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1.  Mother-Infant Attachment and the Intergenerational Transmission of Posttraumatic Stress Disorder 
Evidence for the intergenerational transmission of posttraumatic stress disorder (PTSD) is documented in the literature, though the underlying mechanisms are poorly understood. Attachment theory provides a framework for elucidating the ways in which maternal PTSD may increase offspring PTSD vulnerability. The current study utilized two independent prospective datasets to test the hypotheses that (a) maternal PTSD increases the probability of developing an insecure mother-infant attachment relationship and (b) an insecure mother-infant attachment relationship increases the risk of developing PTSD following trauma exposure in later life. In the first study of urban, primarily low-income ethnic/racial minority mothers and infants (N = 45 dyads), elevated maternal PTSD symptoms at 6 months were associated with increased risk for an insecure, particularly disorganized, mother-infant attachment relationship at 13 months. In the second birth cohort of urban low-income mothers and children (N = 96 dyads), insecure (avoidant or resistant) attachment in infancy was associated in a dose-response manner with increased lifetime risk for a diagnosis of PTSD by adolescence. A history of disorganized attachment in infancy predicted severity of PTSD symptoms, including reexperiencing, avoidance, hyperarousal, and total symptoms, at 17.5 years. In both studies, associations between attachment and PTSD were not attributable to numerous co-occurring risk factors. The findings suggest that promoting positive mother-child relationships in early development, particularly in populations at high risk for trauma exposure, may reduce the incidence of PTSD.
doi:10.1017/S0954579413000515
PMCID: PMC4145695  PMID: 24059819
attachment; PTSD; intergenerational; maternal trauma; infant
2.  Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women 
Introduction
High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women.
Methods
Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models.
Results
The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m2) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm2); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)).
Conclusion
Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0499-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0499-2
PMCID: PMC4303212  PMID: 25522654
3.  Sociodemographic Risk, Developmental Competence, and PTSD Symptoms in Young Children Exposed to Interpersonal Trauma in Early Life 
Journal of traumatic stress  2013;26(6):686-694.
Children under age six years are disproportionately exposed to interpersonal trauma, including maltreatment and witnessing intimate partner violence (IPV), and may be particularly susceptible to negative sequelae. However, young children have generally been neglected from trauma research; thus, little is known about the factors influencing vulnerability to traumatic stress responses and other negative outcomes in early life. This study examined associations among interpersonal trauma exposure, sociodemographic risk, developmental competence, and posttraumatic stress disorder (PTSD) symptoms in 200 children assessed prospectively from birth to 1st grade via home and laboratory observations, record reviews, and maternal and teacher interviews. Greater trauma exposure and sociodemographic risk and lower developmental competence predicted more severe PTSD symptoms. Developmental competence partially mediated the association between exposures and symptoms. Trauma exposure fully mediated the association between sociodemographic risk and symptoms. Neither sociodemographic risk nor developmental competence moderated trauma exposure effects on symptoms. The findings suggest that (a) exposure to maltreatment and IPV has additive effects on posttraumatic stress risk in early life, (b) associations between sociodemographic adversity and poor mental health may be attributable to increased trauma exposure in disadvantaged populations, and (c) early exposures have a negative cascade effect on developmental competence and child mental health.
PMCID: PMC4157899  PMID: 24490247
4.  Genetic Contributions to Continuity and Change in Attachment Security: A Prospective, Longitudinal Investigation from Infancy to Young Adulthood 
Background
Longitudinal research has demonstrated that individual differences in attachment security show only modest continuity from infancy to adulthood. Recent findings based on retrospective reports suggest that individuals’ genetic variation may moderate the developmental associations between early attachment-relevant relationship experiences and adult attachment security. The purpose of this study was to use a prospective, longitudinal design to investigate genetic contributions to continuity and changes in attachment security from infancy to young adulthood in a higher risk sample.
Methods
Infant attachment security was assessed using the Strange Situation Procedure at 12 and 18 months. Adults’ general attachment representations were assessed using the Adult Attachment Interview at age 19 and age 26. Romantic attachment representations were assessed with the Current Relationship Interview at ages 20–21 and ages 26–28. Individuals were genotyped for variants within the oxytocin receptor (OXTR), dopamine D4 receptor (DRD4), and serotonin transporter linked polymorphic region (5-HTTLPR).
Results
The continuity of attachment security from infancy into young adulthood was consistently moderated by OXTR genetic variation. Infant attachment security predicted the security of adults’ general and romantic attachment representations only for individuals with the OXTR G/G genotype. This interaction was significant when predicting adult attachment security as measured by the Adult Attachment Interview at age 19 and 26 and the Current Relationship Interview at ages 26–28. DRD4 and 5-HTTLPR genetic variation did not consistently moderate the longitudinal associations between attachment security during infancy and adulthood.
