Psychometric properties of the Cambridge-Mindreading Face-Voice Battery for Children in children with ASD.

This study examined the psychometric characteristics of the Cambridge-Mindreading Face-Voice Battery for Children (CAM-C) for a sample of 333 children, ages 6-12 years with ASD (with no intellectual disability). Internal consistency was very good for the Total score (0.81 for both Faces and Voices) and respectable for the Complex emotions score (0.72 for Faces and 0.74 for Voices); however, internal consistency was lower for Simple emotions (0.65 for Faces and 0.61 for Voices). Test-retest reliability at 18 and 36 weeks was very good for the faces and voices total (0.76-0.81) and good for simple and complex faces and voices (0.53-0.75). Significant correlations were found between CAM-C Faces and scores on another measure of face-emotion recognition (Diagnostic Analysis of Nonverbal Accuracy-Second Edition), and between Faces and Voices scores and child age, IQ (except perceptual IQ and Simple Voice emotions), and language ability. Parent-reported ASD symptom severity and the Emotion Recognition scale on the SRS-2 were not related to CAM-C scores. Suggestions for future studies and further development of the CAM-C are provided. LAY SUMMARY: Facial and vocal emotion recognition are important for social interaction and have been identified as a challenge for individuals with autism spectrum disorder. Emotion recognition is an area frequently targeted by interventions. This study evaluated a measure of emotion recognition (the CAM-C) for its consistency and validity in a large sample of children with autism. The study found the CAM-C showed many strengths needed to accurately measure the change in emotion recognition during intervention.

RCT of a Comprehensive Outpatient Treatment for Children with Autism Spectrum Disorder.

Objective: This study tested the efficacy of an intensive outpatient psychosocial treatment for children with autism spectrum disorder (ASD) without intellectual disability (ID).Method: Eighty-eight children (ages 7-12 years) were randomly assigned to the treatment or control (waitlist) condition. The 18-week cognitive-behavioral treatment (two 90-min sessions per week) included small-group instruction and therapeutic activities targeting social/social-communication skills, face-emotion recognition, nonliteral language skills, and interest expansion. A behavioral system was used to increase skills development and reduce ASD symptoms. Efficacy was tested immediately following treatment (posttest), with maintenance assessed 4-6 weeks later (follow-up). Measures included parent ratings of the children's social/social-communication skills, ASD symptoms, broad social skills, and behavior symptoms, child tests of social-cognitive skills (emotion recognition and nonliteral language), and behavioral observations.Results:Significant effects favoring the treatment group were found at posttest on the primary measures of ASD symptoms (Social Responsiveness Scale, Second Edition; Constantino & Gruber, 2012) and social/social-communication skills (Adapted Skillstreaming Checklist; Lopata, Thomeer, Volker, Nida & Lee, 2008), and secondary measures of nonliteral language skills, broad social skills, and behavior symptoms (measures of emotion-recognition skills and social behaviors during structured game sessions were non-significant). The significant treatment effects found at posttest were all maintained at follow-up.Conclusions: The outpatient treatment improved several core areas of functioning for children with ASD without ID. Additional elements may be needed to expand the efficacy of the treatment so that the observed skills/symptom improvements generalize to social interactions during gameplay.

Moderators of School Intervention Outcomes for Children with Autism Spectrum Disorder.

A prior cluster randomized controlled trial (RCT) compared outcomes for a comprehensive school intervention (schoolMAX) to typical educational programming (services-as-usual [SAU]) for 103 children with autism spectrum disorder (ASD) without intellectual disability. The schoolMAX intervention was superior to SAU in improving social-cognitive understanding (emotion-recognition), social/social-communication skills, and ASD-related impairment (symptoms). In the current study, a range of demographic, clinical, and school variables were tested as potential moderators of treatment outcomes from the prior RCT. Moderation effects were not evident in demographics, child IQ, language, or ASD diagnostic symptoms, or school SES. Baseline externalizing symptoms moderated the outcome of social-cognitive understanding and adaptive skills moderated the outcome of ASD-related symptoms (no other comorbid symptoms or adaptive skills ratings moderated outcomes on the three measures). Overall, findings suggest that the main effects of treatment were, with two exceptions, unaffected by third variables.

Exploratory factor analysis of the Adapted Skillstreaming Checklist for children with autism spectrum disorder.

The Adapted Skillstreaming Checklist measures social/social-communication skills and behavioral flexibility/regulation of children with autism spectrum disorder without intellectual disability. Prior studies provided support for the reliability and criterion-related validity of the Adapted Skillstreaming Checklist total score for these children; however, no studies have examined the Adapted Skillstreaming Checklist factor structure. This exploratory factor analysis examined the factor structure and internal consistency of parent ratings on the Adapted Skillstreaming Checklist for a sample of 331 children, ages 6-12 years, with autism spectrum disorder without intellectual disability. Results yielded a correlated three-factor solution. The individual factors and total score demonstrated very good internal consistency reliability. Findings supported the presence and interpretability of three subscales, as well as derivation of a total composite reflecting overall prosocial and adaptive skills and behaviors. Implications for assessment and research are discussed.

