Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound.

Exposing the human bronchial epithelial cell line BEAS-2B to the nitric oxide (NO) donor sodium 1-(N,N-diethylamino)diazen-1-ium-1, 2-diolate (DEA/NO) at an initial concentration of 0.6 mM while generating superoxide ion at the rate of 1 microM/min with the hypoxanthine/xanthine oxidase (HX/XO) system induced C:G-->T:A transition mutations in codon 248 of the p53 gene. This pattern of mutagenicity was not seen by 'fish-restriction fragment length polymorphism/polymerase chain reaction' (fish-RFLP/PCR) on exposure to DEA/NO alone, however, exposure to HX/XO led to various mutations, suggesting that co-generation of NO and superoxide was responsible for inducing the observed point mutation. DEA/NO potentiated the ability of HX/XO to induce lipid peroxidation as well as DNA single- and double-strand breaks under these conditions, while 0.6 mM DEA/NO in the absence of HX/XO had no significant effect on these parameters. The results show that a point mutation seen at high frequency in certain common human tumors can be induced by simultaneous exposure to reactive oxygen species and a NO source.

Erreurs innées du métabolisme: transition enfant-adulte [Inborn errors of metabolism: transition from childhood to adulthood].

Les erreurs innées du métabolisme (EIM) sont dues à des mutations de gènes codant pour des enzymes du métabolisme et sont classées selon trois grands groupes de maladies: 1) intoxications; 2) déficit énergétique et 3) déficit de synthèse ou catabolisme des maladies complexes. Le progrès thérapeutique des vingt dernières années a permis d'améliorer le pronostic des enfants atteints d'EIM. Ces enfants grandissent et doivent être pris en charge à l'adolescence et à l'âge adulte par des équipes spécialisées. Cette médecine métabolique pour adultes est une discipline relativement nouvelle avec une information limitée chez l'adulte. Les recommandations pédiatriques sont extrapolées à la prise en charge des adultes tout en intégrant les différentes étapes de vie (indépendance sociale, grossesse, vieillissement et éventuelles complications tardives). Inborn errors of metabolism (IEM) are due to mutations of genes coding for enzymes of intermediary metabolism and are classified into 3 broad categories: 1) intoxication, 2) energy defect and 3) cellular organelles synthesis or catabolism defect. Improvements of therapy over these last 20 years has improved prognosis of children with IEM. These children grow up and should have their transition to specialized adult care. Adult patients with IEM are a relatively new phenomenon with currently only limited knowledge. Extrapolated pediatric guidelines are applied to the adult population taking into account adult life stages (social independence, pregnancy, aging process and potential long-term complications).

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

How institutions shaped the last major evolutionary transition to large-scale human societies.

What drove the transition from small-scale human societies centred on kinship and personal exchange, to large-scale societies comprising cooperation and division of labour among untold numbers of unrelated individuals? We propose that the unique human capacity to negotiate institutional rules that coordinate social actions was a key driver of this transition. By creating institutions, humans have been able to move from the default 'Hobbesian' rules of the 'game of life', determined by physical/environmental constraints, into self-created rules of social organization where cooperation can be individually advantageous even in large groups of unrelated individuals. Examples include rules of food sharing in hunter-gatherers, rules for the usage of irrigation systems in agriculturalists, property rights and systems for sharing reputation between mediaeval traders. Successful institutions create rules of interaction that are self-enforcing, providing direct benefits both to individuals that follow them, and to individuals that sanction rule breakers. Forming institutions requires shared intentionality, language and other cognitive abilities largely absent in other primates. We explain how cooperative breeding likely selected for these abilities early in the Homo lineage. This allowed anatomically modern humans to create institutions that transformed the self-reliance of our primate ancestors into the division of labour of large-scale human social organization.

Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy

Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy

Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Drug-induced mitochondrial dysfunction and cardiotoxicity.

Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.

Hospitalisation du proche : fatigue et coping du proche aidant à l'occasion de cette transition

Le processus de vieillissement entraîne une augmentation et une complexification des besoins de soins. Or, la proportion de personnes vieillissantes dans le monde et en Suisse s'accroit. Les professionnels de la santé ne disposent pas des moyens économiques et humains pour couvrir l'ensemble des besoins de soins. Les proches aidants contribuent de manière importante à la couverture des besoins. Cette contribution devient un élément central de la politique du maintien à domicile. Cependant, l'engagement à long terme des proches aidants auprès de leur parent peut influencer négativement leur état de santé. Pour une même classe d'âge, la population des proches aidants déclare un niveau de fatigue plus élevée que le reste de la population. Dans ce contexte, la fatigue est définie comme le résultat de l'ambivalence entre la demande en soins et les ressources dont dispose le proche aidant. L'hospitalisation du parent, qu'elle soit ou non liée à la fatigue, constitue un moment de crise pour le proche aidant. Face à cette crise, l'aidant mettra en oeuvre des stratégies de coping telles que conceptualisées dans la théorie transactionnelle du stress. Dans le cadre de la théorique intermédiaire de la transition de Meleis, le coping est un indicateur de processus de la transition qui doit permettre d'appréhender la transition vécue par l'aidant à l'occasion de l'hospitalisation du parent. Avec un devis corrélationnel descriptif, cette étude décrit les caractéristiques de l'échantillon de proches aidants, et du rôle qu'ils assument. Elle décrit le degré de fatigue et les styles de coping utilisés, et explore la relation entre la fatigue et le coping du proche aidant à l'occasion de l'hospitalisation du parent. Deux questionnaires auto-administrés ont été complétés par 33 participants. Cette étude a permis de dégager les résultats suivants : le score moyen de fatigue dans cet échantillon indique une fatigue légère selon la classification établie par Piper. Les participants mettent en avant l'influence du rôle d'aidant sur leur fatigue, ainsi que l'influence de leur propre santé et des contraintes économicoprofessionnelles. Le score moyen de fatigue varie en fonction de la nature de l'aide fournie. Il est significativement plus élevé lorsque le proche aidant soutient son parent dans les activités de la vie quotidienne (AVQ). Le style de coping mobilisé préférentiellement dans cet échantillon est le coping centré sur le problème, suivi du coping centré sur la recherche du soutien social, et enfin le coping centré sur l'émotion. Les aidants soutenant leur proche dans les AVQ mobilisent plus le coping centré sur l'émotion que ceux qui n'offrent pas ce type d'aide. Les principales sources de stress nommées par les participants sont l'état de santé du parent, son hospitalisation, et la rencontre avec le système de santé. Dans cet échantillon, nous n'avons pas observé de corrélation entre le degré de fatigue et les trois styles de coping. Des limites liées à la petite taille de l'échantillon amènent à la prudence quant à la généralisation des résultats de cette étude.