Conclusions
This study provides initial longitudinal evidence for genetic contributions to continuity and change in attachment security from infancy to young adulthood. Genetic variation related to the oxytocin system may moderate the stability of attachment security across development.
doi:10.1111/jcpp.12093
PMCID: PMC3775920  PMID: 23731038
Attachment; continuity; genetics; development
5.  The Developmental Significance of Late Adolescent Substance Use for Early Adult Functioning 
Developmental psychology  2012;49(8):1554-1564.
This study examines the predictive significance of late adolescent substance use groups (i.e., abstainers, experimental users, at-risk users, and abusers) for early adult adaptation. Participants (N = 159) were drawn from a prospective longitudinal study of first-born children of low-income mothers. At 17.5 years of age participants were assigned to substance use groups based on their level of substance use involvement. At 26 years, early adult competence was assessed in the areas of education, work, romantic relationships, and global adaptation. Results indicate that 17.5 year substance use group membership significantly predicted high school completion, regular involvement in a long-term romantic relationship, good or better work ethic, and good or better global adjustment at 26 years when controlling for gender; IQ; 16 year internalizing and externalizing behavior problems, parental monitoring, and peer competence; and current substance use at 26 years. Group comparisons indicate that late adolescent substance use experimenters were significantly more likely in early adulthood to have (a) a high school diploma or higher level of education compared to abstainers (OR = 8.83); (b) regular involvement in long-term romantic relationships (OR = 3.23), and good or better global adaptation (OR = 4.08) compared to at-risk users; and (c) good or better work ethic (OR = 4.04) compared to abusers. This research indicates that patterns of late adolescent substance use has implications for early adult functioning in salient developmental domains.
doi:10.1037/a0030229
PMCID: PMC3568218  PMID: 23025264
adolescence; drug use; early adulthood; longitudinal study; competence
6.  Developmental Timing and Continuity of Exposure to Interparental Violence and Externalizing Behavior as Prospective Predictors of Dating Violence 
Development and psychopathology  2013;25(4 0 1):973-990.
This study investigated the prospective pathways of children's exposure to interparental violence (EIPV) in early and middle childhood and externalizing behavior in middle childhood and adolescence as developmental predictors of dating violence perpetration and victimization at ages 23 and 26 years. Participants (N = 168) were drawn from a longitudinal study of low-income families. Path analyses examined whether timing or continuity of EIPV predicted dating violence and whether timing or continuity of externalizing behavior mediated these pathways. Results indicated that EIPV in early childhood directly predicted perpetration and victimization at age 23. There were significant indirect effects from EIPV to dating violence through externalizing behavior in adolescence and life stress at age 23. Independent of EIPV, externalizing behavior in middle childhood also predicted dating violence through externalizing behavior in adolescence and life stress at age 23, but this pathway stemmed from maltreatment. These results highlight that the timing of EIPV and both the timing and continuity of externalizing behavior are critical risks for the intergenerational transmission of dating violence. Findings support a developmental perspective that negative early experiences and children's externalizing behavior are powerful influences for dating violence in early adulthood.
doi:10.1017/S095457941300031X
PMCID: PMC4100589  PMID: 24229543
Keywords: exposure to interparental violence; externalizing behavior; dating violence; prospective developmental pathways; life stress
7.  Contributions of maltreatment and serotonin transporter genotype to depression in childhood, adolescence, and early adulthood 
Journal of affective disorders  2012;149(0):30-37.
Background
Past findings on gene-by-environment (G × E) effects on depression have been mixed, leading to a debate of the plausibility of such mechanisms and methodological considerations that warrant attention. A developmental systems perspective postulates that complex, multi-level G × E effects are likely contributors to depression.
Methods
Participants from families experiencing low-income status at birth were followed over 28 years. Maltreatment was recorded prospectively using multiple means and sources. Depression was measured repeatedly using well-validated interviews in middle childhood, through adolescence, and into adulthood.
Results
Findings support a G × E effect where the less efficient form of the promoter region of the serotonin transporter gene (5-HTTLPR) contributes to a vulnerability to depressogenic aspects of maltreatment in childhood and adolescence. The presence of less efficient forms of the 5-HTTLPR polymorphism and maltreatment together raised risk for depression. This G × E effect was present generally and also among those who reported clinical levels of depression at only one point in time.
Limitations
This study used a low-income sample which limits generalizability to other populations. Sample size and rates of different forms of depression and depression at individual developmental stages supported general analyses, but limited the sorts of specific sub-analyses that were possible.
Conclusions
These findings support the plausibility of G × E effects on depression during childhood, adolescence, and early adulthood, key periods for the development of depression. Ongoing debates about the presence of G × E effects would be well served by additional work that was theoretically informed and employed prospective, longitudinal methodologies with well-validated measures of key constructs.
doi:10.1016/j.jad.2012.08.011
PMCID: PMC3548027  PMID: 22951355
Gene-by-environment interaction; Child maltreatment; 5-HTTLPR; Depression; Childhood; adolescence; and adulthood
8.  Modulation of Adult Hippocampal Neurogenesis by Early-Life Environmental Challenges Triggering Immune Activation 
Neural Plasticity  2014;2014:194396.
The immune system plays an important role in the communication between the human body and the environment, in early development as well as in adulthood. Per se, research has shown that factors such as maternal stress and nutrition as well as maternal infections can activate the immune system in the infant. A rising number of research studies have shown that activation of the immune system in early life can augment the risk of some psychiatric disorders in adulthood, such as schizophrenia and depression. The mechanisms of such a developmental programming effect are unknown; however some preliminary evidence is emerging in the literature, which suggests that adult hippocampal neurogenesis may be involved. A growing number of studies have shown that pre- and postnatal exposure to an inflammatory stimulus can modulate the number of proliferating and differentiating neural progenitors in the adult hippocampus, and this can have an effect on behaviours of relevance to psychiatric disorders. This review provides a summary of these studies and highlights the evidence supporting a neurogenic hypothesis of immune developmental programming.
doi:10.1155/2014/194396
PMCID: PMC4033517  PMID: 24891958
9.  Does IQ influence Associations between ADHD Symptoms and other Cognitive Functions in young Preschoolers? 
Background
Working memory, inhibition, and expressive language are often impaired in ADHD and many children with ADHD have lower IQ-scores than typically developing children. The aim of this study was to test whether IQ-score influences associations between ADHD symptoms and verbal and nonverbal working memory, inhibition, and expressive language, respectively, in a nonclinical sample of preschool children.
Methods
In all, 1181 children recruited from the Norwegian Mother and Child Cohort Study were clinically assessed at the age of 36 to 46 months. IQ-score and working memory were assessed with subtasks from the Stanford Binet test battery, expressive language was reported by preschool teachers (Child Development Inventory), response inhibition was assessed with a subtask from the NEPSY test, and ADHD symptoms were assessed by parent interview (Preschool Age Psychiatric Assessment).
Results
The results showed an interaction between ADHD symptoms and IQ-score on teacher-reported expressive language. In children with below median IQ-score, a larger number of ADHD symptoms were more likely to be accompanied by reports of lower expressive language skills, while the level of ADHD symptoms exerted a smaller effect on reported language skills in children with above median IQ-score. The associations between ADHD symptoms and working memory and response inhibition, respectively, were not influenced by IQ-score.
Conclusions
Level of IQ-score affected the relation between ADHD symptoms and teacher-reported expressive language, whereas associations between ADHD symptoms and working memory and response inhibition, respectively, were significant and of similar sizes regardless of IQ-score. Thus, in preschoolers, working memory and response inhibition should be considered during an ADHD assessment regardless of IQ-score, while language skills of young children are especially important to consider when IQ-scores are average or low.
doi:10.1186/1744-9081-10-16
PMCID: PMC4017812  PMID: 24884579
ADHD; IQ; Intellectual ability; Preschool; Cognition; Working memory; Language skills; Inhibition
10.  Alcohol Use is Not Directly Related to the Perceived Control of Depressive Symptoms in Patients with Depressive Symptoms 
Treatment-seeking patients (N = 233) were recruited as they started a course of relapse prevention and coping with depression. The mean Beck depression inventory (BDI-II) score was 26 points, indicating a moderate degree of depression. The sample was recruited from different outpatient clinics and screened for alcohol-related problems with the alcohol use disorders identification test (AUDIT). Almost half of the total sample had a score on AUDIT >8 indicating an alcohol problem. The participants in this study did not undergo a clinical interview to check out if their symptoms, as assessed with BDI-II and AUDIT, were part of a formal diagnosis in accordance with the criteria in ICD 10 or DSM IV. A specific instrument, perceived uncontrollability of depression (UNCONTROL), was used to measure the persons’ perceived control of depressive symptoms; a set of statements about coping with depressive symptoms where high scores indicate lack of coping with the symptoms. Alcohol problems were not found to be significantly associated with the perceived control of ongoing depressive symptoms and did not moderate the relationship between depressive symptoms and the perceived control of depressive symptoms. The results question the assumption that alcohol use is related to coping with depressive symptoms in patients with alcohol abuse and depressive symptoms.
doi:10.3389/fpsyt.2014.00031
PMCID: PMC3973897  PMID: 24723895
alcohol; depression; coping; Beck depression inventory; prevention and control
11.  Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate 
PLoS Genetics  2014;10(3):e1004229.
Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.
Author Summary
Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable efforts genetic studies have yet to reveal the precise genetic underpinnings of the disorder. In this study we have analyzed a large extended pedigree of Old Order Amish that segregates bipolar disorder. Our study design integrates both dense genotype and whole-genome sequence data. In a combined linkage and association analysis we identify five chromosomal regions with nominally significant or suggestive evidence for linkage, several of which constitute replication of earlier linkage findings for bipolar disorder in non-Amish families. Association analysis of genetic variants in each of the linkage regions yielded a number of plausible candidate genes for bipolar disorder. The striking genetic heterogeneity we observed in this genetic isolate has profound implications for the study of bipolar disorder in the general population.
doi:10.1371/journal.pgen.1004229
PMCID: PMC3953017  PMID: 24625924
12.  Depressive Symptoms in People with and without Alcohol Abuse: Factor Structure and Measurement Invariance of the Beck Depression Inventory (BDI-II) Across Groups 
PLoS ONE  2014;9(2):e88321.
This study explored differences in the factor structure of depressive symptoms in patients with and without alcohol abuse, and differences in the severity of depressive symptoms between the two groups. In a sample of 358 patients without alcohol problems and 167 patients with comorbid alcohol problems, confirmatory factor analysis revealed that the same factor structures, Beck et al.'s two-factor Somatic Affective-Cognitive (SA-C) model, and Buckley et al.'s three-factor Cognitive-Affective- Somatic (C-A-S) model, demonstrated the best fit to the data in both groups. The SA-C model was preferred due to its more parsimonious nature. Evidence for strict measurement invariance across the two groups for the SA-C model was found. MIMIC (multiple-indicator-multiple-cause) modeling showed that the level of depressive symptoms was found to be highest on both factors in the group with comorbid alcohol problems. The magnitude of the differences in latent mean scores suggested a moderate difference in the level of depressive symptoms between the two groups. It is argued that patients with comorbid depression and alcohol abuse should be offered parallel and adequate treatment for both conditions.
doi:10.1371/journal.pone.0088321
PMCID: PMC3922762  PMID: 24533075
13.  RCT of Working Memory Training in ADHD: Long-Term Near-Transfer Effects 
PLoS ONE  2013;8(12):e80561.
Objective
The aim of the study is to evaluate the long-term near-transfer effects of computerized working memory (WM) training on standard WM tasks in children with Attention-Deficit/Hyperactivity Disorder (ADHD).
Method
Sixty-seven children aged 10–12 years in Vestfold/Telemark counties (Norway) diagnosed with F90.0 Hyperkinetic disorder (ICD-10) were randomly assigned to training or control group. The training group participated in a 25-day training program at school, while the control group received treatment-as-usual. Participants were tested one week before intervention, immediately after and eight months later. Based on a component analysis, six measures of WM were grouped into composites representing Visual, Auditory and Manipulation WM.
Results
The training group had significant long-term differential gains compared to the control group on all outcome measures. Performance gains for the training group were significantly higher in the visual domain than in the auditory domain. The differential gain in Manipulation WM persisted after controlling for an increase in simple storage capacity.
Conclusion
Systematic training resulted in a long-term positive gain in performance on similar tasks, indicating the viability of training interventions for children with ADHD. The results provide evidence for both domain-general and domain-specific models. Far-transfer effects were not investigated in this article.
Trial Registration: Controlled-Trials.com ISRCTN19133620
doi:10.1371/journal.pone.0080561
PMCID: PMC3857172  PMID: 24352414
14.  Interpersonal Trauma Exposure and Cognitive Development in Children to Age 8 Years: A Longitudinal Study 
Background
Childhood trauma exposure has been associated with deficits in cognitive functioning. The influence of timing of exposure on the magnitude and persistence of deficits is not well understood. The impact of exposure in early development has been especially under-investigated. This study examined the impact of interpersonal trauma exposure (IPT) in the first years of life on childhood cognitive functioning.
Methods
Children (N = 206) participating in a longitudinal birth cohort study were assessed prospectively for exposure to IPT (physical or emotional abuse or neglect, sexual abuse, witnessing maternal partner violence) between birth and 64 months. Child intelligent quotient scores (IQ) were assessed at 24, 64, and 96 months of age. Race/ethnicity, gender, socioeconomic status, maternal IQ, birth complications, birthweight, and cognitive stimulation in the home were also assessed.
Results
IPT was significantly associated with decreased cognitive scores at all time points, even after controlling for sociodemographic factors, maternal IQ, birth complications, birthweight, and cognitive stimulation in the home. IPT in the first two years appeared to be especially detrimental. On average, compared to children not exposed to IPT in the first two years, exposed children scored one-half standard deviation lower across cognitive assessments.
Conclusion
IPT in early life may have adverse effects on cognitive development. IPT during the first two years may have particular impact, with effects persisting at least into later childhood.
doi:10.1136/jech-2011-200727
PMCID: PMC3731065  PMID: 22493459
cognitive development; IQ; trauma; child abuse; domestic violence
15.  Few Effects of Far Transfer of Working Memory Training in ADHD: A Randomized Controlled Trial 
PLoS ONE  2013;8(10):e75660.
Objective
Studies have shown that children with ADHD profit from working memory training, although few studies have investigated transfer effects comprehensively. The current Randomized Controlled Trial analyzes transfer to other neuropsychological (NP) domains, academic performance and everyday functioning at home and school.
Method
Sixty-seven children with ADHD were randomized into a control group or a training group. The training group underwent Cogmed’s RoboMemo program. All participants were assessed pre-training, immediately after and eight months later with a battery of NP tests, measures of mathematical and reading skills, as well as rating scales filled out by parents and teachers.
Results
There was a significant training effect in psychomotor speed, but not to any other NP measures. Reading and mathematics were improved. There were no training induced changes in symptom rating scales either at home or at school. The increased reading scores remained significant eight months later.
Conclusion
The study is the most comprehensive study of transfer effects to date, and with mixed results compared to previous research. More research is needed regarding how to improve the training program and the conditions and thresholds for successful training.
Trial Registration
Controlled-Trials.com ISRCTN19133620
doi:10.1371/journal.pone.0075660
PMCID: PMC3790857  PMID: 24124503
16.  Bifidobacterial Succession and Correlation Networks in a Large Unselected Cohort of Mothers and Their Children 
Bifidobacteria are a major microbial component of infant gut microbiota, which is believed to promote health benefits for the host and stimulate maturation of the immune system. Despite their perceived importance, very little is known about the natural development of and possible correlations between bifidobacteria in human populations. To address this knowledge gap, we analyzed stool samples from a randomly selected healthy cohort of 87 infants and their mothers with >90% of vaginal delivery and nearly 100% breast-feeding at 4 months. Fecal material was sampled during pregnancy, at 3 and 10 days, at 4 months, and at 1 and 2 years after birth. Stool samples were predicted to be rich in the species Bifidobacterium adolescentis, B. bifidum, B. dentium, B. breve, and B. longum. Due to high variation, we did not identify a clear age-related structure at the individual level. Within the population as a whole, however, there were clear age-related successions. Negative correlations between the B. longum group and B. adolescentis were detected in adults and in 1- and 2-year-old children, whereas negative correlations between B. longum and B. breve were characteristic for newborns and 4-month-old infants. The highly structured age-related development of and correlation networks between bifidobacterial species during the first 2 years of life mirrors their different or competing nutritional requirements, which in turn may be associated with specific biological functions in the development of healthy gut.
doi:10.1128/AEM.02359-12
PMCID: PMC3553782  PMID: 23124244
17.  New insights regarding tissue Se and Hg interactions on oxidative stress from plasma IsoP and IsoF measures in the Canadian Inuit population 
Journal of Lipid Research  2013;54(7):1972-1979.
Despite animal and in vitro studies demonstrating pro-oxidative effects of Hg, previous human work showed no relationship between tissue Hg and plasma levels of F2-isoprostanes (IsoPs), a whole-body oxidative stress marker. We hypothesized that another IsoP species, isofurans (IsoFs), was a more sensitive indicator of Hg-mediated oxidative stress, which can be modified by tissue Se status. A cross-sectional study was carried out involving individuals from a random subset (n = 233) of Inuit adults from a population-based survey (n = 2,595) of 36 Canadian Arctic Inuit communities to assess the relationships of plasma IsoPs to Se and Hg status indicators. F2-IsoPs were inversely correlated with blood Se (r = −0.186, P = 0.005) and toenail Se (r = −0.146, P = 0.044), but not correlated with Hg. IsoFs were inversely correlated with blood Se (r = −0.164, P = 0.014) and positively correlated with Hg (r = 0.228, P < 0.001) and Hg:Se (r = 0.340, P < 0.001). The strength of the correlations remained unchanged after multivariate adjustments. Multivariate analysis showed that F2-IsoPs were not positively associated with Hg but with Hg:Se (β = 0.148, P = 0.021). We conclude that Se and Hg status and their interactions are important factors modulating F2-IsoP and IsoF levels such that the Inuit may be protected from Hg-induced oxidative stress because of their high Se status.
doi:10.1194/jlr.M033068
PMCID: PMC3679398  PMID: 23670530
isoprostane; isofuran; C-reactive protein; mercury; selenium
18.  Symptoms of ADHD in Children with High-Functioning Autism Are Related to Impaired Verbal Working Memory and Verbal Delayed Recall 
PLoS ONE  2013;8(5):e64842.
Symptoms similar to those found in Attention-Deficit/Hyperactivity Disorder (ADHD) often occur in children with Autism Spectrum Disorders (ASD). The objective of the current study was to compare verbal working memory, acquisition and delayed recall in children with High-Functioning Autism (HFA) to children with ADHD and typically developing children (TDC). Thirty-eight children with HFA, 79 with ADHD and 50 TDC (age 8–17) were assessed with a letter/number sequencing task and a verbal list-learning task. To investigate the possible influence of attention problems in children with HFA, we divided the HFA group into children with (HFA+) or without (HFA−) “attention problems” according to the Child Behaviour Checklist 6–18. The children with HFA+ displayed significant impairment compared to TDC on all three neurocognitive measures, while the children with HFA− were significantly impaired compared to TDC only on the working memory and acquisition measures. In addition, the HFA+ group scored significantly below the HFA− group and the ADHD group on the verbal working memory and delayed recall measures. The results support the proposition that children with HFA+, HFA−, and ADHD differ not only on a clinical level but also on a neurocognitive level which may have implications for treatment.
doi:10.1371/journal.pone.0064842
PMCID: PMC3661504  PMID: 23717667
19.  Higher n3-fatty acid status is associated with lower risk of iron depletion among food insecure Canadian Inuit women 
BMC Public Health  2013;13:289.
Background
High rates of iron deficiency and anemia are common among Inuit and Arctic women despite a traditional diet based on animal source foods. However, representative data on iron status and relevant determinants for this population are lacking. The objectives were to determine the prevalence of anemia and depletion of iron stores, then to identify correlates of iron status in non-pregnant Canadian Inuit women.
Methods
In a cross-sectional survey of 1550 women in the International Polar Year Inuit Health Survey, 2007-2008, hemoglobin, serum ferritin, soluble transferrin receptor (on a subset), C-reactive protein (CRP), RBC fatty acid composition, and H pylori serology were analyzed on fasting venous blood. Sociodemographic, food security status, anthropometric, dietary, and health data were collected. Correlates of iron status were assessed with multivariate linear and logistic models.
Results
Anemia was observed in 21.7% and iron deficient erythropoiesis in 3.3% of women. For women with CRP ≤ 10 mg/L (n = 1260) 29.4% had depleted iron stores. Inadequate iron intakes were observed in 16% of premenopausal and <1% of postmenopausal women. Among food insecure women, higher long-chain (n-3) polyunsaturated fatty acid (LC-PUFA) status, which reflects a more traditional food pattern, was associated with reduced risk of iron depletion.
Conclusions
Iron depletion and anemia are a concern for Inuit women despite adequate total dietary iron intake primarily from heme sources. The high prevalence of H. pylori exposure, together with dietary iron adequacy, suggests an inflammation-driven iron deficiency and mild anemia. The anti-inflammatory properties of LC-PUFA may be important for iron status in this population.
doi:10.1186/1471-2458-13-289
PMCID: PMC3623721  PMID: 23547888
20.  A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions 
Next-generation sequencing (NGS) techniques have already shown their potential in the identification of mutations underlying rare inherited disorders. We report here the application of linkage analysis in combination with targeted DNA capture and NGS to a Norwegian family affected by an undiagnosed mental retardation disorder with an autosomal recessive inheritance pattern. Linkage analysis identified two loci on chromosomes 9 and 17 which were subject to target enrichment by hybridization to a custom microarray. NGS achieved 20-fold or greater sequence coverage of 83% of all protein-coding exons in the target regions. This led to the identification of compound heterozygous mutations in NAGLU, compatible with the diagnosis of Mucopolysaccharidosis IIIB (MPS IIIB or Sanfilippo Syndrome type B). This diagnosis was confirmed by demonstrating elevated levels of heparan sulphate in urine and low activity of α-N-acetyl-glucosaminidase in cultured fibroblasts. Our findings describe a mild form of MPS IIIB and illustrate the diagnostic potential of targeted NGS in Mendelian disease with unknown aetiology.
doi:10.1038/ejhg.2011.126
PMCID: PMC3234502  PMID: 21712855
next-generation sequencing; DNA target enrichment; sequence capture; Sanfilippo Syndrome type B; mucopolysaccharidosis; NAGLU
21.  Affective Disorders among Patients with Borderline Personality Disorder 
PLoS ONE  2012;7(12):e50930.
Background
The high co-occurrence between borderline personality disorder and affective disorders has led many to believe that borderline personality disorder should be considered as part of an affective spectrum. The aim of the present study was to examine whether the prevalence of affective disorders are higher for patients with borderline personality disorder than for patients with other personality disorders.
Methods
In a national cross-sectional study of patients receiving mental health treatment in Norway (N = 36 773), we determined whether psychiatric outpatients with borderline personality disorder (N = 1 043) had a higher prevalence of affective disorder in general, and whether they had an increased prevalence of depression, bipolar disorder or dysthymia specifically. They were compared to patients with paranoid, schizoid, dissocial, histrionic, obsessive-compulsive, avoidant, dependent, or unspecified personality disorder, as well as an aggregated group of patients with personality disorders other than the borderline type (N = 2 636). Odds ratios were computed for the borderline personality disorder group comparing it to the mixed sample of other personality disorders. Diagnostic assessments were conducted in routine clinical practice.
Results
More subjects with borderline personality disorder suffered from unipolar than bipolar disorders. Nevertheless, borderline personality disorder had a lower rate of depression and dysthymia than several other personality disorder groups, whereas the rate of bipolar disorder tended to be higher. Odds ratios showed 34% lower risk for unipolar depression, 70% lower risk for dysthymia and 66% higher risk for bipolar disorder in patients with borderline personality disorder compared to the aggregated group of other personality disorders.
Conclusions
The results suggest that borderline personality disorder has a stronger association with affective disorders in the bipolar spectrum than disorders in the unipolar spectrum. This association may reflect an etiological relationship or diagnostic overlapping criteria.
doi:10.1371/journal.pone.0050930
PMCID: PMC3516502  PMID: 23236411
22.  Evaluating Methods to Correct for Population Stratification when Estimating Paternity Indexes 
PLoS ONE  2012;7(11):e49832.
The statistical interpretation of the forensic genetic evidence requires the use of allelic frequency estimates in the reference population for the studied markers. Differences in the genetic make up of the populations can be reflected in statistically different allelic frequency distributions. One can easily figure out that collecting such information for any given population is not always possible. Therefore, alternative approaches are needed in these cases in order to compensate for the lack of information. A number of statistics have been proposed to control for population stratification in paternity testing and forensic casework, Fst correction being the only one recommended by the forensic community. In this study we aimed to evaluate the performance of Fst to correct for population stratification in forensics. By way of simulations, we first tested the dependence of Fst on the relative sizes of the sub-populations, and second, we measured the effect of the Fst corrections on the Paternity Index (PI) values compared to the ones obtained when using the local reference database. The results provide clear-cut evidence that (i) Fst values are strongly dependent on the sampling scheme, and therefore, for most situations it would be almost impossible to estimate real values of Fst; and (ii) Fst corrections might unfairly correct PI values for stratification, suggesting the use of local databases whenever possible to estimate the frequencies of genetic profiles and PI values.
doi:10.1371/journal.pone.0049832
PMCID: PMC3511507  PMID: 23226224
23.  Microscale Electrode Implantation during Nerve Repair: Effects on Nerve Morphology, Electromyography, and Recovery of Muscle Contractile Function 
Plastic and reconstructive surgery  2011;128(4):270e-278e.
Background
Our goal is to develop a peripheral nerve electrode with long-term stability and fidelity for use in nerve-machine interfaces. Microelectromechanical systems (MEMS) use silicon probes that contain multi-channel actuators, sensors, and electronics. We tested the null hypothesis that implantation of MEMS probes do not have a detrimental effect on peripheral nerve function or regeneration.
Methods
A rat hindlimb, peroneal nerve model was utilized in all experimental groups: a) intact nerve (Control, n= 10); b) nerve division and repair (Repair, n= 9); and c) Nerve division, insertion of MEMS probe, and repair (Repair + Probe, n=9). Nerve morphology, nerve to muscle compound action potential (CMAP) studies, walking tracks, and extensor digitorum longus (EDL) muscle function tests were evaluated following an 80 day recovery.
