Polygenic risk and hostile environments: Links to stable and dynamic antisocial behaviors across adolescence.

Adverse environments are linked to elevated youth antisocial behavior. However, this relation is thought to depend, in part, on genetic susceptibility. The present study investigated whether polygenic risk for antisociality moderates relations between hostile environments and stable as well as dynamic antisocial behaviors across adolescence. We derived two antisocial-linked polygenic risk scores (PRS) (N = 721) based on previous genome-wide association studies. Forms of antisocial behavior (nonaggressive conduct problems, physical aggression, social aggression) and environmental hostility (harsh parenting and school violence) were assessed at age 13, 15, and 17 years. Relations to individual differences stable across adolescence (latent stability) vs. time-specific states (timepoint residual variance) of antisocial behavior were assessed via structural equation models. Higher antisocial PRS, harsh parenting, and school violence were linked to stable elevations in antisocial behaviors across adolescence. We identified a consistent polygenic-environment interaction suggestive of differential susceptibility in late adolescence. At age 17, harsher parenting was linked to higher social aggression in those with higher antisocial PRS, and lower social aggression in those with lower antisocial PRS. This suggests that genetics and environmental hostility relate to stable youth antisocial behaviors, and that genetic susceptibility moderates home environment-antisocial associations specifically in late adolescence.

Genomic architecture of phenotypic extremes in a wild cervid.

Identifying the genes underlying fitness-related traits such as body size and male ornamentation can provide tools for conservation and management and are often subject to various selective pressures. Here we performed high-depth whole genome re-sequencing of pools of individuals representing the phenotypic extremes for antler and body size in white-tailed deer (Odocoileus virginianus). Samples were selected from a tissue repository containing phenotypic data for 4,466 male white-tailed deer from Anticosti Island, Quebec, with four pools representing the extreme phenotypes for antler and body size after controlling for age. Our results revealed a largely homogenous population but detected highly divergent windows between pools for both traits, with the mean allele frequency difference of 14% for and 13% for antler and body SNPs in outlier windows, respectively. Genes in outlier antler windows were enriched for pathways associated with cell death and protein metabolism and some of the most differentiated windows included genes associated with oncogenic pathways and reproduction, processes consistent with antler evolution and growth. Genes associated with body size were more nuanced, suggestive of a highly complex trait. Overall, this study revealed the complex genomic make-up of both antler morphology and body size in free-ranging white-tailed deer and identified target loci for additional analyses.

Multi-pathogen serological survey of migratory caribou herds: A snapshot in time.

Pathogens can impact host survival, fecundity, and population dynamics even when no obvious disease is observed. Few baseline data on pathogen prevalence and diversity of caribou are available, which hampers our ability to track changes over time and evaluate impacts on caribou health. Archived blood samples collected from ten migratory caribou herds in Canada and two in Greenland were used to test for exposure to pathogens that have the potential to effect population productivity, are zoonotic or are emerging. Relationships between seroprevalence and individual, population, and other health parameters were also examined. For adult caribou, the highest overall seroprevalence was for alphaherpesvirus (49%, n = 722), pestivirus (49%, n = 572) and Neospora caninum (27%, n = 452). Lower seroprevalence was found for parainfluenza virus type 3 (9%, n = 708), Brucella suis (2%, n = 758), and Toxoplasma gondii (2%, n = 706). No animal tested positive for antibodies against West Nile virus (n = 418) or bovine respiratory syncytial virus (n = 417). This extensive multi-pathogen survey of migratory caribou herds provides evidence that caribou are exposed to pathogens that may have impacts on herd health and revealed potential interactions between pathogens as well as geographical differences in pathogen exposure that could be linked to the bio-geographical history of caribou. Caribou are a keystone species and the socio-economic cornerstone of many indigenous cultures across the North. The results from this study highlight the urgent need for a better understanding of pathogen diversity and the impact of pathogens on caribou health.

Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness.

Recent models propose deoxyribonucleic acid methylation of key neuro-regulatory genes as a molecular mechanism underlying the increased risk of mental disorder associated with early life adversity (ELA). The goal of this study was to examine the association of ELA with oxytocin receptor gene (OXTR) methylation among young adults. Drawing from a 21-year longitudinal cohort, we compared adulthood OXTR methylation frequency of 46 adults (23 males and 23 females) selected for high or low ELA exposure based on childhood socioeconomic status and exposure to physical and sexual abuse during childhood and adolescence. Associations between OXTR methylation and teacher-rated childhood trajectories of anxiousness were also assessed. ELA exposure was associated with one significant CpG site in the first intron among females, but not among males. Similarly, childhood trajectories of anxiousness were related to one significant CpG site within the promoter region among females, but not among males. This study suggests that females might be more sensitive to the impact of ELA on OXTR methylation than males.

Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis.

OBJECTIVE: To estimate the impact of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin started ≤ 16 weeks' gestation on the prevalence of pre-eclampsia (PE) and the delivery of a small-for-gestational-age (SGA) neonate. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed by searching the medical databases PubMed, EMBASE, Web of Science and Cochrane Central. Pregnant women randomized to receive LMWH or unfractionated heparin in addition to low-dose aspirin were compared with those who received low-dose aspirin alone. Outcome measures were PE, severe PE, early-onset PE and SGA. Pooled relative risks (RRs) with 95% CI were calculated using a random-effects model. RESULTS: Eight RCTs met the inclusion criteria; the indication for recruitment was previous recurrent miscarriage in five studies (three included women with thrombophilia) and a history of severe or early-onset PE in three studies (including women with thrombophilia in one). LMWH was administered in seven studies and unfractionated heparin in one. In women with a history of PE, treatment with LMWH and aspirin, compared with aspirin alone, was associated with a significant reduction in development of PE (three trials (n = 379); RR, 0.54 (95% CI, 0.31-0.92); P = 0.03) and in delivery of SGA neonates (two trials (n = 363); RR, 0.54 (95% CI, 0.32-0.91); P = 0.02). These outcomes were not significantly reduced in women with recurrent miscarriage who received LMWH and aspirin, compared with aspirin alone. The small number of studies precluded sensitivity analyses and the evaluation of publication biases. Blinding to the allocation treatment was absent in all RCTs. CONCLUSIONS: Based on limited evidence, the addition of LMWH to low-dose aspirin could reduce the prevalence of PE and SGA in women with a history of PE. This observation should be the basis of a well-conducted future trial rather than a recommendation for immediate clinical application. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Severe congenital malformations, family functioning and parents' separation/divorce: a longitudinal study.

BACKGROUND: We aim to explore the association of a severe congenital malformation (SCM) with postnatal family functioning and parents' separation/divorce and to examine if this association might be moderated by birth order of the child and parental level of education. SCM refers to malformations that, without medical intervention, cause handicap or death. METHODS: Using the Quebec Longitudinal Study of Child Development, an ongoing population-based birth cohort study initiated in 1998, we compared 1675 families of children with and without a SCM to identify if having a child with a SCM was associated with maternal perception of family functioning. We examined if an SCM was associated with parents' separation and examined parents' education level and birth order of the children to evaluate whether these factors had any moderating effect on the results. RESULTS: There were no significant differences in family functioning between families with and without a SCM child at 5 and 17 months. At 5 months, family functioning was significantly better (P = 0.03) for families with a SCM firstborn child than for families with a SCM child that is not firstborn. For parental separation, no significant differences were observed at 5 and 29 months and 4 years. No significant moderating effects were observed for birth order and parental education on parental separation. CONCLUSIONS: Families of children with a SCM do not appear to be at higher risk of family dysfunction within the first 17 months after birth nor of parental separation within the first 4 years after birth. Family functioning tends to be worst in families where the child with SCM is the second or subsequent child born.

Socioeconomic position during childhood and physical activity during adulthood: a systematic review.

OBJECTIVES: A growing body of evidence links socioeconomic position early in life and physical activity during adulthood. This systematic review aimed to summarize this evidence. METHODS: Medline and EMBASE were searched for studies that assessed socioeconomic position before age 18 years and physical activity at age ≥18 years. Studies were rated according to three key methodological quality criteria: (1) was childhood socioeconomic position assessed prospectively? (2) Was socioeconomic position during adulthood included in the statistical analysis? (3) Was a validated instrument used to measure of physical activity? RESULTS: Forty-two publications were included. Twenty-six (61.9 %) found a significant association between socioeconomic position early in life and physical activity during adulthood. Twenty-one studies met at least two methodological quality criteria. Among those, the proportion was higher: 15/21 (71.4 %). Associations were of weak to moderate strength, positive for physical activity during leisure time, and negative for transports and work. CONCLUSIONS: The bulk of the evidence supports the notion that there is a life course association between socioeconomic position early in life and physical activity during adulthood. Studies using more rigorous methodology supported this conclusion more consistently.

Childhood trajectories of inattention, hyperactivity and oppositional behaviors and prediction of substance abuse/dependence: a 15-year longitudinal population-based study.

Numerous prospective studies have shown that children diagnosed with attention deficit/hyperactivity disorder (ADHD) are at higher risk of long-term substance abuse/dependence. However, there are three important limits to these studies: (a) most did not differentiate the role of hyperactivity and inattention; (b) most did not control for associated behavioral problems; and (c) most did not consider females. Our aim was to clarify the unique and interactive contributions of childhood inattention and hyperactivity symptoms to early adulthood substance abuse/dependence. Behavioral problems of 1803 participants (814 males) in a population-based longitudinal study were assessed yearly between 6 and 12 years by mothers and teachers. The prevalence of substance abuse/dependence at age 21 years was 30.7% for nicotine, 13.4% for alcohol, 9.1% for cannabis and 2.0% for cocaine. The significant predictors of nicotine dependence were inattention (odds ratio (OR): 2.25; 95% confidence interval (CI): 1.63-3.11) and opposition (OR: 1.65; 95%: 1.20-2.28). Only opposition contributed to the prediction of cannabis dependence (OR: 2.33; 95% CI: 1.40-3.87) and cocaine dependence (OR: 2.97; 95% CI: 1.06-8.57). The best behavioral predictor of alcohol abuse/dependence (opposition) was only marginally significant (OR: 1.38; 95% CI: 0.98-1.95). Frequent oppositional behaviors during elementary school were clearly the most pervasive predictors of substance abuse/dependence in early adulthood. The association of childhood ADHD with substance abuse/dependence is largely attributable to its association with opposition problems during childhood. However, inattention remained an important predictor of nicotine dependence, in line with genetic and molecular commonalities between the two phenotypes suggested in the literature.

KmL3D: a non-parametric algorithm for clustering joint trajectories.

In cohort studies, variables are measured repeatedly and can be considered as trajectories. A classic way to work with trajectories is to cluster them in order to detect the existence of homogeneous patterns of evolution. Since cohort studies usually measure a large number of variables, it might be interesting to study the joint evolution of several variables (also called joint-variable trajectories). To date, the only way to cluster joint-trajectories is to cluster each trajectory independently, then to cross the partitions obtained. This approach is unsatisfactory because it does not take into account a possible co-evolution of variable-trajectories. KmL3D is an R package that implements a version of k-means dedicated to clustering joint-trajectories. It provides facilities for the management of missing values, offers several quality criteria and its graphic interface helps the user to select the best partition. KmL3D can work with any number of joint-variable trajectories. In the restricted case of two joint trajectories, it proposes 3D tools to visualize the partitioning and then export 3D dynamic rotating-graphs to PDF format.

Heart rate as a predictor of energy expenditure in undisturbed fasting and incubating penguins.

