Environmental chemical stressors as epigenome modifiers:a new horizon in assessment of toxicological effects

In eukaryotic cells, chromatin transformation from euchromatin into heterochromatin as a means of controlling gene expression and replication has been known as the ?accessibility hypothesis?. The interplay of epigenetic changes including histone modifications, DNA methylation, RNA interference (RNAi) and other functional epigenetic components are intricate. It is believed that these changes are well-programmed, inherited and can be modified by environmental contaminant stressors. Environmentally-driven epigenetic alterations during development, e.g. embryonic, foetal or neonatal stage, may influence disease susceptibility in adulthood. Therefore, understanding how epigenome modifications develop in response to environmental chemicals and, how epigenetic-xenobiotic interactions influence human health will shed new insights into gene-environment interactions in the epidemiology of several diseases including cancer. In this review, we consider studies of chemical modifiers including nutritional and xenobiotic effects on epigenetic components in vitro or in vivo. By examining the most-studied epigenome modifications and how their respective roles are interlinked, we highlight the central role of xenbiotic-modified epigenetic mechanisms. A major requirement will be to study and understand effects following environmentally-relevant exposures. We suggest that the study of epigenetic toxicology will open up new opportunities to devise strategies for the prevention or treatment of at-risk populations

Structure of Metaphase Chromosomes: A Role for Effects of Macromolecular Crowding

In metaphase chromosomes, chromatin is compacted to a concentration of several hundred mg/ml by mechanisms which remain elusive. Effects mediated by the ionic environment are considered most frequently because mono- and di-valent cations cause polynucleosome chains to form compact ∼30-nm diameter fibres in vitro, but this conformation is not detected in chromosomes in situ. A further unconsidered factor is predicted to influence the compaction of chromosomes, namely the forces which arise from crowding by macromolecules in the surrounding cytoplasm whose measured concentration is 100–200 mg/ml. To mimic these conditions, chromosomes were released from mitotic CHO cells in solutions containing an inert volume-occupying macromolecule (8 kDa polyethylene glycol, 10.5 kDa dextran, or 70 kDa Ficoll) in 100 µM K-Hepes buffer, with contaminating cations at only low micromolar concentrations. Optical and electron microscopy showed that these chromosomes conserved their characteristic structure and compaction, and their volume varied inversely with the concentration of a crowding macromolecule. They showed a canonical nucleosomal structure and contained the characteristic proteins topoisomerase IIα and the condensin subunit SMC2. These observations, together with evidence that the cytoplasm is crowded in vivo, suggest that macromolecular crowding effects should be considered a significant and perhaps major factor in compacting chromosomes. This model may explain why ∼30-nm fibres characteristic of cation-mediated compaction are not seen in chromosomes in situ. Considering that crowding by cytoplasmic macromolecules maintains the compaction of bacterial chromosomes and has been proposed to form the liquid crystalline chromosomes of dinoflagellates, a crowded environment may be an essential characteristic of all genomes

Reducing Barriers to Optimal Automated External Defibrillator Use: An Elementary School Intervention Study