Results
Repair and Repair + Probe showed no differences in axon count, axon size, percent non-neural area, CMAP amplitude, latency, muscle mass, muscle force, or walking track scores. Though there was some local fibrosis around each MEMS probe, this did not lead to measurable detrimental effects in any anatomic or functional outcome measurements.
Conclusions
The lack of a significant difference between Repair and Repair + Probe groups in histology, CMAP, walking tracks, and muscle force suggests that MEMS electrodes are compatible with regenerating axons and show promise for establishing chemical and electrical interfaces with peripheral nerves.
doi:10.1097/PRS.0b013e3182268ac8
PMCID: PMC3177169  PMID: 21921739
peripheral nerve; electrode; MEMS; skeletal muscle; regeneration; nerve tissue
24.  Dietary correlates of an at-risk BMI among Inuit adults in the Canadian high arctic: cross-sectional international polar year Inuit health survey, 2007-2008 
Nutrition Journal  2012;11:73.
Background
The study’s objective was to investigate the dietary correlates of an at-risk body mass index (BMI) among Inuit adults from thirty-six communities across the Canadian Arctic using data from the cross-sectional International Polar Year Inuit Health Survey, conducted in 2007–2008.
Methods
The survey included assessments of 24-hr dietary recall, sociodemographics, physical activity, and anthropometry. Dietary characteristics of overweight and obesity were similar and therefore combined into one at- risk BMI category (≥25 kg/m2) for analyses. The relationship between an at-risk BMI and energy intake from macronutrients, high sugar drinks, high-fat foods, saturated fatty acids, and traditional foods were examined entering each dietary variable separately into a logistic regression model as an independent variable. Analyses were adjusted for age, sex, region, kcalories, walking, smoking and alcohol consumption. Further multivariable models considered selected dietary variables together in one model.
Results
An at-risk BMI was present for 64% with a prevalence of overweight and obesity of 28% and 36%, respectively. Consumption of high-sugar drinks (>15.5% E) was significantly related with having an at-risk BMI (OR = 1.6; 95% CI 1.2; 2.2), whereas the % E from total carbohydrate evaluated as a continuous variable and as quartiles was inversely related to an at-risk BMI (P -trend < 0.05) in multivariable analyses. While % E from high-fat foods was positively related to an at-risk BMI, the findings were not significant in a model controlling for high-sugar drinks and % E from carbohydrates.
Conclusions
The prevalence of overweight and obesity is of public health concern among Inuit. The current findings highlight the obesogenic potential of high-sugar drink consumption in an ethnically distinct population undergoing rapid cultural changes and raises concerns regarding carbohydrate restricted diets. Health promotion programs aimed at preventing the development of an unhealthy body weight should focus on physical activity and the promotion of healthy diets with reduced intake of sugar drinks.
doi:10.1186/1475-2891-11-73
PMCID: PMC3502283  PMID: 22989025
Obesity; High-sugar drinks; Inuit
25.  Using Object Oriented Bayesian Networks to Model Linkage, Linkage Disequilibrium and Mutations between STR Markers 
PLoS ONE  2012;7(9):e43873.
In a number of applications there is a need to determine the most likely pedigree for a group of persons based on genetic markers. Adequate models are needed to reach this goal. The markers used to perform the statistical calculations can be linked and there may also be linkage disequilibrium (LD) in the population. The purpose of this paper is to present a graphical Bayesian Network framework to deal with such data. Potential LD is normally ignored and it is important to verify that the resulting calculations are not biased. Even if linkage does not influence results for regular paternity cases, it may have substantial impact on likelihood ratios involving other, more extended pedigrees. Models for LD influence likelihoods for all pedigrees to some degree and an initial estimate of the impact of ignoring LD and/or linkage is desirable, going beyond mere rules of thumb based on marker distance. Furthermore, we show how one can readily include a mutation model in the Bayesian Network; extending other programs or formulas to include such models may require considerable amounts of work and will in many case not be practical. As an example, we consider the two STR markers vWa and D12S391. We estimate probabilities for population haplotypes to account for LD using a method based on data from trios, while an estimate for the degree of linkage is taken from the literature. The results show that accounting for haplotype frequencies is unnecessary in most cases for this specific pair of markers. When doing calculations on regular paternity cases, the markers can be considered statistically independent. In more complex cases of disputed relatedness, for instance cases involving siblings or so-called deficient cases, or when small differences in the LR matter, independence should not be assumed. (The networks are freely available at http://arken.umb.no/~dakl/BayesianNetworks.)
doi:10.1371/journal.pone.0043873
PMCID: PMC3439468  PMID: 22984448

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