Reliability and validity of teacher ratings on the Adapted Skillstreaming Checklist for children with autism spectrum disorder.

This study assessed the reliability and criterion-related validity of teacher ratings on the Adapted Skillstreaming Checklist for a sample of 133 children, aged 6-11 years, with autism spectrum disorder (without intellectual disability). Internal consistency for the total sample was 0.93. For a subsample, test-retest reliability was very good (r = 0.74; intraclass correlation coefficient = 0.85) at a 9-month interval. Child age, intelligence quotient, language abilities, and sex were not associated with the Adapted Skillstreaming Checklist total score. The Adapted Skillstreaming Checklist total score was inversely and strongly related to teacher ratings of autism spectrum disorder symptom severity. Significant positive correlations (moderate-to-high) were found between the Adapted Skillstreaming Checklist and prosocial skills scales and significant negative correlations (low-to-moderate) with problem behavior scales on a broad measure of child functioning. Implications and suggestions for future study are discussed.

Psychometric Characteristics of the DANVA-2 in High-Functioning Children with ASD.

This study examined psychometric characteristics of the Diagnostic Analysis of Nonverbal Accuracy-Second Edition (DANVA-2) in 121 children, ages 6 to 13 years, with high-functioning autism spectrum disorder (HFASD). Internal consistency for adult and child faces subtests were .70 and .75, respectively. Immediate test-retest reliability in the total sample (N = 121) ranged from .78 to .84. Reliability for two subsamples for 5- (n = 21) and 12-week (n = 21) intervals ranged from .75 to .90 and from .43 to .68, respectively. DANVA-2 scores strongly converged with two measures of emotion recognition but were unrelated to parent ratings of social functioning and ASD symptoms. Significant correlations (small to medium) were found between DANVA-2 scores and child age, IQ, and language ability.

Brief Report: Examination of Sex-Based Differences in ASD Symptom Severity Among High-Functioning Children with ASD Using the SRS-2.

Prior studies of sex-based differences in autism spectrum disorder (ASD) have yielded mixed findings. This study examined ASD symptom severity and functional correlates in a sample of 34 high-functioning females with ASD (HFASD; M age = 8.93; M IQ = 104.64) compared to 34 matched males (M age = 8.96; M IQ = 104.44) using the Social Responsiveness Scale-Second Edition (SRS-2). Results identified non-significant and minimal differences (negligible-to-small) on the SRS-2 total, DSM-5 symptom subscale, and treatment subscale scores. Significant negative (moderate) correlations were found between the SRS-2 Social Cognition subscale and IQ and language scores and between the SRS-2 Social Motivation subscale and receptive language scores for females only; no significant correlations were found for males.

Active cognitive reserve influences the regional atrophy to cognition link in multiple sclerosis.

Recent research indicates that cognitive reserve mitigates the clinical expression of neuropsychological impairment in multiple sclerosis (MS). This literature primarily uses premorbid intelligence and lifetime experiences as indicators. However, changes in current recreational activities may also contribute to the maintenance of neural function despite brain atrophy. We examined the moderation effects of current changes in recreational activity on the relationship between brain atrophy and information processing speed in 57 relapsing-remitting MS patients. Current enrichment was assessed using the Recreation and Pastimes subscale from the Sickness Impact Profile. In patients reporting current declines in recreational activities, brain atrophy was negatively associated with cognition, but there was no such association in participants reporting stable participation. The MRI metric-by-recreational activity interaction was significant in separate hierarchical regression analyses conducted using third ventricle width, neocortical volume, T2 lesion volume, and thalamic volume as brain measures. Results suggest that recreational activities protect against brain atrophy's detrimental influence on cognition.

X-linked inhibitor of apoptosis regulates lung fibroblast resistance to Fas-mediated apoptosis.

The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)ß-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-ß1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-ß1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fas-mediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.

Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation.

RATIONALE: Extracellular matrix (ECM) is a dynamic tissue that contributes to organ integrity and function, and its regulation of cell phenotype is a major aspect of cell biology. However, standard in vitro culture approaches are of unclear physiologic relevance because they do not mimic the compositional, architectural, or distensible nature of a living organ. In the lung, fibroblasts exist in ECM-rich interstitial spaces and are key effectors of lung fibrogenesis. OBJECTIVES: To better address how ECM influences fibroblast phenotype in a disease-specific manner, we developed a culture system using acellular human normal and fibrotic lungs. METHODS: Decellularization was achieved using treatment with detergents, salts, and DNase. The resultant matrices can be sectioned as uniform slices within which cells were cultured. MEASUREMENTS AND MAIN RESULTS: We report that the decellularization process effectively removes cellular and nuclear material while retaining native dimensionality and stiffness of lung tissue. We demonstrate that lung fibroblasts reseeded into acellular lung matrices can be subsequently assayed using conventional protocols; in this manner we show that fibrotic matrices clearly promote transforming growth factor-ß-independent myofibroblast differentiation compared with normal matrices. Furthermore, comprehensive analysis of acellular matrix ECM details significant compositional differences between normal and fibrotic lungs, paving the way for further study of novel hypotheses. CONCLUSIONS: This methodology is expected to allow investigation of important ECM-based hypotheses in human tissues and permits future scientific exploration in an organ- and disease-specific manner.

