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While self-injurious behaviors (SIB) can cause significant morbidity for children with autism spectrum disorders (ASD), little is known about its associated risk factors. We assessed 7 factors that may influence self-injury in a large cohort of children with ASD: (a) atypical sensory processing; (b) impaired cognitive ability; (c) abnormal functional communication; (d) abnormal social functioning; (e) age; (f) the need for sameness; (g) rituals and compulsions. Half (52.3%, n = 126) of the children (n = 241, aged 2–19 years) demonstrated SIB. Abnormal sensory processing was the strongest single predictor of self-injury followed by sameness, impaired cognitive ability and social functioning. Since atypical sensory processing and sameness have a greater relative impact on SIB, treatment approaches that focus on these factors may be beneficial in reducing self-harm in children with ASD.

Gudrun Rappold and colleagues report the identification of de novo deletions in SHANK2 in two unrelated individuals. One individual was diagnosed with autism spectrum disorder and the other with mental retardation. The authors also identified a de novo nonsense mutation in an individual diagnosed with autism spectrum disorder. Using microarrays, we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation. DNA sequencing of SHANK2 in 396 individuals with ASD, 184 individuals with mental retardation and 659 unaffected individuals (controls) revealed additional variants that were specific to ASD and mental retardation cases, including a de novo nonsense mutation and seven rare inherited changes. Our findings further link common genes between ASD and intellectual disability.

Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin ( Ctnnb1 ) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 ( RSPO3 ), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers. Pre-malignant cells harbouring oncogenic mutations can populate and spread throughout a tissue. Here, using a rainbow mouse system, the authors explore how clonal expansion in the mouse intestine might explain high levels of intra-tumoural heterogeneity observed in the disease.

Autism spectrum disorder (ASD) en- compasses wide variation in symptom severity and functional impact. The core features of ASD include impairments in social communication, repetitive behaviours and restricted interests. Not all people with ASD identify their challenges as a disorder. Autism spectrum disorder affects more than 1% of the population,1 and a dramatic increase in its recognition is creating huge demands on health care systems for timely and accurate diagnosis. Health care professionals in many capacities encounter people and their families coping with ASD, and optimal care depends on a large net- work of providers, given the breadth of the associated medical issues. The Autism and Developmental Disabilities Monitoring Network of the US Centers for Dis- ease Control has surveyed ASD among eight- year-olds from up to 14 US centres every two years since 2000. The most recent analysis, which pertains to the 2008 surveillance year,1 estimates the overall prevalence to be 1 in 88 children - almost double the prevalence re- ported in the original cohort. These data cannot distin guish betwe en an increase cause d b y changes in ascertainment and a true increase in prevalence. Global prevalence, as reported in a comprehensive survey of epidemiological reports from 1966 to 2011,2 suggests that autism is still under-recognized, particularly in developing countries. In Canada, a population prevalence of 1% implies that about 67 000 children, aged 3- 20 years have ASD. Boys with ASD outnumber girls by as much as 4:1, but the underlying rea- sons for this difference remain elusive.3 The diagnostic assessment of ASD allows a physician to determine if a child meets the accepted ASD criteria (usually per Diagnostic and Statistical Manual of Mental Disorders [DSM] criteria), identify comorbid medical or genetic syndromes or psychopathology, and identify the patient's treatment needs. Figure 1 shows the typical paths to diagnosis, starting with concerns (including \"red flags\") raised by parents, teachers, childcare providers, early childhood educators, family physicians or pedia- tricians. Primary care providers then determine whether an assessment is needed for ASD or another developmental issue. A detailed develop- mental history is collected from the parents, and additional information is collected from teachers, early childhood educators and health profession- als. It is essential for the primary care provider to spend time with the child engaged in structured play activities that assess social-emotional relat- edness, the ability of the child to respond to and direct the attention of others, and his or her use of gestures, imitation, imagination and conversa- tion. Multiple prospective and retrospective stud- ies support the recommendations of comprehen- sive reviews and guidelines on diagnosis.18,19

The present paper documents the development of autism/autistic spectrum disorder in a consecutive series of nine high-risk infants followed prospectively from 6 months of age. Evidence is provided for two broadly defined subgroups: the first subgroup (n = 6) showed a decrease in IQ between 12 and 24 or 36 months (from average/near average to severe cognitive impairment), whereas the second subgroup (n = 3) continued to obtain average or near average IQs. Signs of autism emerged and/or were more striking earlier in the first subgroup. In all nine children, early impairment in social-communicative development coexisted with atypical sensory and/or motor behaviors, as did a temperamental profile marked by irritability/distress and dysregulated state. Discussion focuses on issues raised by the pattern of findings.

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR’s pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.

Paraneoplastic neurologic disorders (PNDs) offer an uncommon opportunity to study human tumor immunity and autoimmunity. In small cell lung cancer (SCLC), expression of the HuD neuronal antigen is thought to lead to immune recognition, suppression of tumor growth, and, in a subset of patients, triggering of the Hu paraneoplastic neurologic syndrome. Antigen-specific CTLs believed to contribute to disease pathophysiology were described 10 years ago in paraneoplastic cerebellar degeneration. Despite parallel efforts, similar cells have not been defined in Hu patients. Here, we have identified HuD-specific T cells in Hu patients and provided an explanation for why their detection has been elusive. Different Hu patients harbored 1 of 2 kinds of HuD-specific CD8+ T cells: classical IFN-gamma-producing CTLs or unusual T cells that produced type 2 cytokines, most prominently IL-13 and IL-5, and lacked cytolytic activity. Further, we found evidence that SCLC tumor cells produced type 2 cytokines and that these cytokines trigger naive CD8+ T cells to adopt the atypical type 2 phenotype. These observations demonstrate the presence of an unusual noncytotoxic CD8+ T cell in patients with the Hu paraneoplastic syndrome and suggest that SCLC may evade tumor immune surveillance by skewing tumor antigen-specific T cells to this unusual noncytolytic phenotype.

The article provides the first modern analysis of one of the bestselling transatlantic evangelical poems of the eighteenth century, the Scottish minister Ralph Erskine's Gospel Sonnets. The article argues that the importance of the marriage metaphor and rhyme in the poem provided a specific meaning to the form of the couplet in eighteenth-century transatlantic evangelicalism—a form often associated with an outdated understanding of a monolithic enlightenment. In the case of Erskine, it produced the Calvinist couplet. What the author terms \"espousal poetics\" designates the much larger presence and purpose of the marriage metaphor in the emerging revivalist community: to fuse the paradoxes of a sound Calvinist theology with poetics.

This study explored the experiences of mothers caring for an individual with autism spectrum disorder (ASD) ranging from 5 to 25 years of age, and examined pervasive tensions in caregiving. Guided by ethnographic methods, a retrospective cross-sectional study was conducted. Interviews with 85 mothers were analyzed inductively. Prevalent tensions in maternal caregiving were identified: (a) difficulties obtaining, yet resistance to, an ASD diagnosis; (b) identified giftedness of the child versus notions of deficit imposed by others; (c) disability-related behaviors erroneously interpreted as ‘poor parenting’; (d) contradictory considerations in diagnosis disclosure; (e) the invisibility yet pervasiveness of ASD; (f) extensive need for, yet the lack of, accessible services; (g) ASD-related care demands versus other pressing responsibilities; (h) arguments for inclusive versus exclusive services; and (i) aims of nurturing independence versus managing safety risk. Tensions were heightened by insufficient supports relative to need. Implications and recommendations for practice and policy are offered.

Background The opioid use disorder and overdose crisis in the United States affects public health as well as social and economic welfare. While several genetic and non-genetic risk factors for opioid use disorder have been identified, many of the genetic associations have not been independently replicated, and it is not well understood how these factors interact. This study is designed to evaluate relationships among these factors prospectively to develop future interventions to help prevent or treat opioid use disorder. Methods The Genomics of Opioid Addiction Longitudinal Study (GOALS) is a prospective observational study assessing the interplay of genetic and non-genetic by collecting comprehensive genetic and non-genetic information on 400 participants receiving medication for opioid use disorder. Participants will be assessed at four time points over 1 year. A saliva sample will be collected for large-scale genetic data analyses. Non-genetic assessments include validated surveys measuring addiction severity, depression, anxiety, and adverse childhood experiences, as well as treatment outcomes such as urine toxicology results, visit frequency, and number of pre and post-treatment overdoses extracted from electronic medical records. Discussion We will use these complex data to investigate the relative contributions of genetic and non-genetic risk factors to opioid use disorder and related treatment outcomes.