801 research outputs found
Vulnerable suspects in police interviews: exploring current practice in England and Wales
Mentally disordered individuals are increasingly coming into contact with the police. The current study explored investigative interview practice with mentally disordered suspects to examine how they respond, and the impact this has on the level of information obtained. Transcripts of interviews conducted with vulnerable and non-vulnerable suspects (N = 66) were analysed using a specially designed coding framework. Results highlighted that best practice is generally not being adhered to regarding questioning techniques (for example, the use of open questions). Furthermore, while police officers altered their communication to suit the needs of the vulnerable suspect, they were also more likely to use minimisation tactics. Mentally disordered suspects sought more clarification for open questions and provided more information to closed questions. They also demonstrated higher levels of vulnerability (suggestibility and compliance) when compared to their non-vulnerable counterparts. Implications regarding interviewing methods for this vulnerable group are discussed
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2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells.
The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations
Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients
Abstract
Background
Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample.
Results
We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-Îł-strong signature, with increased expression of genes induced by IFN-Îł in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders.
Conclusions
Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.http://deepblue.lib.umich.edu/bitstream/2027.42/112670/1/12864_2012_Article_5257.pd
Behind the confession: Relating false confession, interrogative compliance, personality traits, and psychopathy
The present study further supports the established notion that personality traits contribute to the phenomenon of false confessions and compliance in an interrogative setting. Furthermore, the study provides an investigation into the more recent interest in the potential effect of psychopathic traits in this context. A sample of university students (N = 607) completed questionnaires measuring psychopathic traits, interrogative compliance, and the big five personality factors. Of these, only 4.9% (n=30) claimed to have falsely confessed to an academic or criminal offense, with no participant taking the blame for both types of offense. Across measures the big five personality traits were the strongest predictors of compliance. The five personality traits accounted for 17.9 % of the total variance in compliance, with neuroticism being the strongest predictor, followed by openness and agreeableness. Psychopathy accounted for 3.3% of variance, with the lifestyle facet being the only significant predictor. After controlling for the big five personality factors, psychopathy only accounted for a small percentage of interrogative compliance, indicating that interrogators should take into account a personâs personality traits during the interrogation.N/
Forensic interviewing of mentally disordered suspects: The impact of interview style on investigation outcomes.
The investigative interviewing of a vulnerable suspect is a complex and difficult task. Current best practice advocates for the use of open questions in order to elicit a free recall. However, those with mental health conditions have limited cognitive abilities that relate to free recall and episodic memory, and there is emerging evidence that suggests open questions may not always be most suitable for the vulnerable interviewee. As such, the present study examined the impact of two different interview models (best practice v modified interview) on the amount and accuracy of investigation relevant information obtained within an experimental vulnerable âsuspectâ sample. Participants engaged in two tasks; a minor transgression and a matched non-transgression. Each participant was then subject to either a best practice (containing largely open questions) or a modified interview (containing largely closed questions). Vulnerable participants provided a significantly higher and more accurate amount of investigation relevant information during the modified interview rather than the best practice interview. In addition, participants that have mental health conditions sought more clarifications during the best practice interviews. The type of interview did not impact upon the level of vulnerability displayed. Our findings challenge current best practice in that vulnerable participants performed worse in interviews containing more open questions than closed questions. These findings add to the emerging evidence base that vulnerable individuals may require an alternative method of questioning, including the use of closed questions as âscaffoldingâ during an investigative interview
Metalloproteinase-Mediated, Context-Dependent Function of Amphiregulin and HB-EGF in Human Keratinocytes and Skin
