Development of the Macquarie Anxiety Behavioural Scale (MABS): A parent measure to assess anxiety in children and adolescents including young people with autism spectrum disorder

Objective: This study examined measurement variance for Autism Spectrum Disorder (ASD) in the Spence Children's Anxiety Scale - Parent Form (SCAS-P; Spence, 1999). In addition, we developed and evaluated a new parent report measure for anxiety (Macquarie Anxiety Behavioural Scale; MABS). Method: The sample consisted of 734 parents of children aged 3–19 years (i) who were seeking help for their child's anxiety, (ii) who had received a diagnosis of ASD, or (iii) from the community. Results: Evidence for measurement variance of the SCAS-P and MABS was found, revealing different factor structures between the ASD and non-ASD groups. MIMIC modelling showed that the scales performed significantly different across ASD and non-ASD groups. Differential item functioning on a number of the SCAS-P and MABS items was also found. Limitations: This study relied on parent report of symptoms and of community acquired diagnoses of ASD. Conclusion: The MABS is a new parent measure to assess anxiety in children and adolescents and the proposed factor structure produced a reasonably good fit for the data. Similar to the SCAS-P, ASD was found to impact on some of the MABS items indicating that ASD influences parental responding. Eighteen MABS items showed measurement invariance across the anxious and ASD groups and can be considered suitable items for the assessment of anxiety in ASD

Bridging the gap between education and employment: A case study of problem-based learning implementation in Postgraduate Sport and Exercise Psychology

The purpose of this case study was to explore Postgraduate Sport and Exercise Psychology students’ and their lecturer’s experiences of PBL, and, its role in developing their employability skills. A focus group was conducted with four students (Mage = 22.75 years, SD = 0.96 years; n female = 2) and a conversational interview was conducted with the lecturer (age = 37 years, teaching experience = 11 years). Inductive thematic analysis of verbatim transcripts was used as a basis for developing portrait and composite vignettes to illustrate their experiences. Their underpinning themes suggested that PBL was instrumental for developing key employability skills: team working, communication and interpersonal sensitivity; thinking critically, creatively and flexibly; for helping students translate academic knowledge into application in future employment contexts, and for increasing awareness that learning is a lifelong developmental process

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.This study was funded by the NHS National Institute of Health Research Biomedical Research Unit for Lewy body dementia at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Tissue for this study was provided by Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. MJK is a Wellcome Trust Clinical Research Training Fellow. PFC is a Wellcome Trust Senior Fellow in Clinical Science and National Institute for Health Research Senior Investigator. He receives funding from the Medical Research Council and the National Institute for Health Research Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Foundation Hospitals National Health Service Trust. The funding sources had no role in study design, data collection/analysis, the writing of the paper or the decision of when or where to publish it. The views expressed here are the views of the authors and not necessarily those of the NHS, NIHR or the Department of Health.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v6/n2/full/tp2015220a.html

Minisequencing mitochondrial DNA pathogenic mutations

<p>Abstract</p> <p>Background</p> <p>There are a number of well-known mutations responsible of common mitochondrial DNA (mtDNA) diseases. In order to overcome technical problems related to the analysis of complete mtDNA genomes, a variety of different techniques have been proposed that allow the screening of coding region pathogenic mutations.</p> <p>Methods</p> <p>We here propose a minisequencing assay for the analysis of mtDNA mutations. In a single reaction, we interrogate a total of 25 pathogenic mutations distributed all around the whole mtDNA genome in a sample of patients suspected for mtDNA disease.</p> <p>Results</p> <p>We have detected 11 causal homoplasmic mutations in patients suspected for Leber disease, which were further confirmed by standard automatic sequencing. Mutations m.11778G>A and m.14484T>C occur at higher frequency than expected by change in the Galician (northwest Spain) patients carrying haplogroup J lineages (Fisher's Exact test, <it>P</it>-value < 0.01). The assay performs well in mixture experiments of wild:mutant DNAs that emulate heteroplasmic conditions in mtDNA diseases.</p> <p>Conclusion</p> <p>We here developed a minisequencing genotyping method for the screening of the most common pathogenic mtDNA mutations which is simple, fast, and low-cost. The technique is robust and reproducible and can easily be implemented in standard clinical laboratories. </p

Paediatric obsessive-compulsive disorder and depressive symptoms: clinical correlates and CBT treatment outcomes.