Transition of young people with chronic conditions: a cross-sectional study of patient perceptions before and after transfer from pediatric to adult health care.

UNLABELLED: The aim of this study was to compare perceived barriers to and the most preferred age for successful transition to adult health care between young people with chronic disorders who had not yet transferred from pediatric to adult health care (pre-transfer) and those who had already transferred (post-transfer). In a cross-sectional study, we compared 283 pre-transfer with 89 post-transfer young people, using a 28-item questionnaire that focused on perceived barriers to transition and beliefs about the most preferred age to transfer. Feeling at ease with the pediatrician was the most important barrier to successful transition in both groups, but was rated significantly higher in the pre-transfer compared to the post-transfer group (OR = 2.03, 95 %CI 1.12-3.71). Anxiety and lack of information were the next most important barriers, rated equally highly by the two groups (OR = 0.67, 95 %CI 0.35-1.28 and OR = 0.71, 95 %CI 0.36-1.38, respectively). More than 80 % of the respondents in both groups reported that 16-19 years was the most preferred age to transfer; more than half of all the respondents reported 18-19 years and older as the most preferred age. CONCLUSION: Better transition planning through the provision of regular and more detailed information about adult health-care providers and the transition process could reduce anxiety and contribute to a more positive attitude to overcome perceived barriers to transition from young people's perspective. Young people's preferences about transferring to adult health care provide a challenge to those children's hospitals that transfer to adult health care at a younger age.

The health of adolescents around a world in transition.

Since several years, the health of adolescents is on the agenda of ministers, decision makers and health professionals. Around the world, while there has been a steady decrease of the death rates among young children, this is not the case for young people. This is mainly linked with the fact that mortality and morbidity during this period of life is largely linked with non communicable diseases and conditions, including deaths from injuries, suicide, homicides and drug abuse. Unplanned pregnancies, illegal abortions, newly acquired HIV infections are also situations that have short and long term consequences. This paper reviews the epidemiological data pertaining to adolescent health and disease. It proposes evidence-informed avenues as how to address these issues in the field of health care (e.g. adolescent friendly services) and of prevention and health promotion. It also stresses the importance of creating safe environments for the development and well-being of young people and thus, of an interdisciplinary and inter sectorial approach to their complex health problems and challenges.

Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons.

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

Tackling Societal Challenges Related to Ageing and Transport Transition: An Introduction to Philosophical Principles of Causation Adapted to the Biopsychosocial Model

In geriatrics, driving cessation is addressed within the biopsychosocial model. This has broadened the scope of practitioners, not only in terms of assessing fitness to drive, but also by helping to maintain social engagements and provide support for transport transition. Causes can be addressed at different levels by adapting medication, improving physical health, modifying behaviour, adapting lifestyle, or bringing changes to the environment. This transdisciplinary approach requires an understanding of how different disciplines are linked to each other. This article reviews the philosophical principles of causality between fields and provides a framework for understanding causality within the biopsychosocial model. Understanding interlevel constraints should help practitioners overcome their differences, and favor transversal approaches to driving cessation.

Transición a la vida adulta de jóvenes con discapacidad intelectual. La opinión de los profesionales de servicios escolares y postescolares = Transition to adulthood of young people with intellectual disabilities. Views of professionals from school and postschool services

La transición a la edad adulta y vida activa es un proceso extremadamente complejo para los jóvenes con discapacidad. Para plantear propuestas de actuación que mejoren sus oportunidades de conseguir objetivos relacionados con la inclusión laboral y social en la vida adulta es imprescindible el diagnóstico en profundidad del contexto en que se construyen y desarrollan los procesos de transición. En este artículo se presenta un estudio en el que se ha aplicado el método Delphi con el propósito de obtener datos sobre la adecuación de los servicios o dispositivos que trabajan con jóvenes con discapacidad a lo largo de su proceso de transición a la edad adulta y vida activa, tanto en el escenario escolar como en el postescolar. Se han constituido dos paneles de expertos, uno con profesionales del ámbito educativo y otro con profesionales que trabajan en servicios postescolares. En ambos casos, los ejes temáticos son: visión del proceso de transición, aspectos curriculares y organizativos de los servicios, existencia de itinerarios de apoyo sistematizados, trabajo colaborativo entre profesionales, acciones de orientación con familias, adecuación de las alternativas postescolares, la formación de los profesionales, y coordinación de servicios. El análisis de los cuestionarios permite constatar las principales dificultades percibidas por los expertos en cada uno de los ámbitos y establece líneas básicas de actuación para mejorar los procesos de tránsito, entre las cuales destaca la necesidad de reforzar el papel de los equipos multiprofesionales en la articulación de redes de trabajo interprofesional