Increased survivin expression contributes to apoptosis-resistance in IPF fibroblasts.

Fibroblasts perform critical functions during the normal host response to tissue injury, but the inappropriate accumulation and persistent activation of these cells results in the development of tissue fibrosis. The mechanisms accounting for the aberrant accumulation of fibroblasts during fibrotic repair are poorly understood, although evidence supports a role for fibroblast resistance to apoptosis as a contributing factor. We have shown that TGF-ß1 and endothelin-1 (ET-1), soluble mediators implicated in fibrogenesis, promote fibroblast resistance to apoptosis. Moreover, we recently found that ET-1 induced apoptosis resistance in normal lung fibroblasts through the upregulation of survivin, a member of the Inhibitor of Apoptosis (IAP) protein family. In the current study, we sought to determine the role of survivin in the apoptosis resistance of primary fibroblasts isolated from the lungs of patients with Idiopathic Pulmonary Fibrosis (IPF), a fibrotic lung disease of unclear etiology for which there is no definitive therapy. First, we examined survivin expression in lung tissue from patients with IPF and found that there is robust expression in the fibroblasts residing within fibroblastic foci (the "active" lesions in IPF which correlate with mortality). Next, we show that survivin expression is increased in fibroblasts isolated from IPF lung tissue compared to cells from normal lung tissue. Consistent with a role in fibrogenesis, we demonstrate that TGF-ß1 increases survivin expression in normal lung fibroblasts. Finally, we show that inhibition of survivin enhances susceptibility of a subset of IPF fibroblasts to apoptosis. Collectively, these findings suggest that increased survivin expression represents one mechanism contributing an apoptosis-resistant phenotype in IPF fibroblasts.

Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.

Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA(-/-)) and wild-type (WT) mice. While EDA(-/-) mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA(-/-) mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance deleterious remodelling responses. Thus, EDA cFN may be a therapeutic target for ameliorating fibrosis associated with chronic cardiac allograft rejection.

TGF-beta, IL-6, IL-17 and CTGF direct multiple pathologies of chronic cardiac allograft rejection.

Cardiac transplantation is an effective treatment for heart failure refractive to therapy. Although immunosuppressive therapeutics have increased first year survival rates, chronic rejection remains a significant barrier to long-term graft survival. Chronic rejection manifests as patchy interstitial fibrosis, vascular occlusion and progressive loss of graft function. Recent evidence from experimental and patient studies suggests that the development of cardiomyocyte hypertrophy is another hallmark of chronic cardiac allograft rejection. This pathologic hypertrophy is tightly linked to the immune cytokine IL-6, which promotes facets of chronic rejection in concert with TGF-beta and IL-17. These factors potentiate downstream mediators, such as CTGF, which promote the fibrosis associated with the disease. In this article, we summarize contemporary findings that have revealed several elements involved in the induction and progression of chronic rejection of cardiac allografts. Further efforts to elucidate the interplay between these factors may direct the development of targeted therapies for this disease.

Control of fibroblast fibronectin expression and alternative splicing via the PI3K/Akt/mTOR pathway.

Fibronectin (FN), a ubiquitous glycoprotein that plays critical roles in physiologic and pathologic conditions, undergoes alternative splicing which distinguishes plasma FN (pFN) from cellular FN (cFN). Although both pFN and cFN can be incorporated into the extracellular matrix, a distinguishing feature of cFN is the inclusion of an alternatively spliced exon termed EDA (for extra type III domain A). The molecular steps involved in EDA splicing are well-characterized, but pathways influencing EDA splicing are less clear. We have previously found an obligate role for inhibition of the tumor suppressor phosphatase and tensin homologue on chromosome 10 (PTEN), the primary regulator of the PI3K/Akt pathway, in fibroblast activation. Here we show TGF-beta, a potent inducer of both EDA splicing and fibroblast activation, inhibits PTEN expression and activity in mesenchymal cells, corresponding with enhanced PI3K/Akt signaling. In pten(-/-) fibroblasts, which resemble activated fibroblasts, inhibition of Akt attenuated FN production and decreased EDA alternative splicing. Moreover, inhibition of mammalian target of rapamycin (mTOR) in pten(-/-) cells also blocked FN production and EDA splicing. This effect was due to inhibition of Akt-mediated phosphorylation of the primary EDA splicing regulatory protein SF2/ASF. Importantly, FN silencing in pten(-/-) cells resulted in attenuated proliferation and migration. Thus, our results demonstrate that the PI3K/Akt/mTOR axis is instrumental in FN transcription and alternative splicing, which regulates cell behavior.