Mise en oeuvre de protocoles spatiaux pour analyser la modulation de processus cognitifs en fonction de la dimension émotionnelle chez le rongeur

Résumé : Emotion et cognition sont deux termes généralement employés pour désigner des processus psychiques de nature opposée. C'est ainsi que les sciences cognitives se sont longtemps efforcées d'écarter la composante «chaude »des processus «froids »qu'elles visaient, si ce n'est pour montrer l'effet dévastateur de la première sur les seconds. Pourtant, les processus cognitifs (de collecte, maintien et utilisation d'information) et émotioAnels (d'activation subjective, physiologique et comportementale face à ce qui est attractif ou aversif) sont indissociables. Par l'approche neuro-éthologique, à l'interface entre le substrat biologique et les manifestations comportementales, nous nous sommes intéressés à une fonction cognitive essentielle, la fonction mnésique, classiquement exprimée chez le rongeur par l'orientation spatiale. Au niveau du substrat, McDonald et White (1993) ont montré la dissociation de trois systèmes de mémoire, avec les rôles de l'hippocampe, du néostriatum et de l'amygdale dans l'encodage des informations respectivement épisodiques, procédurales et émotionnelles. Nous nous sommes penchés sur l'interaction entre ces systèmes en fonction de la dimension émotionnelle par l'éclairage du comportement. L'état émotionnel de l'animal dépend de plusieurs facteurs, que nous avons tenté de contrôler indirectement en comparant leurs effets sur l'acquisition, dans diverses conditions, de la tâche de Morris (qui nécessite la localisation dans un bassin de la position d'une plate-forme submergée), ainsi que sur le style d'exploration de diverses arènes, ouvertes ou fermées, plus ou moins structurées par la présence de tunnels en plexiglas transparent. Nous avons d'abord exploré le rôle d'un composant du système adrénergique dans le rapport à la difficulté et au stress, à l'aide de souris knock-out pour le récepteur à la noradrénaline a-1 B dans un protocole avec 1 ou 4 points de départ dans un bassin partitionné. Ensuite, nous nous sommes penchés, chez le rat, sur les effets de renforcement intermittent dans différentes conditions expérimentales. Dans ces conditions, nous avons également tenté d'analyser en quoi la situation du but dans un paysage donné pouvait interférer avec les effets de certaines formes de stress. Finalement, nous avons interrogé les conséquences de perturbations passées, y compris le renforcement partiel, sur l'organisation des déplacements sur sol sec. Nos résultats montrent la nécessité, pour les souris cont~ô/es dont l'orientation repose sur l'hippocampe, de pouvoir varier les trajectoires, ce qui favoriserait la constitution d'une carte cognitive. Les souris a->B KO s'avèrent plus sensibles au stress et capables de bénéficier de la condition de route qui permet des réponses simples et automatisées, sous-tendues par l'activité du striatum. Chez les rats en bassin 100% renforcé, l'orientation apparaît basée sur l'hippocampe, relayée par le striatum pour le développement d'approches systématiques et rapides, avec réorientation efficace en nouvelle position par réactivation dépendant de l'hippocampe. A 50% de renforcement, on observe un effet du type de déroulement des sessions, transitoirement atténué par la motivation Lorsque les essais s'enchaînent sans pause intrasession, les latences diminuent régulièrement, ce qui suggère une prise en charge possible par des routines S-R dépendant du striatum. L'organisation des mouvements exploratoires apparaît dépendante du niveau d'insécurité, avec différents profils intermédiaires entre la différentiation maximale et la thigmotaxie, qui peuvent être mis en relation avec différents niveaux d'efficacité de l'hippocampe. Ainsi, notre travail encourage à la prise en compte de la dimension émotionnelle comme modulatrice du traitement d'information, tant en phase d'exploration de l'environnement que d'exploitation des connaissances spatiales. Abstract : Emotion and cognition are terms widely used to refer to opposite mental processes. Hence, cognitive science research has for a long time pushed "hot" components away from "cool" targeted processes, except for assessing devastating effects of the former upon the latter. However, cognitive processes (of information collection, preservation, and utilization) and emotional processes (of subjective, physiological, and behavioral activation roue to attraction or aversion) are inseparable. At the crossing between biological substrate and behavioral expression, we studied a chief cognitive function, memory, classically shown in animals through spatial orientation. At the substrate level, McDonald et White (1993) have shown a dissociation between three memory systems, with the hippocampus, neostriatum, and amygdala, encoding respectively episodic, habit, and emotional information. Through the behavior of laboratory rodents, we targeted the interaction between those systems and the emotional axis. The emotional state of an animal depends on different factors, that we tried to check in a roundabout way by the comparison of their effects on acquisition, in a variety of conditions, of the Morris task (in which the location of a hidden platform in a pool is required), as well as on the exploration profile in different apparatus, open-field and closed mazes, more or less organized by clear Plexiglas tunnels. We first tracked the role, under more or less difficult and stressful conditions, of an adrenergic component, with knock-out mice for the a-1 B receptor in a partitioned water maze with 1 or 4 start positions. With rats, we looked for the consequences of partial reinforcement in the water maze in different experimental conditions. In those conditions, we further analyzed how the situation of the goal in the landscape could interfere with the effect of a given stress. At last, we conducted experiments on solid ground, in an open-field and in radial mazes, in order to analyze the organization of spatial behavior following an aversive life event, such as partial reinforcement training in the water maze. Our results emphasize the reliance of normal mice to be able to vary approach trajectories. One of our leading hypotheses is that such strategies are hippocampus-dependent and are best developed for of a "cognitive map like" representation. Alpha-1 B KO mice appear more sensitive to stress and able to take advantage of the route condition allowing simple and automated responses, most likely striatum based. With rats in 100% reinforced water maze, the orientation strategy is predominantly hippocampus dependent (as illustrated by the impairment induced by lesions of this structure) and becomes progressively striatum dependent for the development of systematic and fast successful approaches. Training towards a new platform position requires a hippocampus based strategy. With a 50% reinforcement rate, we found a clear impairment related to intersession disruption, an effect transitorily minimized by motivation enhancement (cold water). When trials are given without intrasession interruption, latencies consistently diminish, suggesting a possibility for striatum dependent stimulus-response routine to occur. The organization of exploratory movements is shown to depend on the level of subjective security, with different intermediary profiles between maximum differentiation and thigmotaxy, which can be considered in parallel with different efficiency levels of the hippocampus dependent strategies. Thus, our work fosters the consideration of emotion as a cognitive treatment modulator, during spatial exploration as well as spatial learning. It leads to a model in which the predominance of hippocampus based exploration is challenged by training conditions of various nature.