Heart rate (f(H)) measurement offers the possibility to monitor energy expenditure (EE) in wild animals if the EE/f(H) relationship for the species, physiological stages and activities of interest is known. This relationship has been extensively studied using oxygen consumption rate ( ) measurement in captive, repeatedly handled king penguins (Aptenodytes patagonicus). Unfortunately, the potential effects of stress on the observed relationships resulting from handling and confinement were not considered. This study is the first involving undisturbed animals, and determines the EE/f(H) relationship in naturally fasting and freely incubating or captivity-acclimatized male and female king penguins. EE determination was based on (1) the measurement of body mass loss during periods of phase II fasting, and (2) the calculation of its energy equivalent from changes in body composition, i.e. 23.9 kJ g(-1). f(H) levels in freely incubating and captivity-acclimatized birds were found to be 50-70% lower than those previously reported for resting king penguins during measurements. Significant EE/f(H) relationships were found in freely incubating and captive males and females (R(2)=0.59 to 0.84), with no difference observed between genders. The best overall relationship was obtained by including fasting duration (t, days) in the model: EE=818+43.7xf(H)+36.3t-1.4txf(H) (R(2)=0.91). This equation yielded EE estimates approximately 26% higher than the previously reported 'best' predictive equation in king penguins, and even more so when f(H) was low. This result suggests that stress induces a disproportionate increase of f(H) vs O(2) consumption, and that the use of EE/f(H) relationships obtained in stressed birds could lead to underestimated EE values.

Genome-wide cross-amplification of domestic sheep microsatellites in bighorn sheep and mountain goats.

We tested for cross-species amplification of microsatellite loci located throughout the domestic sheep (Ovis aries) genome in two north American mountain ungulates (bighorn sheep, Ovis canadensis, and mountain goats, Oreamnos americanus). We identified 247 new polymorphic markers in bighorn sheep (≥ 3 alleles in one of two study populations) and 149 in mountain goats (≥ 2 alleles in a single study population) using 648 and 576 primer pairs, respectively. Our efforts increased the number of available polymorphic microsatellite markers to 327 for bighorn sheep and 180 for mountain goats. The average distance between successive polymorphic bighorn sheep and mountain goat markers inferred from the Australian domestic sheep genome linkage map (mean ± 1 SD) was 11.9 ± 9.2 and 15.8 ± 13.8 centimorgans, respectively. The development of genomic resources in these wildlife species enables future studies of the genetic architecture of trait variation.

Human metapneumovirus infection in adults with community-acquired pneumonia and exacerbation of chronic obstructive pulmonary disease.

We tested nasopharyngeal aspirate specimens by real-time polymerase chain reaction assays and paired serum samples by enzyme-linked immunosorbent assays. Acute human metapneumovirus infections were identified in 6 (4.1%) of 145 adult patients who presented to the emergency department for pneumonia or acute exacerbation of chronic obstructive pulmonary disease during 2 winter/spring seasons in Quebec, Canada.

Very high concentrations of n-3 fatty acids in peri- and postmenopausal Inuit women from Greenland.

OBJECTIVES: The objectives of this study were to examine the profile of relative concentrations in plasma phospholipids of n-3 fatty acids among peri- and postmenopausal Inuit women living in Greenland and to verify their relationships with ischemic heart disease risk factors and more particularly, with concentrations of plasma triacylglycerols. STUDY DESIGN: This study was part of a survey conducted in 2000, which aimed to assess the prevalence of osteoporosis and the associated risk factors among peri- and postmenopausal Greenland Inuit women. METHODS: The study population consisted of 153 women aged 49-69 years (mean +/- SD: 55.3 +/- 4.4 y) randomly selected. Data were obtained through an interview (questionnaire on lifestyle habits, medical history etc) and a clinical session (physiologic and anthropologic measurements). Plasma samples were used to measure the fatty acid composition of plasma phospholipids. RESULTS: The mean body mass index of women was 27.9 +/- 6.1. Seventy-five percent were smokers and 9% were currently on hormone replacement therapy. Relative concentrations of total n-3 fatty acids were very high (13.8%, 95% CI: 13.1-14.6), with docosahexanoic and eicosapentanoic acids accounting for 4.7% and 7.2%, respectively. The ratio of n-3:n-6 fatty acids was 0.67. n-3 fatty acids were inversely correlated to triacylglycerols. CONCLUSION: These data show that peri- and post-menopausal Greenland Inuit women have very high plasma concentrations of n-3 fatty acids that protect them from ischemic heart disease.

