Effects of physiological self-crowding of DNA on shape and biological properties of DNA molecules with various levels of supercoiling.

DNA in bacterial chromosomes and bacterial plasmids is supercoiled. DNA supercoiling is essential for DNA replication and gene regulation. However, the density of supercoiling in vivo is circa twice smaller than in deproteinized DNA molecules isolated from bacteria. What are then the specific advantages of reduced supercoiling density that is maintained in vivo? Using Brownian dynamics simulations and atomic force microscopy we show here that thanks to physiological DNA-DNA crowding DNA molecules with reduced supercoiling density are still sufficiently supercoiled to stimulate interaction between cis-regulatory elements. On the other hand, weak supercoiling permits DNA molecules to modulate their overall shape in response to physiological changes in DNA crowding. This plasticity of DNA shapes may have regulatory role and be important for the postreplicative spontaneous segregation of bacterial chromosomes.

Characterization of the effects of radiation therapy on the tumour microenvironment and their consequences on cancer progression

RESUME La radiothérapie est utilisée avec succès pour le traitement d'un grand nombre de pathologies tumorales (1). Cependant, les récidives post-actiniques sont associées à un risque accru de développer des métastases régionales et à distance (2, 3). La prise en charge de ce type de patients demeure insatisfaisante à l'heure actuelle, principalement parce que les mécanismes physio-pathologiques sous- sous-jacents restent mal compris. Etant donné le rôle primordial du stroma dans la progression tumorale (4) et l'importance des effets de la radiothérapie sur le micro-environnement des tumeurs (5), nous avons émis l'hypothèse que la radiothérapie pouvait engendrer des modifications stromales susceptibles de contribuer à l'émergence d'un phénotype tumoral plus agressif. Nous avons observé que l'exposition préalable d'un environnement tumoral à des radiations ionisantes engendre une inhibition locale et à long terme de l'angiogenèse. Cette inhibition conduit à la création d'un environnement tumoral hypoxique favorisant l'invasion et la métastatisation tumorale. Les mécanismes sous-jacents impliquent l'activation de gènes prométastatiques sous le contrôle du facteur de transcription HIF-1, ainsi que la sélection hypoxique de cellules hautement invasives et métastatiques. Par des analyses de profile d'expression génétique ainsi que par des analyses fonctionnelles, nous avons identifié la protéine matri-cellulaire CYR61 ainsi que ses partenaires d'interaction, les intégrines aVb5/aVb3, comme médiateurs importants de ces effets. De plus, une corrélation significative a également été trouvée entre le niveau d'expression de CYR61 et le taux d'hypoxie dans un grand nombre de carcinomes mammaires chez l'humain. Une association a aussi été observée entre le niveau d'expression de CYR61 et le pronostic de patientes souffrant d'un cancer du sein traité par chimiothérapie adjuvante. Globalement ces résultats identifient l'interaction entre la protéine CYR61 et ses récepteurs aVb5/aVb3 comme un mécanisme important du processus de métastatisation et en font une cible thérapeutique potentielle pour le traitement de patients souffrant d'une récidive tumorale après un traitement de radiothérapie. Finalement, bien que l'inhibition de l'angiogenèse soit locale dans ce cas particulier, nos résultats justifient une surveillance particulière des patients souffrant d'une pathologie tumorale et étant au bénéfice d'un traitement inhibiteur de l'angiogenèse. SUMMARY Radiotherapy is successfully used to treat a large variety of tumours (1 ). However, cancer patients experiencing local recurrent disease after radiation therapy are at increased risk of developing regional and distant metastasis (2, 3). The clinical management of this condition represents a difficult and challenging issue, mainly because the underlying physio-pathological mechanisms remain poorly understood. Given the well established role of the tumour stroma in promoting cancer progression (4) and since radiotherapy is known to persistently alter the tumour microenvironment (5), we hypothesized that ionising radiations may generate stromal modifications contributing to the metastatic spread of relapsing tumours. Here, we report that irradiation of the prospective tumour microenvironment promotes tumour invasion and metastasis through a mechanism of local and sustained impairment of angiogenesis leading to both HIF-1 dependent activation of pro-metastatic genes and hypoxia-mediated selection of highly metastatic tumour cell variants. Through gene expression profiling and functional experiments, we identified the matricellular signalling protein CYR61 and its interaction partners aVb5/ aVb3 integrins as critical mediators of these effects. Furthermore, we found a significant correlation between CYR61 expression and the hypoxic status of a large number of human mammary carcinomas. A positive correlation between increased levels of CYR61 expression and shorter relapse free survival was also identified in breast cancer patients treated with adjuvant chemotherapy. Together, these results identify CYR61 and aVb5/aVb3 integrins as critical mediators of metastasis and potential therapeutic targets to improve outcome in patients with post-radiation tumour recurrences. Finally, although inhibition of angiogenesis is local in this setting, our data warrant close monitoring of tumour progression in patients under anti-angiogenic therapy.

