Origins of inflated responsibility in obsessive compulsive disorder

The pivotal role of inflated responsibility beliefs in the maintenance and treatment of obsessive-compulsive disorder (OCD) has been clearly demonstrated (Rachman, 1993; Salkovskis, 1998; Shafran, 1997; van Oppen & Arntz, 1994). Yet little is known about the origins of these beliefs, their contribution to a sense of inflated responsibility or the symptoms of OCD, or the contribution of personality to inflated responsibility and to OCD, The aims of this thesis were to investigate a model of the inter-relationships among the personality dimensions of neuroticism and psychoticism, inflated responsibility and OCD, and the origins of inflated responsibility to inflated responsibility and to OCD. In order to achieve these aims, a scale was developed to assess the origins of inflated responsibility based upon the five pathways proposed by Salkovskis, Shafran, Rachman, and Freeston (1999) and the additional domains of guilt, vigilance and thought-action fusion (Shafran, Thordarson, & Rachman, 1996; Shafran, Watkins & Charman, 1996; Tallis, 1994). Eighty-four participants with OCD (age M = 43.36) and 74 control participants (age M =37.14) volunteered to participate in the two studies of this thesis. The aim of Study 1 was to develop and validate a measure of the Origins of Inflated Responsibility (OIR). The results of the first study yielded a 25-ttem scale, the Origins of Inflated Responsibility Questionnaire (OIRQ) with five independent factors: responsibility, strictness, protection from responsibility, critical incidents, and peer blame which demonstrated both internal reliability and temporal stability over a 2-week period. In Study 2, participants also completed the Responsibility Attitudes Scale (Salkovskis, Wroe, Gledhill, Morrison, Forrester, Richards, ct al. (2000) (a measure of inflated responsibility), the Padua Inventory (Sanavio, 1988) (to measure of the symptoms of OCD)y and the Eysenck Personality Inventory-Revised (Eysenck & Eysenck, 1991). Multivariatc Analysis of Variance revealed that the OCD group scored higher on all variables than the control group except for strictness where the groups were not different, and psychoticism where the OCD group scored lower. A series of Multiple Regression analyses revealed that both group and the OIR contributed to inflated responsibility (R2 = .56). When all variables, OIR, inflated responsibility and neuroticism were entered as predictors of OCD, 60% of the variance in OCD was explained however, 49% of the variance was shared by the independent variables suggesting the presence of some underlying construct. Structural Equation Modelling, where all the constructs in the model were examined simultaneously, revealed that neuroticism contributed to the OIR, inflated responsibility and OCD. The OIR were also significant predictors of inflated responsibility and indirectly through inflated responsibility predictive of OCD. The OIR also directly predicted OCD and when the total effects are considered, their contribution was greater than the total effect for inflated responsibility alone. The results of these studies provide good support for the origins of inflated responsibility proposed by Salkovskis et al. (1999), as measured by the OIRQ developed for use in the current thesis. The results also support the contribution of inflated responsibility and neuroticism, as well as the OIR, to OCD, The large amount of variance shared by the OIR, inflated responsibility and neuroticism suggest that there might be some underlying construct, perhaps of a biopsychosocial nature, that requires further investigation for its role in the onset and maintenance of OCD. The clinical relevance of these findings is discussed in terms of early prevention strategies and interventions.

Identification of genes differentially regulated by the P210 BCR/ABL1 fusion oncogene using cDNA microarrays

Objective: The t(9;22) translocation is associated with more than 95% of cases of chronic myeloid leukemia. The resulting fusion of the BCR and ABL1 loci produces the constitutively active BCR/ABL1 tyrosine kinase. A wide range of signal transduction molecules are activated by BCR/ABL1, including MYC, PI-3 kinase, and different STAT molecules. In contrast, relatively few genes are known to be regulated by BCR/ABL1 at the level of transcription.

Materials and Methods: In an effort to better understand the transcriptional program activated by BCR/ABL1, we used cDNA microarrays to evaluate the relative expression of approximately 6450 human genes in U937 myelomonocytic cells expressing P210 BCR/ABL1 via a tetracycline-inducible promoter.

Results: We confirmed the previously reported up-regulation of the PIM1 and JUN oncogenes by BCR/ABL1. In addition, we identified 59 more genes up-regulated by BCR/ABL1. Interestingly, roughly one third of these were genes previously reported to be interferon (IFN)-responsive, including the OAS1, IFIT1, IFI16, ISGF3G, and STAT1 genes. An additional seven BCR/ABL1-regulated genes were found to be IFN-responsive in U937 cells. The expression profile also included genes encoding transcription factors, kinases, and signal transduction molecules, as well as genes regulating cell growth, differentiation, apoptosis, and cell adhesion, features previously suggested to be affected by BCR/ABL1.

Conclusion: These observations shed novel insight into the mechanism of BCR/ABL1 action and provide a range of targets for further investigation.