The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in alzheimer's disease-like transgenic mice.

A previous study in our laboratory, involving early stage, amyloid pathology in 8-month-old transgenic mice, demonstrated a selective loss of cholinergic terminals in the cerebral and hippocampal cortices of doubly transgenic (APP(K670N,M671L)+PSl(M146L)) mice, an up-regulation in the single mutant APP(K670N,M671L) mice and no detectable change in the PSl(M146L) transgenics [J Neurosci 19 (1999) 2706]. The present study investigates the impact of amyloid plaques on synaptophysin and vesicular acetylcholine transporter (VAChT) immunoreactive bouton numbers in the frontal cortex of the three transgenic mouse models previously described. When compared as a whole, the frontal cortices of transgenic and control mice show no observable differences in the densities of synaptophysin-immunoreactive boutons. An individual comparison of layer V of the frontal cortex, however, shows a significant increase in density in transgenic models. Analysis of the cholinergic system alone shows significant alterations in the VAChT-immunoreactive bouton densities as evidenced by an increased density in the single (APP(K670N,M671L)) transgenics and a decreased density in the doubly transgenics (APP(K670N,M671L)+PSl(M146L)). In investigating the impact of plaque proximity on bouton density at early stages of the amyloid pathology in our doubly (APP(K670N,M671L)+PSl(M146L)) transgenic mouse line, we observed that plaque proximity reduced cholinergic pre-synaptic bouton density by 40%, and yet increased synaptophysin-immunoreactive pre-synaptic bouton density by 9.5%. Distance from plaques (up to 60 microm) seemed to have no effect on bouton density; however a significant inverse relationship was visible between plaque size and cholinergic pre-synaptic bouton density. Finally, the number of cholinergic dystrophic neurites surrounding the truly amyloid, Thioflavin-S(+) plaque core, was disproportionately large with respect to the incidence of cholinergic boutons within the total pre-synaptic bouton population. Confocal and electron microscopic observations confirmed the preferential infiltration of dystrophic cholinergic boutons into fibrillar amyloid aggregates. We therefore hypothesize that extracellular Abeta aggregation preferentially affects cholinergic terminations prior to progression onto other neurotransmitter systems. This is supported by the observable presence of non-cholinergic sprouting, which may be representative of impending neuritic degeneration.

Leisure physical activity is associated with quantitative ultrasound measurements independently of bone mineral density in postmenopausal women.

The purpose of this study was to assess the magnitude of the relationship between leisure physical activity and bone status as measured either by an Achilles ultrasound bone densitometer (QUS) or dual-energy X-ray absorptiometry (DXA) in postmenopausal women. We studied 1162 French Canadian postmenopausal women, aged 33-84 years (mean age 58 years), for QUS parameters [broadband ultrasound attenuation (BUA), speed of sound (SOS), and stiffness index (SI)] measured at the right calcaneus, and bone mineral density (BMD) measured at the lumbar spine and femoral neck. Multivariate regression analyses revealed that leisure physical activity level was an independent predictor of the heel QUS parameters and of femoral neck BMD. No such association was observed for BMD of the lumbar spine. Heel QUS parameters (BUA, SOS, SI) and femoral neck BMD adjusted for interfering covariables showed a statistically significant difference between sedentary (less than three sessions/month) and active women (three or more sessions/week) (P < or = 0.001). Furthermore, after adjusting each heel QUS parameters for the mean lumbar spine BMD value, the association observed between leisure physical activity and QUS remained significant. These results suggest that regular leisure physical activity could influence QUS parameters, independently of BMD, and that quantitative ultrasound could be a suitable outcome measure in exercise studies in postmenopausal women.

