The Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in Dutch advanced cancer patients

Item does not contain fulltextPURPOSE: Depression is highly prevalent in advanced cancer patients, but the diagnosis of depressive disorder in patients with advanced cancer is difficult. Screening instruments could facilitate diagnosing depressive disorder in patients with advanced cancer. The aim of this study was to determine the validity of the Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in advanced cancer patients. METHODS: Patients with advanced metastatic disease, visiting the outpatient palliative care department, were asked to fill out a self-questionnaire containing the Beck Depression Inventory (BDI-II) and a single screening question "Are you feeling depressed?" The mood section of the PRIME-MD was used as a gold standard. RESULTS: Sixty-one patients with advanced metastatic disease were eligible to be included in the study. Complete data were obtained from 46 patients. The area under the curve of the receiver operating characteristics analysis of the BDI-II was 0.82. The optimal cut-off point of the BDI-II was 16 with a sensitivity of 90% and a specificity of 69%. The single screening question showed a sensitivity of 50% and a specificity of 94%. CONCLUSIONS: The BDI-II seems an adequate screening tool for a depressive disorder in advanced cancer patients. The sensitivity of a single screening question is poor.1 februari 201

Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease

Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease

The relationship between organisational characteristics and the effects of clinical guidelines on medical performance in hospitals, a meta-analysis

We are grateful to our colleagues involved in the systematic review of guideline dissemination and implementation strategies across all settings especially Cynthia Fraser, Graeme MacLennan, Craig Ramsay, Paula Whitty, Martin Eccles, Lloyd Matowe, Liz Shirran. The systematic review of guideline dissemination and implementation strategies across all settings was funded by the UK NHS Health Technology Assessment Program. Dr Ruth Thomas is funded by a Wellcome Training Fellowship in Health Services Research. (Grant number GR063790MA). The Health Services Research Unit is funded by the Chief Scientists Office of the Scottish Executive Department of Health. Dr Jeremy Grimshaw holds a Canada Research Chair in Health Knowledge Transfer and Uptake. However the views expressed are those of the authors and not necessarily the funders.Peer reviewedPublisher PD

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia

Deletion of the Chd6 exon 12 affects motor coordination

Members of the CHD protein family play key roles in gene regulation through ATP-dependent chromatin remodeling. This is facilitated by chromodomains that bind histone tails, and by the SWI2/SNF2-like ATPase/helicase domain that remodels chromatin by moving histones. Chd6 is ubiquitously expressed in both mouse and human, with the highest levels of expression in the brain. The Chd6 gene contains 37 exons, of which exons 12-19 encode the highly conserved ATPase domain. To determine the biological role of Chd6, we generated mouse lines with a deletion of exon 12. Chd6 without exon 12 is expressed at normal levels in mice, and Chd6 Exon 12 −/− mice are viable, fertile, and exhibit no obvious morphological or pathological phenotype. Chd6 Exon 12 −/− mice lack coordination as revealed by sensorimotor analysis. Further behavioral testing revealed that the coordination impairment was not due to muscle weakness or bradykinesia. Histological analysis of brain morphology revealed no differences between Chd6 Exon 12 −/− mice and wild-type (WT) controls. The location of CHD6 on human chromosome 20q12 is overlapped by the linkage map regions of several human ataxias, including autosomal recessive infantile cerebellar ataxia (SCAR6), a nonprogressive cerebrospinal ataxia. The genomic location, expression pattern, and ataxic phenotype of Chd6 Exon 12 −/− mice indicate that mutations within CHD6 may be responsible for one of these ataxias

Genetic approaches to human renal agenesis/hypoplasia and dysplasia

Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These conditions are phenotypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheless, overlap between diseases and challenges in clinical diagnosis complicate studies attempting to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanephric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these strategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still represents a challenge, both for the clinicians who attempt a precise diagnosis and for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goal appears to be feasible with the large multicentric collaborative groups that share the same objectives and resources

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans