Le rôle du stress oxydant dans les changements épigénétiques contribuant aux complications du syndrome métabolique.

La méthylation de l'ADN est l'une des modifications épigénétiques au niveau des îlots CpG. Cette modification épigénétique catalysée par les ADN méthyltransférases (DNMTs) consiste en la méthylation du carbone 5' d’une cytosine ce qui aboutit à la formation de 5-méthylcytosine. La méthylation de l'ADN est clairement impliquée dans l'inactivation des gènes et dans l'empreinte génétique. Elle est modulée par la nutrition, en particulier par les donneurs de méthyle et par une restriction protéique. Ces modifications épigénétiques persistent plus tard dans la vie et conduisent au développement de nombreuses pathologies telles que le syndrome métabolique et le diabète de type 2. En fait, de nombreux gènes clés subissent une modification de leur état de méthylation en présence des composants du syndrome métabolique. Cela montre que la méthylation de l'ADN est un processus important dans l'étiologie du syndrome métabolique. Le premier travail de ce doctorat a porté sur la rédaction d’un article de revue qui a examiné le cadre central du syndrome métabolique et analyser le rôle des modifications épigénétiques susceptibles d'influer sur l'apparition du stress oxydant et des complications cardiométaboliques. D’autre part, les cellules intestinales Caco-2/15, qui ont la capacité de se différencier et d’acquérir les caractéristiques physiologiques de l'intestin grêle, ont été utilisées et traitées avec du Fer-Ascorbate pour induire un stress oxydant. Le Fer-Ascorbate a induit une augmentation significative de l’inflammation et de la peroxydation des lipides (malondialdehyde) ainsi que des altérations de de la défense antioxydante (SOD2 et GPx) accompagnées de modifications épigénétiques. De plus, la pré-incubation des cellules avec de la 5-aza-2'-désoxycytidine, un agent de déméthylation et/ou l’antioxydant Trolox a normalisé la défense antioxydante, réduit la peroxydation des lipides et prévenu l'inflammation. Ce premier travail a démontré que les modifications du redox et l’inflammation induites par le Fer-Ascorbate peuvent impliquer des changements épigénétiques, plus particulièrement des changements dans la méthylation de l’ADN. Pour mieux définir l’impact du stress oxydant au niveau nutritionnel, des cochons d’Inde âgés de trois jours ont été séparés en trois groupes : 1) Témoins: alimentation régulière; 2) Nutrition parentérale (NP) 3) H2O2 : Témoins + 350 uM H2O2. Après quatre jours, pour un groupe, les perfusions ont été stoppées et les animaux sacrifiés pour la collecte des foies. Pour l’autre groupe d’animaux, les perfusions ont été arrêtées et les animaux ont eu un accès libre à une alimentation régulière jusqu'à la fin de l’étude, huit semaines plus tard où ils ont été sacrifiés pour la collecte des foies. Ceci a démontré qu’à une semaine de vie, l'activité DNMT et les niveaux de 5'-méthyl-2'-désoxycytidine étaient inférieurs pour les groupes NP et H2O2 par rapport aux témoins. A neuf semaines de vie, l’activité DNMT est restée basse pour le groupe NP alors que les niveaux de 5'-méthyl-2'-désoxycytidine étaient plus faibles pour les groupes NP et H2O2 par rapport aux témoins. Ce travail a démontré que l'administration de NP ou de H2O2, tôt dans la vie, induit une hypométhylation de l'ADN persistante en raison d'une inhibition de l'activité DNMT. Finalement, des souris ayant reçu une diète riche en gras et en sucre (HFHS) ont été utilisées comme modèle in vivo de syndrome métabolique. Les souris ont été nourris soit avec un régime standard chow (témoins), soit avec une diète riche en gras et en sucre (HFHS) ou avec une diète HFHS en combinaison avec du GFT505 (30 mg/kg), un double agoniste de PPARα et de PPARδ, pendant 12 semaines. La diète HFHS était efficace à induire un syndrome métabolique étant donnée l’augmentation du poids corporel, du poids hépatique, des adiposités viscérales et sous-cutanées, de l’insensibilité à l’insuline, des lipides plasmatiques et hépatiques, du stress oxydant et de l’inflammation au niveau du foie. Ces perturbations étaient accompagnées d’une déficience dans l’expression des gènes hépatiques PPARα et PPARγ concomitant avec une hyperméthylation de leurs promoteurs respectifs. L’ajout de GFT505 à la diète HFHS a empêché la plupart des effets cardiométaboliques induits par la diète HFHS via la modulation négative de l’hyperméthylation des promoteurs, résultant en l’augmentation de l’expression des gènes hépatiques PPARα et PPARγ. En conclusion, GFT505 exerce des effets métaboliques positifs en améliorant le syndrome métabolique induit par l'alimentation HFHS via des modifications épigénétiques des gènes PPARs. Ensemble, les travaux de cette thèse ont démontré que le stress oxydant provenant de la nutrition induit d’importants changements épigénétiques pouvant conduire au développement du syndrome métabolique. La nutrition apparait donc comme un facteur crucial dans la prévention de la reprogrammation fœtale et du développement du syndrome métabolique. Puisque les mécanismes suggèrent que le stress oxydant agit principalement sur les métabolites du cycle de la méthionine pour altérer l’épigénétique, une supplémentation en ces molécules ainsi qu’en antioxydants permettrait de restaurer l’équilibre redox et épigénétique.

Pathogenèse de l’oedème cérébral dans l’encéphalopathie hépatique minimale : rôles du stress oxydatif et du lactate

L’encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique découlant des complications de l'insuffisance hépatique. Les patients souffrant d'une insuffisance hépatique chronique (IHC) présentent fréquemment une EH minimale (EHM) caractérisée par des dysfonctions cognitives subtiles qui affectent leur qualité de vie. L'insuffisance hépatique entraîne une hyperammoniémie, le facteur central dans la pathogenèse de l'EH. Pourtant, les taux d'ammoniaque sérique ne sont pas corrélés avec la sévérité de l'EH lors d'une IHC, suggérant que d'autres facteurs y contribuent. L'oedème cérébral est une caractéristique neuropathologique décrite chez les patients souffrant d'une EHM et plusieurs facteurs dont le stress oxydatif, les altérations du métabolisme énergétique et l'augmentation de la glutamine cérébrale pourraient contribuer à la pathogenèse de l'oedème cérébral lors d'une EHM induite par une IHC. Les mécanismes sous-jacents exacts ainsi que les relations entre ces facteurs et l'ammoniaque ne sont pas connus. Présentement, le seul traitement efficace de l'IHC est la transplantation hépatique, une option thérapeutique très limitée. Le but de cette thèse est de contribuer à l'avancement des connaissances sur les mécanismes sous-jacents liés au rôle du stress oxydatif, de la glutamine et du lactate dans la pathogenèse de l'oedème cérébral lors d'une EHM induite par une IHC afin d'envisager de nouvelles options thérapeutiques. Les objectifs précis étaient: 1. Établir le rôle de l’ammoniaque et sa relation avec le stress oxydatif dans la pathogenèse de l'oedème cérébral lors d'une EHM induite par une IHC. 2. Établir le rôle du stress oxydatif dans la pathogenèse de l'oedème cérébral, sa relation avec l'ammoniaque et l'effet du traitement avec des antioxydants. 3. Confirmer l'effet synergique entre l'ammoniaque et le stress oxydatif dans la pathogenèse de l'oedème cérébral. 4. Établir le rôle du lactate et de la glutamine dans la pathogenèse de l'oedème cérébral et leur relation avec l’ammoniaque. Pour atteindre ces objectifs, 2 modèles animaux d'EHM obtenus par microchirurgie chez le rat ont été utilisés: 1) la ligature de voie biliaire, un modèle d'IHC et 2) l'anastomose porto-cave, un modèle d'hyperammoniémie induite par la dérivation portosystémique. Nos résultats démontrent que l'ammoniaque et le stress oxydatif indépendamment n'induisent pas l'oedème cérébral lors d'une EHM. Pourtant, lorsque les 2 facteurs agissent ensemble ils présentent ii un effet synergique qui entraîne le développement de l'oedème cérébral, le stress oxydatif étant une première insulte, qui est suivie par l'hyperammoniémie comme deuxième insulte. En plus, le stress oxydatif a été mis en évidence seulement au niveau systémique, et non au niveau central dans notre modèle d'IHC en association avec l'oedème cérébral, suggérant que le stress oxydatif systémique est une conséquence de la dysfonction hépatique et que l'hyperammoniémie n’induit pas le stress oxydatif ni systémique ni central. Nous avons démontré qu’une augmentation du lactate cérébral est une conséquence directe de l'hyperammoniémie et joue un rôle important dans la pathogenèse de l'oedème cérébral lors d'une EHM induite par une IHC, tandis qu’une augmentation de la glutamine au niveau cérébral n'est pas un facteur clé. La compréhension de ces mécanismes a entraîné la proposition de 3 nouvelles stratégies thérapeutiques potentielles pour l'EHM. Elles ciblent la diminution de l'ammoniaque sérique, la réduction du stress oxydatif et l'inhibition de la synthèse du lactate.

Stress Of Women Entrepreneurs a Comparative With Women In Selected Groups In The District Of Ernakulam

The focus of this study is the stress of women entrepreneurs.As stress is associated with constraints and demands, and as a set of emerging conditions seem to affect the quality of life of women, it is more than just an occasional need to enquire in to the possibilities of promoting entrepreneurship by empowering women.As women entrepreneurs are increasingly involved in inherently complicated activities of improving their enterprise functioning ,it would be appropriate for women entrepreneurs to focus on transformational coping interventions.The study is limited to women entrepreneurs in the tiny sector.Women entrepreneurs registered in the Distric Industries ( DIC) and in the Kerala State Women’s Industries Association (KSWIA) are only selected for the study.It gaves a detailed description about empowerment of women.The social , economic ,political,ecological,and psychological importance of the study are detailed.It explains the family related stress, and the contextual system.This study is suggested on beliefs and values of women about their self-perception influencing gender bias, which contribute to stress and coping.This study is also needed about women’s believes and expectations about the probable effectiveness of various course of action and their ability to perform those actions.It is also neede for appraising coping potential of women and enhancing their stress base.It is important to research on stress and self-concept

“Stress Responses of Stinging Catfish Heteropneustes fassilis (Bloch) to Organophosphorus Insecticide Monocrotophos”

Poisoning by pesticides from agricultural fields is a serious water pollution problem and its environmental long-term effect may result in the incidence of poisoning of fish and other aquatic life forms (jyothi and Narayan, 1999). Fishes like Heteropneustesfbssilis and C/arius batrac/nus are especially prone to serious pesticide pollution as their habitat is mostly the agriculture area. Though only few studies are conducted in this area, it can be assessed from the local information that, population of such fish is on the verge of vulnerability due to extensive use of pesticides. The knowledge of sublethal effects of xenobiotic compounds on hematological parameters, enzyme activities and metabolite concentrations is very important to delineate the fish health status and provide a future understanding of ecological impacts. These pesticides act by causing inhibition of cholinesterase enzymes (ChE) by formation of enzyme inhibitor complex (O'Brien, 1976) and damaging the nervous system. These effects may result in metabolic disorders. Associated to cholinesterase activities, a study of other enzymes such as phosphatases and aminotransferases close to intermediary metabolite determination provides a wider view of metabolism. Interest in toxicological aspects has grown in recent years and research is now increasingly focused on mechanistic aspects of oxidative damage and cellular responses in biological system. The term ‘biomarker’ is generally used in a broad sense to include almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical or biological (WHO, 1993). As biomarker stands for immediate responses, they are used as early warning signals of biological effects caused by environmental pollutants. The present work attempts to assess the toxicity of organophosphorus insecticide monocrotophos on the experimental organism selected for this study namely stinging catfish (Heteropneustesfossi/is) (Bloch), and to probe into the stress responses of the organism

Some bivariate life time models in discrete time"

The term reliability of an equipment or device is often meant to indicate the probability that it carries out the functions expected of it adequately or without failure and within specified performance limits at a given age for a desired mission time when put to use under the designated application and operating environmental stress. A broad classification of the approaches employed in relation to reliability studies can be made as probabilistic and deterministic, where the main interest in the former is to device tools and methods to identify the random mechanism governing the failure process through a proper statistical frame work, while the latter addresses the question of finding the causes of failure and steps to reduce individual failures thereby enhancing reliability. In the probabilistic attitude to which the present study subscribes to, the concept of life distribution, a mathematical idealisation that describes the failure times, is fundamental and a basic question a reliability analyst has to settle is the form of the life distribution. It is for no other reason that a major share of the literature on the mathematical theory of reliability is focussed on methods of arriving at reasonable models of failure times and in showing the failure patterns that induce such models. The application of the methodology of life time distributions is not confined to the assesment of endurance of equipments and systems only, but ranges over a wide variety of scientific investigations where the word life time may not refer to the length of life in the literal sense, but can be concieved in its most general form as a non-negative random variable. Thus the tools developed in connection with modelling life time data have found applications in other areas of research such as actuarial science, engineering, biomedical sciences, economics, extreme value theory etc.

Studies on the effect of Polycyclic Aromatic Hydrocarbons in the life and activity of Perna spp

In the present study an endeavour has been made to analyse the acute toxicity of WAFs of Bombay High crude and Light Diesel oil on commercially important bivalve species Perna viridis and Perna indica by static bioassay methods. The toxic effects of chemicals in the WAF on the organisms ; their tissues and eventually on rate functions have been elucidated. Marine oil pollution not only affects productivity and quality of marine organisms but also eventually affects the health of human population due to a possible health risk by way of consumption of oil contaminated seafood

Cuidar dos cuidadores : o (des)envolvimento da espiritualidade na prevenção de quadros de stress e burnout

A Humanidade anda cansada, esgotado. Um cansaço que é a soma do fardo de cada um e também parte do fardo de outros. E a Humanidade busca explicações para este cansaço. E quer aliviá-lo. E quer minimizá-lo. Mas busca muito mais que isso. Trata-se, enfim, de buscar não o remédio mas o sentido da própria existência, as respostas adedentro, ou seja, bem no interior do ser humano. O presente trabalho pretende ser uma reflexão – compreender para agir - sobre a busca da dimensão da espiritualidade como possível resposta na prevenção de quadros de stress e burnout. Quem trabalho na área da assistência e na relação de ajuda contínua com pessoas em situação de extrema fragilidade sabe que se não houver um cuidado na reposição de energias, com muita facilidade a pessoa chega a um estado de cansaço e a qualquer momento o turboadrenalina pode queimar. No âmbito da gestão de unidades sociais e bem-estar, cuidar dos cuidadores é a maior e mais nobre missão de qualquer Instituição. Pois, que serviços seriam vivenciados sem as pessoas que formam o corpo e, por isso, a vida de uma Instituição? O caminho da nossa reflexão é orientado para a Comunidade Vida e Paz, como espaço relacional que quer e procura ser um espaço de renovação de vidas – das pessoas sem abrigo – onde, amparadas por um conjunto de Cuidadores, cujo olhar se orienta num trabalho de unificação da pessoa, são imbuídos por uma espiritualidade que se quer colaborante na missão de dignificar cada pessoa e devolvê-la à sua condição original. A pessoa, cada pessoa, é a soma de si, da relação com outros e da relação com o transcendente. Na missão de cuidar, pode a espiritualidade ser ausente? Desta, retiramos um sentido coerente da existência, a verdade do dom e da dádiva e, por isso, uma vida feliz.