Effect of a pilot gait and balance training program: The importance of fear of falling.

Purpose: To determine the evolution of fear of falling, and its relationship with gait performance after a 10-week gait and balance training program. Population and methods: Participants (N=50) were community-dwelling elderly persons enrolled voluntarily in a 10-week, low intensity, gait and balance training program. At baseline, fear of falling was assessed using a previously validated version of Tinetti's Fall Efficacy Scale (FES, range 0-120, higher score indicating higher confidence), that assesses one's confidence in performing 12 activities of daily life without falling. Gait parameters were measured over a 20m walk at preferred gait speed, using the Physilog system (Aminian K, et al., J Biomechanics, 2002). This system uses 4 kinematics sensors attached to the lower limbs and a data logger carried by the subject. Follow-up data on fear of falling and gait were collected one week after completion of the program. Results: Overall, 43 (86%) of the participants completed the program. Mean age was 78.1 years, 79% were women. At baseline, mean FES score was 98.8 (range 58-120) and mean gait speed was 0.92 m/sec (range 0.43-1.47). At follow-up, participants modestly improved their FES score (98.8±17.0 vs 103.2±16.0, P=.04) and gait speed (0.92±0.27 vs 0.99±0.26 m/sec, P<.01). In secondary analyses stratified by subject's baseline FES, those with lower than average confidence (N=21) improved significantly both FES score (84.4±11.8 vs 94.5±17.9, P<.01) and gait speed (0.79±0.26 vs 0.90±0.28 m/sec, P<.01), while no similar improvement was observed in subjects (N=22) with higher baseline confidence (112.5±6.6 vs 111.5±7.5, P=.56 and 1.03±0.22 vs 1.07±0.21 m/sec, P=.41). After adjustment for age, gender and baseline gait speed, subjects with lower baseline confidence had higher odds than the others to improve their confidence (AdjOR=10.8, 95%CI 1.8- 64.8 P=.01) and gait speed (AdjOR=3.3, 95%CI 0.6-19.7, P=.19) at follow-up. Conclusions: This pilot program of low intensity exercise modestly improved participants' fear of falling and gait speed. Interestingly, subjects with higher baseline fear of falling seemed more likely to benefit. Despite methodological limitations (pre-post comparisons, small sample), these results suggest that measuring fear of falling might be useful to better target subjects most likely to benefit from similar programs.