The Effect of Amifostine on Acute and Late Radiation Side Effects in Head and Neck Cancer Patients

Objective: We aimed to investigate the effect of amifostine on acute and late side effects, and its tolerability in head and neck cancer patients treated with radiotherapy (RT). Material and Methods: The study included 87 patients with primary head and neck cancers and cervical lymph node metastases from unknown primary cancers treated with RT alone or combined with chemotherapy (CT). Forty-one patients (47%) received amifostine combined with RT (ART group) and 46 patients (52%) received RT without amifostine (RT group). The patients were evaluated every week during the treatment and at month 1 and 2 after the completion of RT for acute side effects and month 3, 6, 9, 12, and 24 after the treatment for late side effects according to SOMA/LENT scale. Amifostine was administered prior to RT, along with anti-emetic prophylaxis. The two groups were compared with the Student's t and Mann-Whitney U and Chi-square tests. Results: The ART group had significantly less toxicity (grade! 1 mucositis, grade 2 fibrosis) than patients in the RT group (p=0.001, p=0.03, respectively). At week 3 of RT grade 2 mucositis developed in two patients (5%) in the ART group and 10 patients (22%) in the RT group (p=0.02). The protective effect of amifostine on skin reactions developed at week 4 of RT (p=0.05). Grade 3 xerostomia at 9, 12, and 15 months of follow-up (p=0.02, p=0.02, and p=0.02, respectively), grade 2 xerostomia at 18 and 24 months (p=0.02 and p=0.01, respectively) and fibrosis at 15, 18 and 24 months (p=0.05, p=0.02 and p=0.02, respectively) decreased markedly in the ART group compared with the RT group. Emesis was the most common adverse effect of amifostine. Conclusion: Daily administration of amifostine during RT was effective in avoiding late grade 2-3 xerostomia, as well as grade 2 fibrosis.

Disentangling the effects of key innovations on the diversification of Bromelioideae (bromeliaceae).

The evolution of key innovations, novel traits that promote diversification, is often seen as major driver for the unequal distribution of species richness within the tree of life. In this study, we aim to determine the factors underlying the extraordinary radiation of the subfamily Bromelioideae, one of the most diverse clades among the neotropical plant family Bromeliaceae. Based on an extended molecular phylogenetic data set, we examine the effect of two putative key innovations, that is, the Crassulacean acid metabolism (CAM) and the water-impounding tank, on speciation and extinction rates. To this aim, we develop a novel Bayesian implementation of the phylogenetic comparative method, binary state speciation and extinction, which enables hypotheses testing by Bayes factors and accommodates the uncertainty on model selection by Bayesian model averaging. Both CAM and tank habit were found to correlate with increased net diversification, thus fulfilling the criteria for key innovations. Our analyses further revealed that CAM photosynthesis is correlated with a twofold increase in speciation rate, whereas the evolution of the tank had primarily an effect on extinction rates that were found five times lower in tank-forming lineages compared to tank-less clades. These differences are discussed in the light of biogeography, ecology, and past climate change.

Coloration signals the ability to cope with elevated stress hormones: effects of corticosterone on growth of barn owls are associated with melanism.

Stressful situations during development can shape the phenotype for life by provoking a trade-off between development and survival. Stress hormones, mainly glucocorticoids, play an important orchestrating role in this trade-off. Hence, how stress sensitive an animal is critically determines the phenotype and ultimately fitness. In several species, darker eumelanic individuals are less sensitive to stressful conditions than less eumelanic conspecifics, which may be due to the pleiotropic effects of genes affecting both coloration and physiological traits. We experimentally tested whether the degree of melanin-based coloration is associated with the sensitivity to an endocrine response to stressful situations in the barn owl. We artificially administered the mediator of a hormonal stress response, corticosterone, to nestlings to examine the prediction that corticosterone-induced reduction in growth rate is more pronounced in light eumelanic nestlings than in darker nest mates. To examine whether such an effect may be genetically determined, we swapped hatchlings between randomly chosen pairs of nests. We first showed that corticosterone affects growth and, thus, shapes the phenotype. Second, we found that under corticosterone administration, nestlings with large black spots grew better than nestlings with small black spots. As in the barn owl the expression of eumelanin-based coloration is heritable and not sensitive to environmental conditions, it is therefore a reliable, genetically based sign of the ability to cope with an increase in blood corticosterone level.

Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis.

Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk. The biological effects of these low doses of IR on the healthy tissue surrounding the tumor area, and in particular on the vasculature remain largely to be determined. We found that doses of IR lower or equal to 0.8 Gy enhance endothelial cell migration without impinging on cell proliferation or survival. Moreover, we show that low-dose IR induces a rapid phosphorylation of several endothelial cell proteins, including the Vascular Endothelial Growth Factor (VEGF) Receptor-2 and induces VEGF production in hypoxia mimicking conditions. By activating the VEGF Receptor-2, low-dose IR enhances endothelial cell migration and prevents endothelial cell death promoted by an anti-angiogenic drug, bevacizumab. In addition, we observed that low-dose IR accelerates embryonic angiogenic sprouting during zebrafish development and promotes adult angiogenesis during zebrafish fin regeneration and in the murine Matrigel assay. Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis and that these effects were prevented by the administration of a VEGF receptor-tyrosine kinase inhibitor immediately before IR exposure. These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR and may provide a new rationale basis to the improvement of current radiotherapy protocols.

Estimation of the radiation risks in diagnostic procedures to populations and patients

Since 1895, when X-rays were discovered, ionizing radiation became part of our life. Its use in medicine has brought significant health benefits to the population globally. The benefit of any diagnostic procedure is to reduce the uncertainty about the patient's health. However, there are potential detrimental effects of radiation exposure. Therefore, radiation protection authorities have become strict regarding the control of radiation risks.¦There are various situations where the radiation risk needs to be evaluated. International authority bodies point to the increasing number of radiologic procedures and recommend population surveys. These surveys provide valuable data to public health authorities which helps them to prioritize and focus on patient groups in the population that are most highly exposed. On the other hand, physicians need to be aware of radiation risks from diagnostic procedures in order to justify and optimize the procedure and inform the patient.¦The aim of this work was to examine the different aspects of radiation protection and investigate a new method to estimate patient radiation risks.¦The first part of this work concerned radiation risk assessment from the regulatory authority point of view. To do so, a population dose survey was performed to evaluate the annual population exposure. This survey determined the contribution of different imaging modalities to the total collective dose as well as the annual effective dose per caput. It was revealed that although interventional procedures are not so frequent, they significantly contribute to the collective dose. Among the main results of this work, it was shown that interventional cardiological procedures are dose-intensive and therefore more attention should be paid to optimize the exposure.¦The second part of the project was related to the patient and physician oriented risk assessment. In this part, interventional cardiology procedures were studied by means of Monte Carlo simulations. The organ radiation doses as well as effective doses were estimated. Cancer incidence risks for different organs were calculated for different sex and age-at-exposure using the lifetime attributable risks provided by the Biological Effects of Ionizing Radiations Report VII. Advantages and disadvantages of the latter results were examined as an alternative method to estimate radiation risks. The results show that this method is the most accurate, currently available, to estimate radiation risks. The conclusions of this work may guide future studies in the field of radiation protection in medicine.¦-¦Depuis la découverte des rayons X en 1895, ce type de rayonnement a joué un rôle important dans de nombreux domaines. Son utilisation en médecine a bénéficié à la population mondiale puisque l'avantage d'un examen diagnostique est de réduire les incertitudes sur l'état de santé du patient. Cependant, leur utilisation peut conduire à l'apparition de cancers radio-induits. Par conséquent, les autorités sanitaires sont strictes quant au contrôle du risque radiologique.¦Le risque lié aux radiations doit être estimé dans différentes situations pratiques, dont l'utilisation médicale des rayons X. Les autorités internationales de radioprotection indiquent que le nombre d'examens et de procédures radiologiques augmente et elles recommandent des enquêtes visant à déterminer les doses de radiation délivrées à la population. Ces enquêtes assurent que les groupes de patients les plus à risque soient prioritaires. D'un autre côté, les médecins ont également besoin de connaître le risque lié aux radiations afin de justifier et optimiser les procédures et informer les patients.¦Le présent travail a pour objectif d'examiner les différents aspects de la radioprotection et de proposer une manière efficace pour estimer le risque radiologique au patient.¦Premièrement, le risque a été évalué du point de vue des autorités sanitaires. Une enquête nationale a été réalisée pour déterminer la contribution des différentes modalités radiologiques et des divers types d'examens à la dose efficace collective due à l'application médicale des rayons X. Bien que les procédures interventionnelles soient rares, elles contribuent de façon significative à la dose délivrée à la population. Parmi les principaux résultats de ce travail, il a été montré que les procédures de cardiologie interventionnelle délivrent des doses élevées et devraient donc être optimisées en priorité.¦La seconde approche concerne l'évaluation du risque du point de vue du patient et du médecin. Dans cette partie, des procédures interventionnelles cardiaques ont été étudiées au moyen de simulations Monte Carlo. La dose délivrée aux organes ainsi que la dose efficace ont été estimées. Les risques de développer des cancers dans plusieurs organes ont été calculés en fonction du sexe et de l'âge en utilisant la méthode établie dans Biological Effects of Ionizing Radiations Report VII. Les avantages et inconvénients de cette nouvelle technique ont été examinés et comparés à ceux de la dose efficace. Les résultats ont montré que cette méthode est la plus précise actuellement disponible pour estimer le risque lié aux radiations. Les conclusions de ce travail pourront guider de futures études dans le domaine de la radioprotection en médicine.

Feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated concomitant-boost radiation therapy.

OBJECTIVE: To assess the feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated radiotherapy (RT). DESIGN: Retrospective study. SETTING: University of Lausanne, Lausanne, Switzerland. PATIENTS: Thirty-three consecutive patients (male-female ratio, 4.5; median age, 54 years [age range, 39-76 years]). INTERVENTIONS: Between November 2000 and January 2003, the 33 patients were treated with curative definitive (n = 19) or postoperative (n = 14) RT with (n = 26) or without (n = 7) chemotherapy. All patients received conformal RT. Fractionation schedule consisted of concomitant-boost (Friday afternoon session) accelerated RT using 70 Gy (2 Gy per fraction) in 6 weeks in patients treated with definitive RT and 66 Gy (2 Gy per fraction) in 5 weeks and 3 days in the postoperative setting. Parotid glands received at least 50 Gy in all patients. Amifostine was administered to a total dose of 500 mg subcutaneously, 15 to 30 minutes before morning RT sessions. RESULTS: All patients received their planned treatment (including chemotherapy). Ten patients received the full schedule of amifostine (at least 25 injections), 9 received 20 to 24 doses, 4 received 10 to 19 doses, 5 received 5 to 9 doses, and 5 received fewer than 5 doses. Fifteen patients (45%) did not show any intolerance related to amifostine use. Amifostine therapy was discontinued because of nausea in 11 patients (33%) and hypotension in 6 patients (18%), and 1 patient refused treatment. No grade 3, amifostine-related, cutaneous toxic effects were observed. Radiotherapy-induced grade 3 acute toxic effects included mucositis in 14 patients (42%), erythema in 14 patients (42%), and dysphagia in 13 patients (39%). Late toxic effects included grade 2 or more xerostomia in 17 patients (51%) and fibrosis in 3 patients (9%). Grade 2 or more xerostomia was observed in 8 (42%) of 19 patients receiving 20 injections or more vs 9 (64%) of 14 patients receiving fewer than 20 injections (P = .15). CONCLUSIONS: Subcutaneous amifostine administration in combination with accelerated concomitant-boost RT with or without chemotherapy is feasible. The major adverse effect of subcutaneous administration was nausea despite prophylactic antiemetic medication, and hypotension was observed in only 6 patients (18%).

Effects of corticosterone pellets on baseline and stress-induced corticosterone and corticosteroid-binding-globulin.

Exogenous administration of glucocorticoids is a widely used and efficient tool to investigate the effects of elevated concentrations of these hormones in field studies. Because the effects of corticosterone are dose and duration-dependent, the exact course of plasma corticosterone levels after exogenous administration needs to be known. We tested the performance of self-degradable corticosterone pellets (implanted under the skin) in elevating plasma corticosterone levels. We monitored baseline (sampled within 3min after capture) total corticosterone levels and investigated potential interactions with corticosteroid-binding-globulin (CBG) capacity and the endogenous corticosterone response to handling in Eurasian kestrel Falco tinnunculus and barn owl Tyto alba nestlings. Corticosterone pellets designed for a 7-day-release in rodents elevated circulating baseline total corticosterone during only 2-3 days compared to placebo-nestlings. Highest levels occurred 1-2days after implantation and levels decreased strongly thereafter. CBG capacity was also increased, resulting in a smaller, but still significant, increase in baseline free corticosterone levels. The release of endogenous corticosterone as a response to handling was strong in placebo-nestlings, but absent 2 and 8 days after corticosterone pellet implantation. This indicates a potential shut-down of the hypothalamo-pituitary-adrenal axis after the 2-3 days of elevated baseline corticosterone levels. 20 days after pellet implantation, the endogenous corticosterone response to handling of nestlings implanted with corticosterone pellets attained similar levels as in placebo-nestlings. Self-degradable pellets proved to be an efficient tool to artificially elevate circulating baseline corticosterone especially in field studies, requiring only one intervention. The resulting peak-like elevation of circulating corticosterone, the concomitant elevation of CBG capacity, and the absence of an endogenous corticosterone response to an acute stressor have to be taken into account.

Visual representation of food in the brain : effects of repeated exposure and gut hormone secretion

