Physiological reactivity to fear in children: effects of temperament, attachment & the serotonin transporter gene

This thesis addressed the physiological impact of fear in 4- and 7-year-old children, induced by media and social fear-inducing tasks (the Trier Social Stress Test for Children). The main question pertained to individual differences in physiological reactivity to fear-inducing stimuli. The possibly relevant factors of attachment security, the child’s temperamental fearfulness, and variations in the serotonin transporter gene (5-HTTLPR; long vs. short allele) were taken into account. Results showed that temperament, attachment, and genetic influences play significant and interactive roles in the expression of fear reactivity. A secure relationship affected the reactivity to media-induced fear stimuli in temperamentally more fearful children but not in less fearful children irrespective of children’s ages. This finding adds to the growing literature showing that children high in negative emotion are more susceptible to positive as well as negative rearing influences. Furthermore, we found evidence that reactivity to the social fear-inducing task was explained by a combination of variations in the serotonin transporter gene and attachment security. Children with a secure attachment representation and two long 5-HTT alleles showed the lowest levels of fear reactivity, indicating that physiological reactivity to a social fear-inducing task is a product of the child’s biology and environment.LEI Universiteit LeidenFSW - Gezinsopvoeding - Ou

Demographic risk factors for suicide among youths in the Netherlands

In 2000 to 2016 the highest number of suicides among Dutch youths under 20 in any given year was 58 in 2013. In 2017 this number increased to 81 youth suicides. To get more insight in what types of youths died by suicide, particularly in recent years (2013-2017) we looked at micro-data of Statistics Netherlands and counted suicides among youths till 23, split out along gender, age, regions, immigration background and place in household and compared this to the general population of youths in the Netherlands. We also compared the demographics of young suicide victims to those of suicide victims among the population as a whole. We found higher suicide rates among male youths, older youths, those of Dutch descent and youths living alone. These differences were generally smaller than in the population as a whole. There were also substantial geographical differences between provinces and healthcare regions. The method of suicide is different in youth compared to the population as a whole: relatively more youth suicides by jumping or lying in front of a moving object and relatively less youth suicides by autointoxication or drowning, whereas the most frequent method of suicide among both groups is hanging or suffocation

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Contains fulltext : 88828.pdf (publisher's version ) (Open Access)BACKGROUND: A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. METHODS AND RESULTS: Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. SIGNIFICANCE: These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk

Where Do Core Thalamocortical Axons Terminate in Mammalian Neocortex When There Is No Cytoarchitecturally Distinct Layer 4?

Although the mammalian cerebral cortex is most often described as a hexalaminar structure, there are cortical areas (primary motor cortex) and species (elephants, cetaceans, and hippopotami), where a cytoarchitecturally indistinct, or absent, layer 4 is noted. Thalamocortical projections from the core, or first order, thalamic system terminate primarily in layers 4/inner 3. We explored the termination sites of core thalamocortical projections in cortical areas and in species where there is no cytoarchitecturally distinct layer 4 using the immunolocalization of vesicular glutamate transporter 2, a known marker of core thalamocortical axon terminals, in 31 mammal species spanning the eutherian radiation. Several variations from the canonical cortical column outline of layer 4 and core thalamocortical inputs were noted. In shrews/microchiropterans, layer 4 was present, but many core thalamocortical projections terminated in layer 1 in addition to layers 4 and inner 3. In primate primary visual cortex, the sublaminated layer 4 was associated with a specialized core thalamocortical projection pattern. In primate primary motor cortex, no cytoarchitecturally distinct layer 4 was evident and the core thalamocortical projections terminated throughout layer 3. In the African elephant, cetaceans, and river hippopotamus, no cytoarchitecturally distinct layer 4 was observed and core thalamocortical projections terminated primarily in inner layer 3 and less densely in outer layer 3. These findings are contextualized in terms of cortical processing, perception, and the evolutionary trajectory leading to an indistinct or absent cortical layer 4

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder

Content-based recommender support system for counselors in a suicide prevention chat helpline: Design and evaluation study

Background: The working environment of a suicide prevention helpline requires high emotional and cognitive awareness from chat counselors. A shared opinion among counselors is that as a chat conversation becomes more difficult, it takes more effort and a longer amount of time to compose a response, which, in turn, can lead to writer's block. Objective: This study evaluates and then designs supportive technology to determine if a support system that provides inspiration can help counselors resolve writer's block when they encounter difficult situations in chats with help-seekers. Methods: A content-based recommender system with sentence embedding was used to search a chat corpus for similar chat situations. The system showed a counselor the most similar parts of former chat conversations so that the counselor would be able to use approaches previously taken by their colleagues as inspiration. In a within-subject experiment, counselors' chat replies when confronted with a difficult situation were analyzed to determine if experts could see a noticeable difference in chat replies that were obtained in 3 conditions: (1) with the help of the support system, (2) with written advice from a senior counselor, or (3) when receiving no help. In addition, the system's utility and usability were measured, and the validity of the algorithm was examined. Results: A total of 24 counselors used a prototype of the support system; the results showed that, by reading chat replies, experts were able to significantly predict if counselors had received help from the support system or from a senior counselor (P=.004). Counselors scored the information they received from a senior counselor (M=1.46, SD 1.91) as significantly more helpful than the information received from the support system or when no help was given at all (M=-0.21, SD 2.26). Finally, compared with randomly selected former chat conversations, counselors rated the ones identified by the content-based recommendation system as significantly more similar to their current chats (β=.30, P<.001). Conclusions: Support given to counselors influenced how they responded in difficult conversations. However, the higher utility scores given for the advice from senior counselors seem to indicate that specific actionable instructions are preferred. We expect that these findings will be beneficial for developing a system that can use similar chat situations to generate advice in a descriptive style, hence helping counselors through writer's block

Assessing the legitimacy of flood risk governance arrangements in Europe: insights from intra-country evaluations

Legitimacy has received comparatively less attention than societal resilience in the context of flooding, thus methods for assessing and monitoring the legitimacy of Flood Risk Governance Arrangements (FRGA) are noticeably lacking. This study attempts to address this gap by assessing the legitimacy of FRGAs in six European countries through cross-disciplinary and comparative research methods. On the basis of this assessment, recommendation