Relação entre factores ambientais causadores de stress e doença renal felina

A Doença Renal Crónica (DRC) é de natureza insidiosa, progressiva e irreversível e uma grande causa de morbilidade e mortalidade em gatos. O comportamento natural da espécie felina fica comprometido no meio doméstico, originando situações de stress que desempenham um papel importante na patogénese da doença crónica. A literatura sugere que a activação contínua do sistema nervoso simpático desencadeia uma série de processos fisiológicos que se traduzem por último no aparecimento de fibrose renal, contribuindo assim para a progressão da DRC. Esta dissertação pretende avaliar essa relação. Para tal, foram analisados questionários que permitissem avaliar as condições em que viviam uma amostra de 139 gatos e realizados painéis hematológicos e bioquímicos a uma sub-amostra para verificar as correlações existentes. Ainda que não tenha sido possível concluir que a presença de um parâmetro individual possa ser apontada como causa directa do desenvolvimento de DRC, podemos identificar um conjunto de factores ambientais causadores de stress como prováveis factores de risco para a degradação desta doença e a sua transição para fases mais avançadas. Desta forma, a implementação de estratégias de enriquecimento ambiental MEMO (Multimodal Environmental Modification) não só visa melhorar a qualidade de vida destes animais como se pode revelar uma chave de sucesso na prevenção e maneio de doenças crónicas.

The joint effects of larval density and C-14-cypermethrin on the life history and population growth rate of the midge Chironomus riparius

1. Chemical effects on organisms are typically assessed using individual-level endpoints or sometimes population growth rate (PGR), but such measurements are generally made at low population densities. In contrast most natural populations are subject to density dependence and fluctuate around the environmental carrying capacity as a result of individual competition for resources. As ecotoxicology aims to make reliable population projections of chemical impacts in the field, an understanding of how high-density or resource-limited populations respond to environmental chemicals is essential. 2. Our objective was to determine the joint effects of population density and chemical stress on the life history and PGR of an important ecotoxicological indicator species, Chironomus riparius, under controlled laboratory conditions. Populations were fed the same ration but initiated at different densities and exposed to a solvent control and three concentrations of C-14-cypermethrin in a sediment-water test system for 67 days at 20 +/- 1 degreesC. 3. Density had a negative effect on all the measured life-history traits, and PGR declined with increasing density in the controls. Exposure to C-14-cypermethrin had a direct negative effect on juvenile survival, presumably within the first 24 h because the chemical rapidly dissipated from the water column. Reductions in the initial larval densities resulted in an increase in the available resources for the survivors. Subsequently, exposed populations emerged sooner and started producing offspring earlier than the controls. C-14-cypermethrin had no effect on estimated fecundity and adult body weight but interacted with density to reduce the time to first emergence and first reproduction. As a result, PGR increased with cypermethrin concentration when populations were initiated at high densities. 4. Synthesis and applications. The results showed that the effects of C-14-cypermethrin were buffered at high density, so that the joint effects of density and chemical stress on PGR were less than additive. Low levels of chemical stressors may increase carrying capacity by reducing juvenile competition for resources. More and perhaps fitter adults may be produced, similar to the effects of predators and culling; however, toxicant exposure may result in survivors that are less tolerant to changing conditions. If less than additive effects are typical in the field, standard regulatory tests carried out at low density may overestimate the effects of environmental chemicals. Further studies over a wide range of chemical stressors and organisms with contrasting life histories are needed to make general recommendations.

Damage rate is a predictor of fatigue life and creep strain rate in fatigue of tensile human cortical bone samples

We present results on the growth of damage in 29 fatigue tests of human femoral cortical bone from four individuals, aged 53–79. In these tests we examine the interdependency of stress, cycles to failure, rate of creep strain, and rate of modulus loss. The behavior of creep rates has been reported recently for the same donors as an effect of stress and cycles (Cotton, J. R., Zioupos, P., Winwood, K., and Taylor, M., 2003, "Analysis of Creep Strain During Tensile Fatigue of Cortical Bone," J. Biomech. 36, pp. 943–949). In the present paper we first examine how the evolution of damage (drop in modulus per cycle) is associated with the stress level or the "normalized stress" level (stress divided by specimen modulus), and results show the rate of modulus loss fits better as a function of normalized stress. However, we find here that even better correlations can be established between either the cycles to failure or creep rates versus rates of damage than any of these three measures versus normalized stress. The data indicate that damage rates can be excellent predictors of fatigue life and creep strain rates in tensile fatigue of human cortical bone for use in practical problems and computer simulations.

Posttraumatic stress symptoms in London school children following September 11, 2001: an exploratory investigation of peri-traumatic reactions and intrusive imagery

Threatening intrusive images are central to posttraumatic stress disorder. It has been suggested that intrusive imagery in the context of a sense of threat leads to the development and persistence of posttraumatic stress symptoms. This study investigates London school children's (N = 76; age 10-11 years) self-reported posttraumatic stress symptoms in response to viewing the attacks of September 11, 2001 on television. Assessments were made at two time points. A minority of participants reported moderate-severe symptoms with functional impairment at 2 months (14.5%) and 6 months (9.2%) after viewing the September 11events. After controlling for symptom stability, persistent symptoms were associated with peri-traumatic factors, notably perceiving that one's life was in danger. The combined effect of intrusive imagery and peri-traumatic life threat was associated with symptom persistence. Assessments of intrusive image content via checklist and free-report indicated that the images were directly related to September 11 and were fairly stable over time. Implications for treating children's intrusive images following stressful events are explored. (C) 2007 Elsevier Ltd. All rights reserved.

A longitudinal analysis of self‐regulation and well-being: avoidance personal goals, avoidance coping, stress generation, and subjective well-being

We conducted 2 longitudinal meditational studies to test an integrative model of goals, stress and coping, and well‐being. Study 1 documented avoidance personal goals as an antecedent of life stressors and life stressors as a partial mediator of the relation between avoidance goals and longitudinal change in subjective well‐being (SWB). Study 2 fully replicated Study 1 and likewise validated avoidance goals as an antecedent of avoidance coping and avoidance coping as a partial mediator of the relation between avoidance goals and longitudinal change in SWB. It also showed that avoidance coping partially mediates the link between avoidance goals and life stressors and validated a sequential meditational model involving both avoidance coping and life stressors. The aforementioned results held when controlling for social desirability, basic traits, and general motivational dispositions. The findings are discussed with regard to the integration of various strands of research on self‐regulation. (PsycINFO Database Record (c) 2012 APA, all rights reserved)(journal abstract)

Purpose in life predicts better emotional recovery from negative stimuli

Purpose in life predicts both health and longevity suggesting that the ability to find meaning from life’s experiences, especially when confronting life’s challenges, may be a mechanism underlying resilience. Having purpose in life may motivate reframing stressful situations to deal with them more productively, thereby facilitating recovery from stress and trauma. In turn, enhanced ability to recover from negative events may allow a person to achieve or maintain a feeling of greater purpose in life over time. In a large sample of adults (aged 36-84 years) from the MIDUS study (Midlife in the U.S., http://www.midus.wisc.edu/), we tested whether purpose in life was associated with better emotional recovery following exposure to negative picture stimuli indexed by the magnitude of the eyeblink startle reflex (EBR), a measure sensitive to emotional state. We differentiated between initial emotional reactivity (during stimulus presentation) and emotional recovery (occurring after stimulus offset). Greater purpose in life, assessed over two years prior, predicted better recovery from negative stimuli indexed by a smaller eyeblink after negative pictures offset, even after controlling for initial reactivity to the stimuli during the picture presentation, gender, age, trait affect, and other well-being dimensions. These data suggest a proximal mechanism by which purpose in life may afford protection from negative events and confer resilience is through enhanced automatic emotion regulation after negative emotional provocation.

Maternal postnatal depression predicts altered offspring biological stress reactivity in adulthood

The offspring of depressed parents have been found to show elevated basal levels of the stress hormone cortisol. Whether heightened cortisol stress reactivity is also present in this group has yet to be clearly demonstrated. We tested whether postnatal maternal depression predicts subsequent increases in offspring biological sensitivity to social stress, as indexed by elevated cortisol reactivity. Participants (mean age 22.4-years) derived from a 22-year prospective longitudinal study of the offspring of mothers who had postnatal depression (PND group; n=38) and a control group (n=38). Salivary cortisol response to a social-evaluative threat (Trier Social Stress Test) was measured. Hierarchical linear modelling indicated that PND group offspring showed greater cortisol reactivity to the stress test than control group participants. Group differences were not explained by offspring depressive or anxiety symptoms, experiences of negative life events, elevated basal cortisol at age 13-years, subsequent exposure to maternal depression, or other key covariates. The findings indicate that the presence of early maternal depression can predict offspring biological sensitivity to social stress in adulthood, with potential implications for broader functioning.