Wilms' tumour (WT) is a pediatric tumor of the kidney that arises via failure of the fetal developmental program. The absence of identifiable mutations in the majority of WTs suggests the frequent involvement of epigenetic aberrations in WT. We therefore conducted a genome-wide analysis of promoter hypermethylation in WTs and identified hypermethylation at chromosome 5q31 spanning 800 kilobases (kb) and more than 50 genes. The methylated genes all belong to α-, β-, and γ-protocadherin (PCDH) gene clusters (Human Genome Organization nomenclature PCDHA@, PCDHB@, and PCDHG@, respectively). This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors. Bisulfite polymerase chain reaction analysis showed that PCDH hypermethylation is a frequent event found in all Wilms' tumor subtypes. Hypermethylation is concordant with reduced PCDH expression in tumors. WT precursor lesions showed no PCDH hypermethylation, suggesting that de novo PCDH hypermethylation occurs during malignant progression. Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain. Silenced genes are marked with non-permissive histone 3 lysine 9 dimethylation. Expression analysis of embryonic murine kidney and differentiating rat metanephric mesenchymal cells demonstrates that Pcdh expression is developmentally regulated and that Pcdhg@ genes are expressed in blastemal cells. Importantly, we show that PCDHs negatively regulate canonical Wnt signalling, as short-interfering RNA–induced reduction of PCDHG@ encoded proteins leads to elevated β-catenin protein, increased β-catenin/T-cell factor (TCF) reporter activity, and induction of Wnt target genes. Conversely, over-expression of PCDHs suppresses β-catenin/TCF-reporter activity and also inhibits colony formation and growth of cancer cells in soft agar. Thus PCDHs are candidate tumor suppressors that modulate regulatory pathways critical in development and disease, such as canonical Wnt signaling.
Regional regulations of parental imprinting in the IGF2-H19 domain of imprinted genes was studied in the Beckwith-Wiedemann syndrome (BWS). We identified BWS patients who had inherited a normal biparental chromosome complement of the chromosome 11p15.5 region (where IGF2 and H19 reside), but had an altered pattern of allelic methylation of both genes, with the maternal chromosome carrying a parental imprinting pattern. In fibroblasts, IGF2 was expressed from both parental alleles and H19 was not expressed, precisely as predicted from the altered pattern of allelic methylation. Interestingly, DNA replication patterns of the 11p15.5 region remained asynchronous as in controls. Our results therefore provide the first example of the dissociation of regional control of DNA replication from regional control of allelic methylation and expression in imprinting. We suggest that the altered pattern of allelic methylation and expression arises in the germline or in the early embryo from defects in resetting or setting of imprinting in maternal germline. Potential candidate regions for mutations include the previously identified translocation breakpoint clusters and the H19 gene itself. The finding of possible 'imprinting mutations' in BWS raises the prospect of identifying genetic factors that control imprinting in this region.
A total of 105 patients with post-traumatic stress disorder (PTSD) were randomly allocated to eye-movement desensitization and reprocessing (EMDR) .n = 39/ versus exposure plus cognitive restructuring (E Y CR) (n = 37) versus waiting list (WL) (n = 29) in a primary care setting. EMDR and E Y CR patients received a maximum of 10 treatment sessions over a 10-week period. All patients were assessed by blind raters prior to randomization and at end of the 10-week treatment or waiting list period. EMDR and E Y CR patients were also assessed by therapists at the mid-point of the 10-week treatment period and on average at 15 months follow-up. Patients were assessed on a variety of assessor-rated and self-report measures of PTSD symptomatology including the Clinician Administered PTSD Scale (CAPS), the Impact of Events Scale (IOE) and a self-report version of the SI-PTSD Checklist. Measures of anxiety and depression included the Montgomery Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Scale (HAM-A) and the Hospital Anxiety and Depression Scale (HADS). A measure of social function, the Sheehan Disability Scale was also used. Drop-out rates between the three groups were 12 EMDR, 16 E Y CR and five WL. Treatment end-point analyses were conducted on the remaining 72 patients. Repeated measures analysis of variance of treatment outcome at 10 weeks revealed significant time, interaction and group effects for all the above measures. In general there were significant and substantial
Aims and MethodWe undertook a postal questionnaire survey of all consultant psychiatrists working in Scotland to examine whether psychiatrists themselves may contribute to the misunderstandings surrounding schizophrenia by avoiding discussion of the diagnosis with their patients.ResultsTwo-hundred and forty-six (76%) responded. Ninety-five per cent thought the consultant psychiatrist was the most appropriate person to tell a patient their diagnosis of schizophrenia, although only 59% reported doing so in the first established episode of schizophrenia, rising to 89% for recurrent schizophrenia. Fifteen per cent would not use the term ‘schizophrenia’ and a variety of confusing terminology was reported. Over 95% reported telling patients they had mood disorders or anxiety, under 50% that they had dementia or personality disorders.Clinical ImplicationGreater openness by psychiatrists about the diagnosis of schizophrenia may be an essential first step in reducing stigma.
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