Background: Timely use of an automated external defibrillator (AED) improves outcomes in sudden cardiopulmonary arrest (SCA). Our project aims were to: 1) identify the barriers to optimal AED use in the Québec City area elementary schools; 2) create targeted educational material regarding AEDs; and 3) measure the impact of the teaching module. Methods: Using a quality improvement in health-care framework, a survey exploring the barriers to AED use was sent to 139 elementary schools. We then developed a video teaching module on using AEDs to address these barriers. A convenience sample of 92 elementary school professionals participated in a mock scenario. Metrics related to AED use were assessed at baseline and after completing the post-teaching module. The primary outcome was the time to first shock and secondary outcomes consisted of evaluating the completion of each step required for safe and effective AED use. Results: The barrier analysis survey received a response rate of 52.5%. Most schools reported having an AED (95%), but 48.6% indicated that no formal training was offered. After the teaching module, the appropriate use of the AED in an SCA simulation improved from 53% to 92% (P < 0.001). The average time elapsed before first shock was 66 (95% confidence interval [CI], 63-70) seconds at baseline compared with 47 (95% CI, 45-49) seconds post-teaching module (P < 0.001). Conclusions: Lack of training, the main barrier to optimal use of AEDs in elementary schools, can be addressed through a brief video teaching module, thus improving the ability to deliver timely and effective defibrillation. Résumé: Contexte: L’utilisation rapide d’un défibrillateur externe automatisé (DEA) améliore les résultats en cas d’arrêt cardiorespiratoire soudain (ACS). Les objectifs de notre projet étaient les suivants : 1) déterminer les obstacles à l’utilisation optimale d’un DEA dans les écoles primaires de la région de Québec; 2) créer du matériel éducatif ciblé à propos des DEA; et 3) mesurer l’impact du module d’enseignement. Méthodologie: Dans le cadre d’un projet d’amélioration de la qualité des soins de santé, un sondage explorant les obstacles à l’utilisation des DEA a été envoyé à 139 écoles primaires. Nous avons ensuite mis au point un module d’enseignement vidéo sur l’utilisation des DEA afin de surmonter ces obstacles. Un échantillon de commodité comprenant 92 professionnels des écoles primaires a participé à un scénario fictif. Les paramètres liés à l’utilisation des DEA ont été évalués au départ et après le visionnement du module d’enseignement vidéo. Le principal critère d’évaluation était le temps écoulé entre l’ACS et l’administration du premier choc et les critères secondaires consistaient à évaluer la réalisation de chaque étape requise pour une utilisation sûre et efficace d’un DEA. Résultats: Le sondage d’analyse des obstacles a généré un taux de réponse de 52,5 %. La plupart des écoles ont signalé avoir un DEA (95 %), mais 48,6 % ont indiqué qu’aucune formation n’était offerte. Après le visionnement du module d’enseignement, l’utilisation appropriée du DEA dans le cadre d’une simulation d’ACS est passée de 53 à 92 % (P < 0,001). Le temps moyen écoulé avant l’administration du premier choc était de 66 secondes (intervalle de confiance [IC] à 95 %, 63-70) au départ, comparativement à 47 secondes (IC à 95 %, 45-49) après le visionnement du module d’enseignement (P < 0,001). Conclusions: Le principal obstacle à l’utilisation optimale d’un DEA dans les écoles primaires, soit l’absence de formation, peut être surmonté grâce à un court module d’enseignement vidéo, améliorant ainsi la capacité de procéder à une défibrillation rapide et efficace

Society Guidelines 2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult

ABSTRACT Many developments have occurred since the publication of the widelyused 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total RÉSUMÉ De nombreux développements sont survenus depuis la publication communément utilisée des Lignes directrices 2009 de la Société canadienne de cardiologie (SCC) sur la dyslipidémie. Nous présentons ici une version mise à jour des lignes directrices, qui inclut des nouvelles recommandations fondées sur des résultats récents qui harmonisent les lignes directrices de la SCC à celles d&apos;autres sociétés. La méth-ode GRADE (Grading This statement was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific recommendations. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The statement is not intended to be a substitute for physicians using their individual judgement in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case

Availability, affordability, and consumption of fruits and vegetables in 18 countries across income levels: findings from the Prospective Urban Rural Epidemiology (PURE) study

Background: Several international guidelines recommend the consumption of two servings of fruits and three servings of vegetables per day, but their intake is thought to be low worldwide. We aimed to determine the extent to which such low intake is related to availability and affordability. Methods: We assessed fruit and vegetable consumption using data from country-specific, validated semi-quantitative food frequency questionnaires in the Prospective Urban Rural Epidemiology (PURE) study, which enrolled participants from communities in 18 countries between Jan 1, 2003, and Dec 31, 2013. We documented household income data from participants in these communities; we also recorded the diversity and non-sale prices of fruits and vegetables from grocery stores and market places between Jan 1, 2009, and Dec 31, 2013. We determined the cost of fruits and vegetables relative to income per household member. Linear random effects models, adjusting for the clustering of households within communities, were used to assess mean fruit and vegetable intake by their relative cost. Findings: Of 143 305 participants who reported plausible energy intake in the food frequency questionnaire, mean fruit and vegetable intake was 3·76 servings (95% CI 3·66–3·86) per day. Mean daily consumption was 2·14 servings (1·93–2·36) in low-income countries (LICs), 3·17 servings (2·99–3·35) in lower-middle-income countries (LMICs), 4·31 servings (4·09–4·53) in upper-middle-income countries (UMICs), and 5·42 servings (5·13–5·71) in high-income countries (HICs). In 130 402 participants who had household income data available, the cost of two servings of fruits and three servings of vegetables per day per individual accounted for 51·97% (95% CI 46·06–57·88) of household income in LICs, 18·10% (14·53–21·68) in LMICs, 15·87% (11·51–20·23) in UMICs, and 1·85% (−3·90 to 7·59) in HICs (ptrend=0·0001). In all regions, a higher percentage of income to meet the guidelines was required in rural areas than in urban areas (p<0·0001 for each pairwise comparison). Fruit and vegetable consumption among individuals decreased as the relative cost increased (ptrend=0·00040). Interpretation: The consumption of fruit and vegetables is low worldwide, particularly in LICs, and this is associated with low affordability. Policies worldwide should enhance the availability and affordability of fruits and vegetables. Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries

ADP-ribosyltransferases, an update on function and nomenclature

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes

ADP-ribosyltransferases, an update on function and nomenclature

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes