Timescales of developmental toxicity impacting on research and needs for intervention

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision‐making must be weighed against the costs and necessary duration of research, as well as the long‐term costs to human health because of delayed protection of vulnerable early‐life stages of human development and, possibly, future generations. Although two‐generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY‐BPA‐type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.     

Pre‐natal brain development as a target for urban air pollution

Air pollution is the main urban‐related environmental hazard and one of the major contributors to the global burden of disease based on its cardiovascular‐respiratory impacts. In children, exposure to urban air pollution is associated, among others, with decelerated neurodevelopment early in life and increased risk of neurodevelopmental problems such as attention‐deficit hyperactivity disorder, autism spectrum disorders, academic failure and the start of Alzheimer's pathogenesis. However, the evidence of the effects of air pollution on brain development is still inadequate, mainly due to the limitations in (a) characterizing brain development (most studies were based on subjective tools such as questionnaires or neuropsychological tests) and (b) air pollution exposure (most studies only used residential levels based on geographical modelling and also overlooking the variation in the mixture of air pollutants as well as the composition and hence toxicity of particulate pollutants in different settings), (c) the lack of studies during the most vulnerable stages of brain development (foetal and early life (first two years post‐natally)) and (d) the lack of structural and functional imaging data underlying these effects. In mice, in utero exposure to fine particles was linked to structural brain changes and there is a need to establish the generalizability of these findings in human beings. Though scarce, current evidence in children supports the importance of the pre‐natal period as a susceptible window of exposure. Two studies in schoolchildren found that pre‐natal air pollution exposure might damage brain structure while exposure during childhood was not linked to any structural alteration. Another study showed that children with higher traffic‐related air pollution at school had lower functional integration in key brain networks, but no changes in brain structure, possibly partly because of the time window of air pollution exposure (in utero versus childhood exposure). A key development is to discover the windows of greatest sensitivity of structural brain changes to air pollution exposure by incorporating the recent advances in non‐invasive imaging to characterize natal and post‐natal brain development and exploring whether and to what extend placental dysfunction could mediate such an association. Studying pre‐natal life is important because effects at this time are of a potentially irreversible nature and because the largest preventive opportunities occur during these periods.     

Impact of heterogeneity and socioeconomic factors on individual behavior in decentralized sharing ecosystems

Tens of millions of individuals around the world use decentralized content distribution systems, a fact of growing social, economic, and technological importance. These sharing systems are poorly understood because, unlike in other technosocial systems, it is difficult to gather large-scale data about user behavior. Here, we investigate user activity patterns and the socioeconomic factors that could explain the behavior. Our analysis reveals that (i) the ecosystem is heterogeneous at several levels: content types are heterogeneous, users specialize in a few content types, and countries are heterogeneous in user profiles; and (ii) there is a strong correlation between socioeconomic indicators of a country and users behavior. Our findings open a research area on the dynamics of decentralized sharing ecosystems and the socioeconomic factors affecting them, and may have implications for the design of algorithms and for policymaking.Every month, ∼150 million users worldwide share files over the Internet using BitTorrent (1), the most widely used decentralized peer-to-peer (P2P) communication protocol. Eleven years after its inception, file sharing through BitTorrent is one of the top three major contributors to the overall Internet traffic, accounting for 9–27% of the total traffic, depending on the continent (2, 3).The expansion in scale and breadth of decentralized file-sharing has highlighted the conflicts between the interests of creators (musicians and writers, e.g.) and those of P2P users. Creators and creative industries argue that they are being deprived of fair compensation for their work (4), which is being widely distributed for free in violation of copyright laws. Users, however, argue that P2P can be (and is) used for sharing nonproprietary contents, and warn that widespread monitoring of online activity by corporations and law enforcement violates P2P users’ right to privacy. Proof of the complexity of the situation includes the rejection of the Anti-Counterfeiting Trade Agreement by the European Parliament and the controversy with the Stop Online Piracy Act in the United States.Despite the growing social, economic, and technological importance of BitTorrent (4), there is currently little understanding of how users behave in this complex technosocial (5, 6) ecosystem. Due to the decentralized structure of P2P ecosystems, it is very difficult to gather large-scale data about interactions and behavioral patterns of the users without their explicit consent; this is in contrast to other forms of online exchange where all of the information is stored in a central system, be it publicly accessible as in Wikipedia (7), partially accessible through a public interface as in Twitter (8, 9) or Google [through its search logs (10) or its public services (11, 12)], or restricted as in Facebook (13, 14) or in email communications within organizations (15–18).Because of the difficulty to collect complete user-level data of large and representative samples of users (3), studies of user behavior in P2P networks have so far been based on (i) small datasets; (ii) aggregate data collected from “trackers” or from individual Internet service providers (ISPs); and (iii) incomplete user data collected using a single crawler client connected to the network (19–23).Here, we investigate the complete activity patterns of a large and representative pool of BitTorrent users. Our analysis reveals that P2P sharing is highly heterogeneous, that users are specialized, giving rise to well-defined user profiles, and that the abundance of certain user profiles in a country is highly correlated with socioeconomic factors. Our findings open a research area on the dynamics of decentralized sharing ecosystems, and may have implications for the understanding and design of algorithms and for policymaking.     

Genetic determinants of 5-lipoxygenase pathway in a Spanish population and their relationship with cardiovascular risk

ObjectiveLeukotrienes (LT) play a role in inflammation, cardiovascular diseases, and cancer. Although some studies suggest that there are genes that determine variability of some LT-related phenotypes, the genetic influence on these phenotypes has not been evaluated.MethodsThe relative contributions of genetic and environmental influences to the 5-lipoxygenase pathway-related phenotypes (5-Lipoxygenase, five lipoxygenase activating protein (FLAP), LTA₄-hydrolase and LTC₄-synthase expression, and LTB₄-plasma concentration and LTB₄ production by stimulated whole blood) were assessed in a sample of 934 individuals in 35 extended families. Our design is based on extended families recruited through a probands with idiopathic thrombophilia. This strategy allows us the analysis of the effects of measured covariates (such as sex, age and smoking), genes, and environmental variables shared by members of a household.ResultsAll of these phenotypes showed significant genetic contributions, with heritabilities ranging from 0.33 to 0.51 for enzyme expression and from 0.25 to 0.50 for LTB₄ production of the residual phenotypic variance. Significant phenotypic and genetic correlation among the LT-related traits was found. More importantly, FLAP and LTA₄-hydrolase expression exhibit significant genetic correlations with arterial thrombosis, indicating that some of the genes that influence quantitative variation in these phenotypes also influence the risk of thrombosis.ConclusionThis is the first study that quantifies the genetic component of 5-Lipoxygenase pathway phenotypes. The high heritability of these traits and the significant genetic correlations between arterial thrombosis and some of these phenotypes suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.     

Strong relationship between elemental stoichiometry and metabolome in plants

Shifts in the elemental stoichiometry of organisms in response to their ontogeny and to changing environmental conditions should be related to metabolomic changes because elements operate mostly as parts of molecular compounds. Here we show this relationship in leaves of Erica multiflora throughout their seasonal development and in response to moderate experimental field conditions of drought and warming. The N/P ratio in leaves decreased in the metabolically active growing seasons, coinciding with an increase in the content of primary metabolites. These results support the growth-rate hypothesis that states that rapidly growing organisms present low N/P ratios because of the increase in allocation of P to RNA. The foliar N/K and P/K ratios were lower in summer and in the drought treatment, in accordance with the role of K in osmotic protection, and coincided with the increase of compounds related to the avoidance of water stress. These results provide strong evidence of the relationship between the changes in foliar C/N/P/K stoichiometry and the changes in the leaf's metabolome during plant growth and environmental stress. Thus these results represent a step in understanding the relationships between stoichiometry and an organism's lifestyle.     

Bupivacaine 0.5% versus articaine 4% for the removal of lower third molars. A crossover randomized controlled trial

Objective: To compare the anesthetic action of 0.5% bupivacaine in relation to 4% articaine, both with 1:200,000 epinephrine, in the surgical removal of lower third molars. As a secondary objective hemodynamic changes using both anesthetics were analyzed. Study Design: Triple-blind crossover randomized clinical trial. Eighteen patients underwent bilateral removal of impacted lower third molars using 0.5% bupivacaine or 4% articaine in two different appointments. Preoperative, intraoperative and postoperative variables were recorded. Differences were assessed with McNemar tests and repeated measures ANOVA tests. Results: Both solutions exhibited similar latency times and intraoperative efficacy. Statistical significant lower pain levels were observed with bupivacaine between the fifth (p=0.011) and the ninth (p=0.007) postoperative hours. Bupivacaine provided significantly longer lasting soft tissue anesthesia (p<0.05). Systolic blood pressure and heart rate values were significantly higher with articaine. Conclusions: Bupivacaine could be a valid alternative to articaine especially due to its early postoperative pain prevention ability. Key words:Bupivacaine, articaine, third molar, anesthesia, postoperative pain.