Depression frequently co-occurs with paediatric obsessive-compulsive disorder (OCD), yet the clinical correlates and impact of depression on CBT outcomes remain unclear. The prevalence and clinical correlates of depression were examined in a paediatric specialist OCD-clinic sample (N = 295; Mean = 15 [7 - 18] years, 42 % female), using both dimensional (Beck Depression Inventory-youth; n = 261) and diagnostic (Development and Wellbeing Assessment; n = 127) measures of depression. The impact of depressive symptoms and suspected disorders on post-treatment OCD severity was examined in a sub-sample who received CBT, with or without SSRI medication (N = 100). Fifty-one per-cent of patients reported moderately or extremely elevated depressive symptoms and 26 % (95 % CI: 18 - 34) met criteria for a suspected depressive disorder. Depressive symptoms and depressive disorders were associated with worse OCD symptom severity and global functioning prior to CBT. Individuals with depression were more likely to be female, have had a psychiatric inpatient admission and less likely to be attending school (ps < 0.01). OCD and depressive symptom severity significantly decreased after CBT. Depressive symptoms and depressive disorders predicted worse post-treatment OCD severity (βs = 0.19 and 0.26, ps < 0.05) but became non-significant when controlling for pre-treatment OCD severity (βs = 0.05 and 0.13, ns). Depression is common in paediatric OCD and is associated with more severe OCD and poorer functioning. However, depression severity decreases over the course of CBT for OCD and is not independently associated with worse outcomes, supporting the recommendation for treatment as usual in the presence of depressive symptoms

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEAD227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a Kd of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEAD227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEAD227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10−10M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEAD227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEAD227A. Thus, 5T4FabV13-SEAD227A has highly attractive properties for therapy of human NSCLC. © 2001 Cancer Research Campaign http://www.bjcancer.co

Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Discovering joint associations between disease and gene pairs with a novel similarity test

Genes in a functional pathway can have complex interactions. A gene might activate or suppress another gene, so it is of interest to test joint associations of gene pairs. To simultaneously detect the joint association between disease and two genes (or two chromosomal regions), we propose a new test with the use of genomic similarities. Our test is designed to detect epistasis in the absence of main effects, main effects in the absence of epistasis, or the presence of both main effects and epistasis. Results: The simulation results show that our similarity test with the matching measure is more powerful than the Pearson's chi(2) test when the disease mutants were introduced at common haplotypes, but is less powerful when the disease mutants were introduced at rare haplotypes. Our similarity tests with the counting measures are more sensitive to marker informativity and linkage disequilibrium patterns, and thus are often inferior to the similarity test with the matching measure and the Pearson 's chi(2) test. Conclusions: In detecting joint associations between disease and gene pairs, our similarity test is a complementary method to the Pearson's chi(2) test

Temperature differences are associated with malignancy on lung lesions: a clinical study

BACKGROUND: Although new endoscopic techniques can enhance the ability to detect a suspicious lung lesion, the primary diagnosis still depends on subjective visual assessment. We evaluated whether thermal heterogeneity of solid tumors, in bronchial epithelium, constitutes an additional marker for the diagnosis of benign and malignant lesions. METHODS: A new method, developed in our institute, is introduced in order to detect temperature in human pulmonary epithelium, in vivo. This method is based on a thermography catheter, which passes the biopsy channel of the fiber optic bronchoscope. We calculated the temperature differences (ΔT) between the lesion and a normal bronchial epithelium area on 22 lesions of 20 subjects, 50 – 65 years old. RESULTS: Eleven lesions were benign and 11 were malignant, according to the biopsy histology followed the thermography procedure. We found significant differences of ÄT between patients with benign and malignant tumor (0.71 ± 0.6 vs. 1.23 ± 0.4°C, p < 0.05). Logistic regression analysis showed that 1-Celsius degree differences between normal tissue and suspicious lesion six-fold the probability of malignancy (odds ratio = 6.18, 95% CI 0.89 – 42.7). Also, ΔT values greater than 1.05°C, constitutes a crucial point for the discrimination of malignancy, in bronchial epithelium, with sensitivity (64%) and specificity (91%). CONCLUSION: These findings suggest that the calculated ΔT between normal tissue and a neoplastic area could be a useful criterion for the diagnosis of malignancy in tumors of lung lesions