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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  Low serum magnesium concentrations are associated with a high prevalence of premature ventricular complexes in obese adults with type 2 diabetes 
Background
Premature ventricular complexes (PVC) predict cardiovascular mortality among several adult populations. Increased arrhythmia prevalence has been reported during controlled magnesium (Mg) depletion studies in adults. We thus hypothesized that serum magnesium (sMg) concentrations are inversely associated with the prevalence of PVC in adults at high cardiovascular risk.
Methods
Anthropometric, demographic and lifestyle characteristics were assessed in 750 Cree adults, aged > 18 yrs, who participated in an age-stratified, cross-sectional health survey in Quebec, Canada. Holter electrocardiograms recorded heart rate variability and cardiac arrhythmias for two consecutive hours. Multivariate logistic regression was used to evaluate the associations between sMg and PVC.
Results
PVC prevalence in adults with hypomagnesemia (sMg ≤ 0.70 mmol/L) was more than twice that of adults without hypomagnesemia (50% vs. 21%, p = 0.015); results were similar when adults with cardiovascular disease history were excluded. All hypomagnesemic adults with PVC had type 2 diabetes (T2DM). Prevalence of PVC declined across the sMg concentration gradient in adults with T2DM only (p < 0.001 for linear trend). In multivariate logistic regressions adjusted for age, sex, community, body mass index, smoking, physical activity, alcohol consumption, kidney disease, antihypertensive and cholesterol lowering drug use, and blood docosahexaenoic acid concentrations, the odds ratio of PVC among T2DM subjects with sMg > 0.70 mmol/L was 0.24 (95% CI: 0.06-0.98) p = 0.046 compared to those with sMg ≤ 0.70 mmol/L.
Conclusions
sMg concentrations were inversely associated with the prevalence of PVC in patients with T2DM in a dose response manner, indicating that suboptimal sMg may be a contributor to arrhythmias among patients with T2DM.
doi:10.1186/1475-2840-11-23
PMCID: PMC3337820  PMID: 22405520
Magnesium; Hypomagnesemia; Premature ventricular complexes; Premature ventricular beats; Ectopic beats; Arrhythmia; Type 2 diabetes
21.  Higher body mass, older age and higher monounsaturated fatty acids intake reflect better quantitative ultrasound parameters in Inuit preschoolers 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.18999.
Objectives
Investigate the effects of selected factors associated with quantitative ultrasound parameters among Inuit preschoolers living in Arctic communities (56° 32′–72° 40′N).
Materials and methods
Children were selected randomly in summer and early fall (n=296). Dietary intake was assessed through the administration of a 24-h dietary recall (24-h recall) and a food frequency questionnaire (FFQ). Anthropometry was measured using standardized procedures. Plasma 25-hydroxy vitamin D (25(OH)D) and parathyroid hormone (PTH) were measured using a chemiluminescent assay (Liaison, Diasorin). Quantitative ultrasound parameters were measured using Sahara Sonometer, (Hologic Inc.).
Results
Children divided by speed of sound (SoS) and broadband ultrasound attenuation (BUA) quartiles were not different for age (years), sex (M/F), calcium (mg/d) and vitamin D intake (µg/d) and plasma 25(OH)D concentration (nmol/L). However, children in the highest BUA and SoS quartile had higher body mass index (BMI) compared to those in quartile 1. Using multivariate linear regression, higher BMI, older age and monounsaturated fatty acids (MUFA) intake were predictors of BUA while only BMI was a predictor of SoS.
Conclusions
Further investigation assessing intakes of traditional foods (TF) and nutrients affecting bone parameters along with assessment of vitamin D status of Inuit children across seasons is required.
doi:10.3402/ijch.v71i0.18999
PMCID: PMC3417545  PMID: 22789515
speed of sound; broadband ultrasound attenuation; preschoolers; Inuit; vitamin D
22.  Association between socioeconomic status and overweight and obesity among Inuit adults: International Polar Year Inuit Health Survey, 2007–2008 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.18419.
Objectives
To evaluate the socio-economic correlates of overweight and obesity among Inuit undergoing rapid cultural changes.
Study design
A cross-sectional health survey of 2,592 Inuit adults from 36 communities in the Canadian Arctic.
Methods
Main outcome measures were overweight and obesity (BMI>25 kg/m2 and >30 kg/m2, respectively) and as characteristics were similar, groups were combined into an at-risk BMI category (BMI>25 kg/m2). Logistic regression was used to determine the association between various sociodemographic characteristics and physical activity with overweight and obesity.
Results
The prevalence of overweight and obesity was 28 and 36%, respectively, with a total prevalence of overweight and obesity of 64%. In analyses of sociodemographic variables adjusted for age, gender and region, higher education, any employment, personal income, and private housing were all significantly positively correlated with an at-risk BMI (p≤0.001). Smoking, Inuit language as primary language spoken at home, and walking were inversely associated with overweight and obesity.
Conclusions
The current findings highlight the social disparities in overweight and obesity prevalence in an ethnically distinct population undergoing rapid cultural changes.
doi:10.3402/ijch.v71i0.18419
PMCID: PMC3417717  PMID: 22584513
obesity; socioeconomic status; Inuit
23.  Poor self-reported health and its association with biomarkers among Canadian Inuit 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.18589.
Objectives
To determine the extent to which demographic characteristics, clinical measurements and biomarkers were associated with poor self-reported health (SRH) among Inuit adults in the Canadian Arctic.
Study design
Cross-sectional survey was adopted as the study design.
Methods
The International Polar Year Inuit Health Survey carried out in 36 Canadian Arctic communities in 2007 and 2008 included Inuit men and women, aged 18 years or older, recruited from randomly selected households. The main outcome measure was SRH, which was dichotomized into good health (excellent, very good and good responses) and poor health (fair and poor responses).
Results
Of the 2,796 eligible households, 1,901 (68%) households and 2,595 participants took part in the survey. The weighted prevalence of poor SRH was 27.8%. Increasing age was significantly associated with poor SRH. The relative risk ratios for poor SRH was 2.0 (95% confidence interval [CI] 1.3–3.1) for men aged 50 years or older and 2.3 (95% CI 1.7–3.0) for women aged 50 years or older, compared with men and women aged 29 years or younger. After adjusting for age, gender and body mass index, poor SRH was significantly associated with smoking status (odds ratio [OR]=1.5; CI 1.1–2.0), at-risk fasting glucose levels (≥6.1 mmol/L) (OR=2.5; 95%; CI 1.5–4.2) and elevated hs C-reactive protein levels (>3–≤10 mg/L) (OR=2.1; 95% CI 1.4–3.1). Poor SRH was also significantly associated with a hypertriglyceridemic waist phenotype (high-risk waist circumference ≥102 cm for men and ≥88 cm for women with high triglyceride levels, ≥1.7 mmol/L), adjusted for age and gender, OR=1.6; 95% CI 1.1–2.3.
Conclusions
Clinically relevant indicators of chronic disease risk were related to subjective assessment of SRH among Inuit.
doi:10.3402/ijch.v71i0.18589
PMCID: PMC3426798  PMID: 22973568
Inuit; health research; self-reported health; biomarkers
24.  Design and methods of the Adult Inuit Health Survey 2007–2008 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.19752.
Background
The Canadian International Polar Year (IPY) program made it possible to undertake much needed health research in 3 jurisdictions within the Canadian Inuit Nunangat (homeland) over a 2-year period: Inuvialuit Settlement Region (ISR), Nunavut Territory, and Nunatsiavut.
Design
The Adult Inuit Health Survey (IHS) was a cross-sectional survey and provides baseline data upon which future comparisons can be made for prospectively assessing factors leading to the progression of chronic diseases among Canadian Inuit. With the help of the Canadian Coast Guard Ship Amundsen, which was equipped with research and laboratory facilities, 33 coastal communities were visited; land survey teams visited 3 inland communities.
Results
The Adult IHS succeeded in obtaining important baseline information concerning the health status and living conditions of 2,595 adults living in ISR, Nunavut and Nunatsiavut.
Conclusion
Information from this survey will be useful for future comparisons and the opportunity to link with the International Inuit Cohort, a follow-up evaluation, and for the development of future health policies and public health interventions.
doi:10.3402/ijch.v71i0.19752
PMCID: PMC3500824  PMID: 23166895
International Polar Year; Inuit; health research; survey; Canadian Arctic
25.  A Statistical Framework for the Interpretation of mtDNA Mixtures: Forensic and Medical Applications 
PLoS ONE  2011;6(10):e26723.
Background
Mitochondrial DNA (mtDNA) variation is commonly analyzed in a wide range of different biomedical applications. Cases where more than one individual contribute to a stain genotyped from some biological material give rise to a mixture. Most forensic mixture cases are analyzed using autosomal markers. In rape cases, Y-chromosome markers typically add useful information. However, there are important cases where autosomal and Y-chromosome markers fail to provide useful profiles. In some instances, usually involving small amounts or degraded DNA, mtDNA may be the only useful genetic evidence available. Mitochondrial DNA mixtures also arise in studies dealing with the role of mtDNA variation in tumorigenesis. Such mixtures may be generated by the tumor, but they could also originate in vitro due to inadvertent contamination or a sample mix-up.
Methods/Principal Findings
We present the statistical methods needed for mixture interpretation and emphasize the modifications required for the more well-known methods based on conventional markers to generalize to mtDNA mixtures. Two scenarios are considered. Firstly, only categorical mtDNA data is assumed available, that is, the variants contributing to the mixture. Secondly, quantitative data (peak heights or areas) on the allelic variants are also accessible. In cases where quantitative information is available in addition to allele designation, it is possible to extract more precise information by using regression models. More precisely, using quantitative information may lead to a unique solution in cases where the qualitative approach points to several possibilities. Importantly, these methods also apply to clinical cases where contamination is a potential alternative explanation for the data.
Conclusions/Significance
We argue that clinical and forensic scientists should give greater consideration to mtDNA for mixture interpretation. The results and examples show that the analysis of mtDNA mixtures contributes substantially to forensic casework and may also clarify erroneous claims made in clinical genetics regarding tumorigenesis.
doi:10.1371/journal.pone.0026723
PMCID: PMC3203886  PMID: 22053205

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