Glutathione depletion overcomes resistance to arsenic trioxide in arsenic-resistant cell lines.

Arsenic trioxide (As(2)O(3)) is an effective treatment for acute promyelocytic leukemia (APL), but is less effective against other leukemias. Although the response of APL cells to As(2)O(3) has been linked to degradation of the PML/RARalpha fusion oncoprotein, there is evidence that PML/RARalpha expression is not the only mediator of arsenic sensitivity. Indeed, we found that exogenous expression of PML/RARalpha did not sensitize a non-APL leukemic line to As(2)O(3). To evaluate possible other determinants of sensitivity of leukemic cells to As(2)O(3), we derived two arsenic-resistant NB4 subclones. Despite being approximately 10-fold more resistant to arsenic than their parental cell line, PML/RARalpha protein was still degraded by As(2)O(3) in these cells, providing further evidence that loss of expression of the oncoprotein does not confer arsenic sensitivity. Both arsenic-resistant clones contained high glutathione (GSH) levels, however, and we found that GSH depletion coupled with As(2)O(3) treatment dramatically inhibited their growth. Annexin V-staining and TUNEL analysis confirmed a synergistic induction of apoptosis. In addition, these cells failed to accumulate ROS in response to arsenic treatment, in contrast to their arsenic-sensitive parental cells, unless cotreated with buthionine sulfoximine. While other malignant cells did not show a good correlation between arsenic sensitivity and GSH content, GSH depletion nevertheless sensitized all cell lines examined, regardless of their initial response to arsenic alone. These findings suggest that PML/RARalpha expression is not a determinant of arsenic sensitivity, and further support the coupling of GSH depletion and arsenic treatment as a novel treatment for human malignancies that are unresponsive to arsenic alone.

Microsatellite DNA evidence for genetic drift and philopatry in Svalbard reindeer.

Mainland populations of Arctic reindeer and caribou Rangifer tarandus often undergo extensive movements, whereas populations on islands tend to be isolated and sedentary. To characterize the genetic consequences of this difference, levels of genetic diversity and subdivision of Svalbard reindeer (R. t. platyrhynchus) from two adjacent areas on Nordenskjiöldland, Spitsbergen were estimated using data from up to 14 microsatellites. The mean number of alleles per locus in Svalbard reindeer was 2.4 and mean expected heterozygosity per locus was 0.36. The latter value was significantly lower than in Canadian caribou and Norwegian reindeer but higher than in some other cervid species. Large samples of females (n = 743) and small samples of males (n = 38) from two sites approximately 45 km apart showed genetic subdivision, which could be due to local population fluctuations or limited gene flow. To our knowledge, this is the first study to report significant differentiation at microsatellite loci in Rangifer at such short geographical distances. Neither population showed genetic evidence for recent population bottlenecks when loci unbiased with respect to heterozygosity were analysed. In contrast, false signals of a recent bottleneck were detected when loci upwardly biased with respect to heterozygosity were analysed. Thus, Svalbard reindeer appeared to conform to the paradigm of island populations made genetically depauperate by genetic drift.

Urea substitutes toxic formamide as destabilizing agent in nucleic acid hybridizations with RNA probes.

Since their introduction some three decades ago, methods for hybridization analysis of nucleic acids immobilized on solid supports have evolved to improve the sensitivity, speed, and convenience of their application. However, in many cases these methods still require the use of solutions containing formamide, a recognized hazardous solvent with potential toxicity. Here, we have compared the efficiency of urea to that of formamide as denaturing agent in nucleic acid hybridization with RNA probes. We show that urea at concentrations of 2-4 molar in solution performs as good as 50% formamide to reduce heterologous background hybridization in Northern blotting experiments realized at 68 degrees C. Presence of urea at higher concentrations resulted in reduced hybridization sensitivity, possibly due to increased viscosity. When tested in Southern blot analysis of genomic DNA, our results revealed that the use of urea in hybridization solution is also suitable to carry out single-copy gene detection. Together, these findings show that urea can efficiently and safely replace formamide in solutions.