The thesis at hand is concerned with the spatio-temporal brain mechanisms of visual food perception as investigated by electrical neuroimaging. Due to the increasing prevalence of obesity and its associated challenges for public health care, there is a need to better understand behavioral and brain processes underlying food perception and food-based decision-making. The first study (Study A) of this thesis was concerned with the role of repeated exposure to visual food cues. In our everyday lives we constantly and repeatedly encounter food and these exposures influence our food choices and preferences. In Study A, we therefore applied electrical neuroimaging analyses of visual evoked potentials to investigate the spatio-temporal brain dynamics linked to the repeated viewing of high- and low-energy food cues (published manuscript: "The role of energetic value in dynamic brain response adaptation during repeated food image viewing" (Lietti et al., 2012)). In this study, we found that repetitions differentially affect behavioral and brain mechanisms when high-energy, as opposed to low-energy foods and non-food control objects, were viewed. The representation of high-energy food remained invariant between initial and repeated exposures indicating that the sight of high-energy dense food induces less behavioral and neural adaptation than the sight of low-energy food and non-food control objects. We discuss this finding in the context of the higher salience (due to greater motivation and higher reward or hedonic valuation) of energy- dense food that likely generates a more mnemonically stable representation. In turn, this more invariant representation of energy-dense food is supposed to (partially) explain why these foods are over-consumed despite of detrimental health consequences. In Study Β we investigated food responsiveness in patients who had undergone Roux-en-Y gastric bypass surgery to overcome excessive obesity. This type of gastric bypass surgery is not only known to alter food appreciation, but also the secretion patterns of adipokines and gut peptides. Study Β aimed at a comprehensive and interdisciplinary investigation of differences along the gut-brain axis in bypass-operated patients as opposed to weight-matched non-operated controls. On the one hand, the spatio-temporal brain dynamics to the visual perception of high- vs. low-energy foods under differing states of motivation towards food intake (i.e. pre- and post-prandial) were assessed and compared between groups. On the other hand, peripheral gut hormone measures were taken in pre- and post-prandial nutrition state and compared between groups. In order to evaluate alterations in the responsiveness along the gut-brain-axis related to gastric bypass surgery, correlations between both measures were compared between both participant groups. The results revealed that Roux-en- Y gastric bypass surgery alters the spatio-temporal brain dynamics to the perception of high- and low-energy food cues, as well as the responsiveness along the gut-brain-axis. The potential role of these response alterations is discussed in relation to previously observed changes in physiological factors and food intake behavior post-Roux-en-Y gastric bypass surgery. By doing so, we highlight potential behavioral, neural and endocrine (i.e. gut hormone) targets for the future development of intervention strategies for deviant eating behavior and obesity. Together, the studies showed that the visual representation of foods in the brain is plastic and that modulations in neural activity are already noted at early stages of visual processing. Different factors of influence such as a repeated exposure, Roux-en-Y gastric bypass surgery, motivation (nutrition state), as well as the energy density of the visually perceived food were identified. En raison de la prévalence croissante de l'obésité et du défi que cela représente en matière de santé publique, une meilleure compréhension des processus comportementaux et cérébraux liés à la nourriture sont nécessaires. En particulier, cette thèse se concentre sur l'investigation des mécanismes cérébraux spatio-temporels liés à la perception visuelle de la nourriture. Nous sommes quotidiennement et répétitivement exposés à des images de nourriture. Ces expositions répétées influencent nos choix, ainsi que nos préférences alimentaires. La première étude (Study A) de cette thèse investigue donc l'impact de ces exposition répétée à des stimuli visuels de nourriture. En particulier, nous avons comparé la dynamique spatio-temporelle de l'activité cérébrale induite par une exposition répétée à des images de nourriture de haute densité et de basse densité énergétique. (Manuscrit publié: "The role of energetic value in dynamic brain response adaptation during repeated food image viewing" (Lietti et al., 2012)). Dans cette étude, nous avons pu constater qu'une exposition répétée à des images représentant de la nourriture de haute densité énergétique, par opposition à de la nourriture de basse densité énergétique, affecte les mécanismes comportementaux et cérébraux de manière différente. En particulier, la représentation neurale des images de nourriture de haute densité énergétique est similaire lors de l'exposition initiale que lors de l'exposition répétée. Ceci indique que la perception d'images de nourriture de haute densité énergétique induit des adaptations comportementales et neurales de moindre ampleur par rapport à la perception d'images de nourriture de basse densité énergétique ou à la perception d'une « catégorie contrôle » d'objets qui ne sont pas de la nourriture. Notre discussion est orientée sur les notions prépondérantes de récompense et de motivation qui sont associées à la nourriture de haute densité énergétique. Nous suggérons que la nourriture de haute densité énergétique génère une représentation mémorielle plus stable et que ce mécanisme pourrait (partiellement) être sous-jacent au fait que la nourriture de haute densité énergétique soit préférentiellement consommée. Dans la deuxième étude (Study Β) menée au cours de cette thèse, nous nous sommes intéressés aux mécanismes de perception de la nourriture chez des patients ayant subi un bypass gastrique Roux- en-Y, afin de réussir à perdre du poids et améliorer leur santé. Ce type de chirurgie est connu pour altérer la perception de la nourriture et le comportement alimentaire, mais également la sécrétion d'adipokines et de peptides gastriques. Dans une approche interdisciplinaire et globale, cette deuxième étude investigue donc les différences entre les patients opérés et des individus « contrôles » de poids similaire au niveau des interactions entre leur activité cérébrale et les mesures de leurs hormones gastriques. D'un côté, nous avons investigué la dynamique spatio-temporelle cérébrale de la perception visuelle de nourriture de haute et de basse densité énergétique dans deux états physiologiques différent (pre- et post-prandial). Et de l'autre, nous avons également investigué les mesures physiologiques des hormones gastriques. Ensuite, afin d'évaluer les altérations liées à l'intervention chirurgicale au niveau des interactions entre la réponse cérébrale et la sécrétion d'hormone, des corrélations entre ces deux mesures ont été comparées entre les deux groupes. Les résultats révèlent que l'intervention chirurgicale du bypass gastrique Roux-en-Y altère la dynamique spatio-temporelle de la perception visuelle de la nourriture de haute et de basse densité énergétique, ainsi que les interactions entre cette dernière et les mesures périphériques des hormones gastriques. Nous discutons le rôle potentiel de ces altérations en relation avec les modulations des facteurs physiologiques et les changements du comportement alimentaire préalablement déjà démontrés. De cette manière, nous identifions des cibles potentielles pour le développement de stratégies d'intervention future, au niveau comportemental, cérébral et endocrinien (hormones gastriques) en ce qui concerne les déviances du comportement alimentaire, dont l'obésité. Nos deux études réunies démontrent que la représentation visuelle de la nourriture dans le cerveau est plastique et que des modulations de l'activité neurale apparaissent déjà à un stade très précoce des mécanismes de perception visuelle. Différents facteurs d'influence comme une exposition repetee, le bypass gastrique Roux-en-Y, la motivation (état nutritionnel), ainsi que la densité énergétique de la nourriture qui est perçue ont pu être identifiés.

Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/-) mice.

Light influences sleep and alertness either indirectly through a well-characterized circadian pathway or directly through yet poorly understood mechanisms. Melanopsin (Opn4) is a retinal photopigment crucial for conveying nonvisual light information to the brain. Through extensive characterization of sleep and the electrocorticogram (ECoG) in melanopsin-deficient (Opn4(-/-)) mice under various light-dark (LD) schedules, we assessed the role of melanopsin in mediating the effects of light on sleep and ECoG activity. In control mice, a light pulse given during the habitual dark period readily induced sleep, whereas a dark pulse given during the habitual light period induced waking with pronounced theta (7-10 Hz) and gamma (40-70 Hz) activity, the ECoG correlates of alertness. In contrast, light failed to induce sleep in Opn4(-/-) mice, and the dark-pulse-induced increase in theta and gamma activity was delayed. A 24-h recording under a LD 1-hratio1-h schedule revealed that the failure to respond to light in Opn4(-/-) mice was restricted to the subjective dark period. Light induced c-Fos immunoreactivity in the suprachiasmatic nuclei (SCN) and in sleep-active ventrolateral preoptic (VLPO) neurons was importantly reduced in Opn4(-/-) mice, implicating both sleep-regulatory structures in the melanopsin-mediated effects of light. In addition to these acute light effects, Opn4(-/-) mice slept 1 h less during the 12-h light period of a LD 12ratio12 schedule owing to a lengthening of waking bouts. Despite this reduction in sleep time, ECoG delta power, a marker of sleep need, was decreased in Opn4(-/-) mice for most of the (subjective) dark period. Delta power reached after a 6-h sleep deprivation was similarly reduced in Opn4(-/-) mice. In mice, melanopsin's contribution to the direct effects of light on sleep is limited to the dark or active period, suggesting that at this circadian phase, melanopsin compensates for circadian variations in the photo sensitivity of other light-encoding pathways such as rod and cones. Our study, furthermore, demonstrates that lack of melanopsin alters sleep homeostasis. These findings call for a reevaluation of the role of light on mammalian physiology and behavior.

Traitement non chirurgical des rectites postactiniques ou radiques chroniques [Non-surgical treatment of acute and late radiation proctitis]

Pelvic external radiotherapy with or without brachytherapy plays an important role in the management of pelvic cancers. Despite recent technical innovations including conformal three-dimensional (3D) external beam radiotherapy and more recently intensity modulated radiotherapy (IMRT), local side effects can occur secondary to normal tissue damage caused by ionising radiation. Morbidity depends on the anatomic position of the rectum within the pelvis and the fast turnover rate of the mucosa, as well as the characteristics of the radiation treatment and patient co-morbidities. Medical management is sometimes complex and merits herein a short review.

Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: implications for secondary cancer risk assessment.

To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart).

Protection from radiation-induced colitis requires MHC class II antigen expression by cells of hemopoietic origin.

Ulcerative colitis, an inflammatory bowel disease, is believed to result from a breakdown of dominant tolerance mechanisms that normally control intestinal immunity. Although CD4+ T lymphocyte subpopulations and expression of MHC class II molecules have been shown to play a role in the pathogenesis of the disease, the nature of the responsible mechanisms remains unclear. In this paper we describe a novel mouse model for inflammatory bowel disease, radiation-induced colitis, that occurs with complete penetrance 6-8 wk postinduction. A combination of high dose gamma-irradiation and lack of MHC class II expression on cells of hemopoietic origin results in development of colitis in C57BL/6 mice. Because of its versatility (due to susceptibility of mice of the widely genetically manipulated C57BL/6 background), high reproducibility, and 100% penetrance, radiation-induced colitis will be a useful mouse model for colitis and a significant tool to study dominant immunological tolerance mechanisms. Moreover, our data imply that tolerization to enteric Ags requires MHC class II mediated presentation by APC of hemopoietic origin.