Human keratinocytes (KCs) express multiple EGF receptor (EGFR) ligands; however, their functions in specific cellular contexts remain largely undefined. To address this issue, first we measured mRNA and protein levels for multiple EGFR ligands in KCs and skin. Amphiregulin (AREG) was by far the most abundant EGFR ligand in cultured KCs, with >19 times more mRNA and >7.5 times more shed protein than any other family member. EGFR ligand expression in normal skin was low (<8â° of RPLP0/36B4); however, HB-EGF and AREG mRNAs were strongly induced in human skin organ culture. KC migration in scratch wound assays was highly metalloproteinase (MP)- and EGFR dependent, and was markedly inhibited by EGFR ligand antibodies. However, lentivirus-mediated expression of soluble HB-EGF, but not soluble AREG, strongly enhanced KC migration, even in the presence of MP inhibitors. Lysophosphatidic acid (LPA)-induced ERK phosphorylation was also strongly EGFR and MP dependent and markedly inhibited by neutralization of HB-EGF. In contrast, autocrine KC proliferation and ERK phosphorylation were selectively blocked by neutralization of AREG. These data show that distinct EGFR ligands stimulate KC behavior in different cellular contexts, and in an MP-dependent fashion
Psoriasis drug development and GWAS interpretation through in silico analysis of transcription factor binding sites
BackgroundPsoriasis is a cytokineâmediated skin disease that can be treated effectively with immunosuppressive biologic agents. These medications, however, are not equally effective in all patients and are poorly suited for treating mild psoriasis. To develop more targeted therapies, interfering with transcription factor (TF) activity is a promising strategy.MethodsMetaâanalysis was used to identify differentially expressed genes (DEGs) in the lesional skin from psoriasis patients (nâ=â237). We compiled a dictionary of 2935 binding sites representing empiricallyâdetermined binding affinities of TFs and unconventional DNAâbinding proteins (uDBPs). This dictionary was screened to identify âpsoriasis response elementsâ (PREs) overrepresented in sequences upstream of psoriasis DEGs.ResultsPREs are recognized by IRF1, ISGF3, NFâkappaB and multiple TFs with helixâturnâhelix (homeo) or other allâalphaâhelical (highâmobility group) DNAâbinding domains. We identified a limited set of DEGs that encode proteins interacting with PRE motifs, including TFs (GATA3, EHF, FOXM1, SOX5) and uDBPs (AVEN, RBM8A, GPAM, WISP2). PREs were prominent within enhancer regions near cytokineâencoding DEGs (IL17A, IL19 and IL1B), suggesting that PREs might be incorporated into complex decoy oligonucleotides (cdODNs). To illustrate this idea, we designed a cdODN to concomitantly target psoriasisâactivated TFs (i.e., FOXM1, ISGF3, IRF1 and NFâkappaB). Finally, we screened psoriasisâassociated SNPs to identify risk alleles that disrupt or engender PRE motifs. This identified possible sites of alleleâspecific TF/uDBP binding and showed that PREs are disproportionately disrupted by psoriasis risk alleles.ConclusionsWe identified new TF/uDBP candidates and developed an approach that (i) connects transcriptome informatics to cdODN drug development and (ii) enhances our ability to interpret GWAS findings. Disruption of PRE motifs by psoriasis risk alleles may contribute to disease susceptibility.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/1/ctm2s4016901500545-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/2/ctm2s4016901500545-sup-0018.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/3/ctm2s4016901500545-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/4/ctm2s4016901500545.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/5/ctm2s4016901500545-sup-0009.pd
Molecular Dissection of Psoriasis: Integrating Genetics and Biology
Psoriasis is a common and debilitating disease of the skin, nails, and joints, with an acknowledged but complex genetic basis. Early genome-wide linkage studies of psoriasis focused on segregation of microsatellite markers in families; however, the only locus consistently identified resided in the major histocompatibility complex. Subsequently, several groups mapped this locus to the vicinity of HLA-C, and two groups have reported HLA-Cw6 itself to be the major susceptibility allele. More recently, the development of millions of single-nucleotide polymorphisms, coupled with the development of high-throughput genotyping platforms and a comprehensive map of human haplotypes, has made possible a genome-wide association approach using cases and controls rather than families. Taking advantage of these developments, we participated in a collaborative genome-wide association study of psoriasis involving thousands of cases and controls. Initial analysis of these data revealed and/or confirmed association between psoriasis and seven genetic lociâHLA-C, IL12B, IL23R, IL23A, IL4/IL13, TNFAIP3, and TNIP1âand ongoing studies are revealing additional loci. Here, we review the epidemiology, immunopathology, and genetics of psoriasis, and present a disease model integrating its genetics and immunology
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