Granulocyte-activating mediators (GRAM)

In the present study we investigated the capability of human epidermal cells to generate granulocyte-activating mediators (GRAM). It could be shown that human epidermal cells as well as an epidermoid carcinoma cell line (A431) produce an epidermal cell-derived granulocyte-activating mediator (EC-GRAM) which stimulates human granulocytes to release significant levels of toxic oxygen radicals as measured by a lucigenin-dependent chemiluminescence (CL). For further characterization of EC-GRAM the A431 cell line was used. Supernatants of A431 cells usually contained maximal EC-GRAM levels within 24 h of incubation. Factor production was enhanced by bacterial lipopolysaccharide (LPS), but not by silica particles and PHA. Moreover, freeze-thaw lysates of A431 cells and extracts of heat-separated human epidermis contained significant levels of EC-GRAM. Preincubation of granulocytes with EC-GRAM resulted in an enhanced response to subsequent stimulation with the chemotactic peptide f-met-phe. In contrast EC-GRAM did not affect the response to PMA or zymosan particles. However, EC-GRAM treated granulocytes were unresponsive to restimulation with EC-GRAM. Upon high performance liquid chromatography (HPLC) gel filtration EC-GRAM eluted within two major peaks exhibiting a molecular weight of 17 kD and 44 kD. According to its biochemical and biological properties EC-GRAM can be separated from other cytokines such as ETAF/-interleukin 1, interleukin 2, interferons, granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor (TNF). However, an antibody to human GM-CSF neutralized about 75% of the activity. These results indicate that EC-GRAM activity stimulating the generation of reactive oxygen species by granulocytes is probably due to GM-CSF

Deconstructing Diagnosis: Four Commentaries on a Diagnostic Tool to Assess Individuals for Autism Spectrum Disorders

This is the final version. Available on open access from Autreach Press via the link in this recordDiagnostic assessment tools are widely used instruments in research and clinical practice to assess and evaluate autism symptoms for both children and adults. These tools typically involve observing the child or adult under assessment, and rating their behaviour for signs or so-called symptoms of autism. In order to examine how autism diagnosis is constructed, how diagnostic tools are positioned, and how their trainings are delivered, we paid for four places on a training course for a diagnostic tool. We asked the attendees (the first four authors) to each produce a critical commentary about their impressions of the training and the diagnostic tool itself. Their commentaries are published here in full. They have various disciplinary backgrounds: one is a social scientist, one an ethicist, one a psychiatrist, and one a developmental psychologist. The commentaries are followed by a concluding section that summarises the themes, commonalities, and differences between their accounts of the training course. Authors differed as to whether the diagnostic tool is a useful and necessary endeavour. Nevertheless, all critiqued of the tool’s lack of transparency, recognizing context, emotion, and differences in interpretation and power imbalances as playing an unidentified role in the assessment process. Based on this project, we recommend that training for raters for such tools should be accessible to a wider group of people, and incorporate more explicit recognition of its own limitations and commercialisation.Wellcome Trus

5-alpha-reductase type I (SRD5A1) is up-regulated in non-small cell lung cancer but does not impact proliferation, cell cycle distribution or apoptosis

<p>Abstract</p> <p>Background</p> <p>Non-small cell lung cancer (NSCLC) is one of the most frequent malignancies and has a high mortality rate due to late detection and lack of efficient treatments. Identifying novel drug targets for this indication may open the way for new treatment strategies. Comparison of gene expression profiles of NSCLC and normal adjacent tissue (NAT) allowed to determine that 5-alpha-reductase type I (SRD5A1) was up-regulated in NSCLC compared to NAT. This raised the question whether SRD5A1 was involved in sustained proliferation and survival of NSCLC.</p> <p>Methods</p> <p>siRNA-mediated silencing of SRD5A1 was performed in A549 and NCI-H460 lung cancer cell lines in order to determine the impact on proliferation, on distribution during the different phases of the cell cycle, and on apoptosis/necrosis. In addition, lung cancer cell lines were treated with 4-azasteroids, which specifically inhibit SRD5A1 activity, and the effects on proliferation were measured. Statistical analyses using ANOVA and post-hoc Tamhane-T2-test were performed. In the case of non-parametric data, the Kruskal-Wallis test and the post-hoc Mann-Whitney-U-test were used.</p> <p>Results</p> <p>The knock-down of SRDA51 expression was very efficient with the SRD5A1 transcripts being reduced to 10% of control levels. Knock-down efficiency was furthermore confirmed at the protein level. However, no effect of SRD5A1 silencing was observed in the proliferation assay, the cell cycle analysis, and the apoptosis/necrosis assay. Treatment of lung cancer cell lines with 4-azasteroids did not significantly inhibit proliferation.</p> <p>Conclusions</p> <p>In summary, the results suggest that SRD5A1 is not a crucial enzyme for the sustained proliferation of NSCLC cell lines.</p

Is disclosing an autism spectrum disorder in school associated with reduced stigmatization?

This is the final version. Available on open access from SAGE Publications via the DOI in this recordDisclosing an autism diagnosis is associated with reduced stigmatization for autistic adults. However, it is unknown whether this is true for autistic adolescents. We used a vignette-and-questionnaire design to study stigmatizing attitudes with adolescents (aged 11- 12 and 14-16 years, total N=250) in a UK school. We investigated the effect of disclosing that a fictional adolescent was autistic on stigmatizing attitudes of peers by testing the effect of disclosure on the social and emotional distance pupils wanted to maintain from the autistic adolescent and their assessment of the adolescent’s responsibility for their own behaviour. Moderation of effects by gender and age-group were analysed. Disclosing autism made no improvement to the social and emotional distance peers wanted to maintain from the autistic adolescent, but was associated with significant reduction in personal responsibility attributed to the adolescent’s behaviour. Boys attributed more personal responsibility to the autistic adolescent than girls, but this gender effect was reduced when autism was disclosed. These findings suggest that disclosing autism to other pupils may be of limited use in reducing stigmatization by peers in UK schools.Wellcome Trus

Mapping the autistic advantage from the accounts of adults diagnosed with autism: A qualitative study

This is the final version. Available on open access from Mary Ann Liebert via the DOI in this recordBackground: Autism has been associated with specific cognitive strengths. Strengths and weaknesses have traditionally been conceptualized as dichotomous. Methods: We conducted 28 semi-structured interviews with autistic adults. Maximum variation sampling was used to ensure diversity in relation to support needs. We asked which personal traits adults attributed to their autism, and how these have helped in the workplace, in relationships, and beyond. Data were collected in two stages. Responses were analyzed using content and thematic techniques. Results: The ability to hyperfocus, attention to detail, good memory, and creativity were the most frequently described traits. Participants also described specific qualities relating to social interaction, such as honesty, loyalty, and empathy for animals or for other autistic people. In thematic analysis we found that traits associated with autism could be experienced either as advantageous or disadvantageous dependent on moderating influences. Moderating influences included the social context in which behaviors occurred, the ability to control behaviors, and the extent to which traits were expressed. Conclusions: Separating autistic strengths from weaknesses may be a false dichotomy if traits cannot be isolated as separate constructs of strengths or deficits. If attempts to isolate problematic traits from advantageous traits are ill conceived, there may be implications for interventions that have reduction in autistic traits as a primary outcome measure.Wellcome Trus

A comprehensive evaluation of the activity and selectivity profile of ligands for RGD-binding integrins

Integrins, a diverse class of heterodimeric cell surface receptors, are key regulators of cell structure and behaviour, affecting cell morphology, proliferation, survival and differentiation. Consequently, mutations in specific integrins, or their deregulated expression, are associated with a variety of diseases. In the last decades, many integrin-specific ligands have been developed and used for modulation of integrin function in medical as well as biophysical studies. The IC50-values reported for these ligands strongly vary and are measured using different cell-based and cell-free systems. A systematic comparison of these values is of high importance for selecting the optimal ligands for given applications. In this study, we evaluate a wide range of ligands for their binding affinity towards the RGD-binding integrins avß3, avß5, avß6, avß8, a5ß1, aIIbß3, using homogenous ELISA-like solid phase binding assay.Postprint (published version