Gm(1,2,4,10,21) and Km(1) factors in vitreous humor.

The presence of Gm(1,2,4,10,21) and Km(1) factors in vitreous humor taken from human corpses was investigated. The results revealed a good agreement between the factors detected in this biological material and in blood. Their presence in vitreous humor is independent of the secretor type.

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Current applications of cardiac magnetic resonance (CMR) imaging offer a wide spectrum of indications in the setting of acute cardiac care. In particular, CMR is helpful for the differential diagnosis of chest pain by detection of myocarditis and pericarditis. Also, takotsubo cardiomyopathy and acute aortic diseases can be evaluated by CMR and are important differential diagnoses in patients with acute chest pain. In patients with restricted windows for echocardiography, CMR is the method of choice to evaluate complications of acute myocardial infarction (AMI). In AMI, CMR allows for a unique characterization of myocardial damage by quantifying necrosis, microvascular obstruction, oedema (=area at risk), and haemorrhage. These capabilities will help us to understand better the pathophysiological events during infarction and will also allow to assess new treatment strategies in AMI. To what extent the information on tissue damage will guide patient management is not yet clear and further research in this field is warranted. In the near future, CMR will certainly become more routine in acute cardiac care units, as manufacturers are now focusing strongly on this aspect of user-friendliness. Finally, in the next decade or so, MRI of other nuclei such as fluorine and carbon might become a clinical reality, which would allow for metabolic and targeted molecular imaging with excellent sensitivity and specificity

A dramatic lung cancer course in a patient with a rare EGFR germline mutation exon 21 V843I: Is EGFR TKI resistance predictable?

We report on the medical history of a Caucasian smoker woman diagnosed with a stage IV NSCLC adenocarcinoma, characterized by a rare epidermal growth factor receptor (EGFR) point mutation in exon 21 codon 843 (p.V843I/c.2527G>A/COSMIC ID 85894). This genetic alteration revealed to be germline, after its presence was demonstrated in chondroblasts from the bone biopsy. While it is the first description of germline V843I mutation without concomitant additional known EGFR activating mutation, we modeled the EGFR ATP catalytic domain in complex with ATP, gefitinib and erlotinib using computer-aided approaches to estimate possible changes in affinity upon the V843I mutation.

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Das Management von öffentlichen Organisationen hat sich in den letzen drei, vier Jahrzehnten beachtlich weiterentwickelt. Stichworte sind: verstärkte Ergebnisorientierung, grössere Autonomie bezüglich der Nützung der Ressourcen und der Prioritätensetzung, gesteigerte Ansprüche hinsichtlich der Rechenschaftslegung (Accountability), das gestiegene Interesse der Bürger und Medien an Entscheidungen und Tätigkeiten der öffentlichen Hand usw. Managementmethoden, die teils aus der Privatwirtschaft stammen, teils jedoch speziell für den öffentlichen Sektor entwickelt wurden, vervollständigen die Palette an Instrumenten, die den Public Managern heute zur Verfügung stehen. Dabei spielt die Kommunikation eine wichtige Rolle - sowohl innerhalb der Organisationen selbst wie Auch gegenüber der Gesamtheit ihrer Anspruchsgruppen und der Gesellschaft als Ganzes. Von den Verantwortlichen der öffentlichen Hand wird zunehmend erwartet, dass sie die Probleme und Herausforderungen der Politik offen darlegen, getroffene Entscheidungen erklären, die dazu benötigten Mittel rechtfertigen und die Bedürfnisse und Anforderungen der Leistungsempfänger berücksichtigen.

Meeting highlights of the 8th Annual Scientific Sessions of the Society For Cardiovascular Magnetic Resonance, January 21 to 23, 2005.

Parallel tracks for clinical scientists, basic scientists, and pediatric imagers was the novel approach taken for the highly successful 8th Annual Scientific Sessions of the Society for Cardiovascular Magnetic Resonance, held in San Francisco, California, January 21 to 23, 2005. Attendees were immersed in information on the latest scientific advances in cardiovascular magnetic resonance (CMR) from mice to man and technological advances from systems with field strengths from 0.5 T to 11.7 T. State-of-the-art applications were reviewed, spanning a wide range from molecular imaging to predicting outcome with CMR in large patient populations.