Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease

RATIONALE: Children with congenital heart disease are at risk of gut barrier dysfunction and translocation of gut bacterial antigens into the bloodstream. This may contribute to inflammatory activation and organ dysfunction postoperatively. OBJECTIVES: To investigate the role of intestinal injury and endotoxemia in the pathogenesis of organ dysfunction after surgery for congenital heart disease. METHODS: We analyzed blood levels of intestinal fatty acid binding protein and endotoxin (endotoxin activity assay) alongside global transcriptomic profiling and assays of monocyte endotoxin receptor expression in children undergoing surgery for congenital heart disease. MEASUREMENTS AND MAIN RESULTS: Levels of intestinal fatty acid binding protein and endotoxin were greater in children with duct-dependent cardiac lesions. Endotoxemia was associated with severity of vital organ dysfunction and intensive care stay. We identified activation of pathogen-sensing, antigen-processing, and immune-suppressing pathways at the genomic level postoperatively and down-regulation of pathogen-sensing receptors on circulating immune cells. CONCLUSIONS: Children undergoing surgery for congenital heart disease are at increased risk of intestinal mucosal injury and endotoxemia. Endotoxin activity correlates with a number of outcome variables in this population, and may be used to guide the use of gut-protective strategies.

Effects of psychotherapy for anxiety in children and adolescents: a meta-analytic review

This paper provides a comprehensive quantitative review of high quality randomized controlled trials of psychological therapies for anxiety disorders in children and young people. Using a systematic search for randomized controlled trials which included a control condition and reported data suitable for meta-analysis, 55 studies were included. Eligible studies were rated for methodological quality and outcome data were extracted and analyzed using standard methods. Trial quality was variable, many studies were underpowered and adverse effects were rarely assessed; however, quality ratings were higher for more recently published studies. Most trials evaluated cognitive behavior therapy or behavior therapy and most recruited both children and adolescents. Psychological therapy for anxiety in children and young people was moderately effective overall, but effect sizes were small to medium when psychological therapy was compared to an active control condition. The effect size for non-CBT interventions was not significant. Parental involvement in therapy was not associated with differential effectiveness. Treatment targeted at specific anxiety disorders, individual psychotherapy, and psychotherapy with older children and adolescents had effect sizes which were larger than effect sizes for treatments targeting a range of anxiety disorders, group psychotherapy, and psychotherapy with younger children. Few studies included an effective follow-up. Future studies should follow CONSORT reporting standards, be adequately powered, and assess follow-up. Research trials are unlikely to address all important clinical questions around treatment delivery. Thus, careful assessment and formulation will remain an essential part of successful psychological treatment for anxiety in children and young people.

An experimental manipulation of responsibility in children: a test of the inflated responsibility model of obsessive-compulsive disorder

The objective of this study was to investigate whether Salkovskis (1985) inflated responsibility model of obsessive-compulsive disorder (OCD) applied to children. In an experimental design, 81 children aged 9– 12 years were randomly allocated to three conditions: an inflated responsibility group, a moderate responsibility group, and a reduced responsibility group. In all groups children were asked to sort sweets according to whether or not they contained nuts. At baseline the groups did not differ on children’s self reported anxiety, depression, obsessive-compulsive symptoms or on inflated responsibility beliefs. The experimental manipulation successfully changed children’s perceptions of responsibility. During the sorting task time taken to complete the task, checking behaviours, hesitations, and anxiety were recorded. There was a significant effect of responsibility level on the behavioural variables of time taken, hesitations and check; as perceived responsibility increased children took longer to complete the task and checked and hesitated more often. There was no between-group difference in children’s self reported state anxiety. The results offer preliminary support for the link between inflated responsibility and increased checking behaviours in children and add to the small but growing literature suggesting that cognitive models of OCD may apply to children.

Reduced cortico-motor facilitation in a normal sample with high traits of autism

Recent research in social neuroscience proposes a link between mirror neuron system (MNS) and social cognition. The MNS has been proposed to be the neural mechanism underlying action recognition and intention understanding and more broadly social cognition. Pre-motor MNS has been suggested to modulate the motor cortex during action observation. This modulation results in an enhanced cortico-motor excitability reflected in increased motor evoked potentials (MEPs) at the muscle of interest during action observation. Anomalous MNS activity has been reported in the autistic population whose social skills are notably impaired. It is still an open question whether traits of autism in the normal population are linked to the MNS functioning. We measured TMS-induced MEPs in normal individuals with high and low traits of autism as measured by the autistic quotient (AQ), while observing videos of hand or mouth actions, static images of a hand or mouth or a blank screen. No differences were observed between the two while they observed a blank screen. However participants with low traits of autism showed significantly greater MEP amplitudes during observation of hand/mouth actions relative to static hand/mouth stimuli. In contrast, participants with high traits of autism did not show such a MEP amplitude difference between observation of actions and static stimuli. These results are discussed with reference to MNS functioning.

'Response and Responsibility: Theories of the Implied Reader in Children's Literature Criticism'

Reader Response Theory remains popular within Children's Literature Criticism. It seems to offer a sensible resolution to the question of whether meaning derives from text or reader. Through a close reading of one example of this criticism, I suggest that its dualisms are constantly collapsing into appeals to singular authority. at various stages the text or the reader is wholly responsible for meaning. I further suggest that the criticism bypasses the question of interpretation through claiming knowledge of a child reader whose opinions and reactions can be unproblematically accessed. We do not have to worry about reading texts, because we can, apparently, know the child's response to them with certainty. Anything other than this claim to certainty is taken to be a failure of responsibility, a wallowing in the subjective, obscure and perverse. My intention is to reinstate reading as the responsibility of criticism.

Disrupted white matter in language and motor tracts in developmental stuttering

White matter tractsc onnecting areas involved in speech and motor control were examined using diffusion-tensor imagingingin a sample of peoplewhostutter (n=29) who were heterogeneous with respect to age, sex, handedness and stuttering severity. The goals were to replicate previous findings in developmental stuttering and to extend ourknowledge by evaluating the relationship between white matter differences in people who stutter and factors such as age, sex, handedness and stuttering severity. We replicated previous findings that showed reduced integrity in white matter underlying ventral premotorcortex, cerebral peduncles and posteriorcorpus callosum in people who stutter, relative to controls. Tractography analysis additionally revealed significantly reduced white matter integrity in the arcuate fasciculus bilaterally and the left corticospinal tract and significantly reduced connectivity within theleft corticobulbar tract in people who stutter. Region-of-interest analyses revealed reduced white matter integrity in people whostutter in the three pairs ocerebellar peduncles thatcarry the afferent and efferent fibers of the cerebellum. Within thegroup of people who stutter, the higher the stuttering severity index, the lower the white matter integrity in the leftangular gyrus but the greater the white matter connectivity in theleft corticobulbartract. Also,in people who stutter, handedness and age predicted the integrity of the corticospinal tract and peduncles, respectively. Further studies are needed to determine which of these white matter differences relate to the neural basis of stuttering and which reflect experience-dependent plasticity.

PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European Youth Heart Study.

AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.

Deficits in orthographic knowledge in children poor at rapid automatized naming (RAN) tasks?

The degree to which orthographic knowledge accounts for the link between Rapid Automatized Naming (RAN) and reading is contested, with mixed results reported. This longitudinal study compared two groups of 10-11 year old children, a low RAN group (N=69) and matched controls (N=74) on various measures of orthographic knowledge. The low RAN group showed a deficit in orthographic knowledge, both at the level of sub-word letter sequences and of whole words, as well as an unexpected strength in orthographic learning. Our findings underline the persistence of RAN-related reading problems, and raise questions about reading strategies in this group.

Assessment and management of anxiety disorders in children and adolescents

Anxiety disorders in childhood and adolescence are extremely common and are often associated with lifelong psychiatric disturbance. Consistent with DSM-5 and the extant literature, this review concerns the assessment and treatment of specific phobias, separation anxiety disorder, generalised anxiety disorder, social anxiety disorder, panic disorder and agoraphobia. Evidence-based psychological treatments (cognitive behaviour therapy; CBT) for these disorders have been developed and investigated, and in recent years promising low-intensity versions of CBT interventions have been proposed that offer a means to increase access to evidence-based treatments. There is some evidence of effectiveness of pharmacological treatments for anxiety disorders in children and young people, however, routine prescription is not recommended due to concerns about potential harm.

Restrictive feeding practices and adiposity are differentially related to P3b cortical responses to food stimuli in children

Across two studies, we examined the association between adiposity, restrictive feeding practices and cortical processing bias to food stimuli in children. We assessed P3b event-related potential (ERP) during visual oddball tasks in which the frequently presented stimulus was non-food and the infrequently presented stimulus was either a food (Study 1) or non-food (Study 2) item. Children responded to the infrequently presented stimulus and accuracy and speed responses were collected. Restrictive feeding practices, children's height and weight were also measured. In Study 1, the difference in P3b amplitude for infrequently presented food stimuli, relative to frequently presented non-food stimuli, was negatively associated with adiposity and positively associated with restrictive feeding practices after controlling for adiposity. There was no association between P3b amplitude difference and adiposity or restriction in Study 2, suggesting that the effects seen in Study 1 were not due to general attentional processes. Taken together, our results suggest that attentional salience, as indexed by the P3b amplitude, may be important for understanding the neural correlates of adiposity and restrictive feeding practices in children.

The experience of friendship, victimization and bullying in children with an autism spectrum disorder: associations with child characteristics and school placement

Children with an autism spectrum disorder (ASD) may be vulnerable to social isolation and bullying. We measured the friendship, fighting/bullying and victimization experiences of 10–12-year-old children with an ASD (N = 100) using parent, teacher and child self-report. Parent and teacher reports were compared to an IQ-matched group of children with special educational needs (SEN) without ASD (N = 80) and UK population data. Parents and teachers reported a lower prevalence of friendships compared to population norms and to children with SEN without an ASD. Parents but not teachers reported higher levels of victimization than the SEN group. Half of the children with an ASD reported having friendships that involved mutuality. By teacher report children with an ASD who were less socially impaired in mainstream school experienced higher levels of victimization than more socially impaired children; whereas for more socially impaired children victimization did not vary by school placement. Strategies are required to support and improve the social interaction skills of children with an ASD, to enable them to develop and maintain meaningful peer friendships and avoid victimization.

Computerised therapies for anxiety and depression in children and young people: a systematic review and meta-anaylsis

One quarter of children and young people (CYP) experience anxiety and/or depression before adulthood, but treatment is sometimes unavailable or inadequate. Self-help interventions may have a role in augmenting treatment and this work aimed to systematically review the evidence for computerised anxiety and depression interventions in CYP aged 5–25 years old. Databases were searched for randomised controlled trials and 27 studies were identified. For young people (12–25 years) with risk of diagnosed anxiety disorders or depression, computerised CBT (cCBT) had positive effects for symptoms of anxiety (SMD −0.77, 95% CI −1.45 to −0.09, k = 6, N = 220) and depression (SMD −0.62, 95% CI −1.13 to −0.11, k = 7, N = 279). In a general population study of young people, there were small positive effects for anxiety (SMD −0.15, 95% CI −0.26 to −0.03; N = 1273) and depression (SMD −0.15, 95% CI −0.26 to −0.03; N = 1280). There was uncertainty around the effectiveness of cCBT in children (5–11 years). Evidence for other computerised interventions was sparse and inconclusive. Computerised CBT has potential for treating and preventing anxiety and depression in clinical and general populations of young people. Further program development and research is required to extend its use and establish its benefit in children.

Transcription factor NF-kappaB is transported to the nucleus via cytoplasmic dynein/dynactin motor complex in hippocampal neurons

Background Long-term changes in synaptic plasticity require gene transcription, indicating that signals generated at the synapse must be transported to the nucleus. Synaptic activation of hippocampal neurons is known to trigger retrograde transport of transcription factor NF-κB. Transcription factors of the NF-κB family are widely expressed in the nervous system and regulate expression of several genes involved in neuroplasticity, cell survival, learning and memory. Principal Findings In this study, we examine the role of the dynein/dynactin motor complex in the cellular mechanism targeting and transporting activated NF-κB to the nucleus in response to synaptic stimulation. We demonstrate that overexpression of dynamitin, which is known to dissociate dynein from microtubules, and treatment with microtubule-disrupting drugs inhibits nuclear accumulation of NF-κB p65 and reduces NF-κB-dependent transcription activity. In this line, we show that p65 is associated with components of the dynein/dynactin complex in vivo and in vitro and that the nuclear localization sequence (NLS) within NF-κB p65 is essential for this binding. Conclusion This study shows the molecular mechanism for the retrograde transport of activated NF-κB from distant synaptic sites towards the nucleus.

Serotonin transporter [corrected] methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.