i.e.+spironolactone 25mg, then +furosemide 20-40mg, then +amiloride 5mg, n=82) or RB (ramipril 5-10mg, then bisoprolol 5-10mg, RB group, n=82) for 12 weeks. MA was scored according to 4 criteria: (i) trough/peak plasma irbesartan (Irb) concentration (HPLC); (ii) urinary AcSDKP/creatinine ratio (UR) to evaluate ramipril intake; (iii) delay of last medication intake before visit (LMI); and (iv) pill counting (PC, %). One point of MA score was attributed to trough Irb >20ng/ml, UR >4nmol/mmol, LMI <24h and PC >80%. MA was defined as low (LMA, score <2), intermediate (IMA, score=3), and optimal (OMA, score=4).Results82 pts among 164 had OMA (46 SNB and 36 RB); 52 pts had IMA (23 SNB and 29 RB); and 30 pts had LMA (13 SNB and 17 RB) (inter-groups difference: NS). LMA pts were younger than SMA pts (50±11 vs. 56±10 yrs, p<0.011). In OMA pts, the difference in dASBP/dADBP between SNB vs RB was significant (–11 [–17;–6]/–6 [–9;–2] mmHg, p<0.0001/p=0.0025), favoring SNB, whereas in LMA pts the significant difference between the two groups was no more observed (–6 [–19;7]/–1 [–10;7] mmHg, p=0.352/p=0.7096).ConclusionThe major BP lowering effect of SNB vs. RB observed in pts with OMA is lost in pts LMA. Combined methods for assessing MA allow determining the true efficacy of antihypertensive strategies in patients with RH. Reinforcement of MA in RH pts is deemed necessary

Real-world experience with ultrasound renal denervation utilizing home blood pressure monitoring:the Global Paradise System registry study design

Background: Hypertension is a major public health issue due to its association with cardiovascular disease risk. Despite the availability of effective antihypertensive drugs, rates of blood pressure (BP) control remain suboptimal. Renal denervation (RDN) has emerged as an effective non-pharmacological, device-based treatment option for patients with hypertension. The multicenter, single-arm, observational Global Paradise™ System (GPS) registry has been designed to examine the long-term safety and effectiveness of ultrasound RDN (uRDN) with the Paradise System in a large population of patients with hypertension. Methods: The study aims to enroll up to 3000 patients undergoing uRDN in routine clinical practice. Patients will be recruited over a 4-year period and followed for 5 years (at 3, 6, and 12 months after the uRDN procedure and annually thereafter). Standardized home BP measurements will be taken every 3 months with automatic upload to the cloud. Office and ambulatory BP and adverse events will be collected as per routine clinical practice. Quality-of-Life questionnaires will be used to capture patient-reported outcomes. Conclusions: This observational registry will provide real-world information on the safety and effectiveness of uRDN in a large population of patients treated during routine clinical practice, and also allow for a better understanding of responses in prespecified subgroups. The focus on home BP in this registry is expected to improve completeness of long-term follow-up and provide unique insights into BP over time. Graphical abstract: Global Paradise System registry study design. ABP, ambulatory blood pressure; BP, blood pressure; FU, follow-up; M, month; OBP, office blood pressure. [Figure not available: see fulltext.].</p

Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons.

Local translation regulates the axonal proteome, playing an important role in neuronal wiring and axon maintenance. How axonal mRNAs are localized to specific subcellular sites for translation, however, is not understood. Here we report that RNA granules associate with endosomes along the axons of retinal ganglion cells. RNA-bearing Rab7a late endosomes also associate with ribosomes, and real-time translation imaging reveals that they are sites of local protein synthesis. We show that RNA-bearing late endosomes often pause on mitochondria and that mRNAs encoding proteins for mitochondrial function are translated on Rab7a endosomes. Disruption of Rab7a function with Rab7a mutants, including those associated with Charcot-Marie-Tooth type 2B neuropathy, markedly decreases axonal protein synthesis, impairs mitochondrial function, and compromises axonal viability. Our findings thus reveal that late endosomes interact with RNA granules, translation machinery, and mitochondria and suggest that they serve as sites for regulating the supply of nascent pro-survival proteins in axons