313 research outputs found
Prader-Willi syndrome and psychotic symptoms: report of a further case
A 21 year-old woman with Prader-Willi syndrome (PWS) and a delusional disorder (paranoid psychosis) is described. Other reports of psychoses associated with PWS are reviewed. Reasons for the co-existence of the two disorders are considered, with discussion of the possible role of auditory information processing deficits in the genesis of psychotic symptoms. Such symptoms must be differentiated from maladaptive behaviours not arising from psychosis, the latter being relatively common in PWS. Treatment with a small dose of flupenthixol greatly reduced the impact of the patient's psychotic symptoms, with a corresponding improvement in her quality of lif
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Investigation of Prader-Willi-like Phenotype using a Whole Genome Array
IntroductionPrader-Willi syndrome (PWS) is characterised byobesity, short stature, small hands and feet, neonatalhypotonia with difficulty in feeding at birth,hypogonadism and eye problems. At about two years ofage the feeding difficulties with poor suck are graduallyreplaced by hyperphagia and obsession with food,leading to the obesity. In addition to developmentaldelay which is manifested by short stature, small handsand feet, growth hormone deficiency andhypogenitalism/hypogonadism, there are alsobehavioural characteristics including learningdisabilities, temper tantrums, aggression, repetitivespeech, obsessive compulsive behaviour, sleep disorderand skin picking (Cassidy and Driscoll, 2009). Thisdisparate collection of symptoms led Holm et al (1993)to define the major and minor characteristics whichallowed a clinical diagnosis of this the most commongenetic form of obesity. Consensus diagnostic criteriawere defined and weighted scores in which the majorcriteria were awarded one point and the minor criteriahalf a point calculated. A score of 8 or more is clinicallydiagnostic for PWS.The majority of people with PWS have a paternallyderived deletion of approximately 5-7Mb in 15q11-q13,others have maternal disomy of chromosome 15(UPD15mat) and a minority have a defect of theimprinting centre located in exon 1 of the SNRPN genewhich leads to a maternal imprint on the paternallyderived chromosome. Any of these abnormalities willresult in loss of the paternal contribution to the Prader-Willi syndrome critical region (PWSCR), demonstratedby loss of a paternally derived unmethylated band at theimprinting centre and a lack of expression of the SNRPNgene. Although these do not differentiate between thedifferent genetic types of PWS they are diagnostic forthe syndrome (Cassidy and Driscoll, 2009; Ramsden etal, 2010; Zeschnigk et al, 1997).Within 15q11-q13 the complex imprintedSNURF/SNRPN gene hosts several untranslated snoRNAgenes located within intronic sequences. The finding ofa microdeletion involving SNORD116 in a boy with PWSled to the identification of this snoRNA as the candidategene for the syndrome (Sahoo et al, 2008).In the course of a large study of PWS in the UK(Whittington et al, 2001; Soni et al, 2007) three peoplewere identified who fulfilled the criteria for a clinicaldiagnosis of the syndrome but not the geneticlaboratory diagnostic criteria.The Affymetrix Cytogenetics Whole-Genome 2.7M arraywhile providing high resolution whole genome coveragereliably detects changes in copy number. Deletionsand/or duplications present in all three participants ifinvolved in annotated genes could potentiallycontribute to the Prader-Willi-like phenotype.Candidate genes can subsequently be evaluated toestimate their transcription levels and compared withthose shown by people with PWS and with unaffectedindividuals
Experience-based utility and own health state valuation for a health state classification system: why do it and how to do it
In the estimation of population value sets for health state classification systems such as the EQ-5D,
there is increasing interest in asking respondents to value their own health state, sometimes referred to as "experienced-based utility values" or more correctly ownrather than hypothetical health states. Own health
state values differ to hypothetical health state values, and this may be attributed to many reasons. This paper
critically examines: whose values matter; why there is a difference between own and hypothetical values; how
to measure own health state values; and why to use own health state values. Finally, the paper also examines
other ways that own health state values can be taken into account, such as including the use of informed general
population preferences that may better take into account experience-based values
Hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival
Chronic myeloid leukemia (CML) stem/progenitor cells (SPC) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPC maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase dependent pathway mediated by the up-regulation of hsa-mir183, the down-regulation of its direct target EGR1 and, as a consequence, up-regulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPC. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPC, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication
Prisonersâ Familiesâ Research: Developments, Debates and Directions
After many years of relative obscurity, research on prisonersâ families has gained significant momentum. It has expanded from case-oriented descriptive analyses of family experiences to longitudinal studies of child and family development and even macro analyses of the effects on communities in societies of mass incarceration. Now the field engages multi-disciplinary and international interest although it arguably still remains on the periphery of mainstream criminological, psychological and sociological research agendas. This chapter discusses developments in prisonersâ familiesâ research and its positioning in academia and practice. It does not aim to provide an all-encompassing review of the literature rather it will offer some reflections on how and why the field has developed as it has and on its future directions. The chapter is divided into three parts. The first discusses reasons for the historically small body of research on prisonersâ families and for the growth in research interest over the past two decades. The second analyses patterns and shifts in the focus of research studies and considers how the field has been shaped by intersecting disciplinary interests of psychology, sociology, criminology and socio-legal studies. The final part reflects on substantive and ethical issues that are likely to shape the direction of prisonersâ familiesâ research in the future
Prevalence and architecture of de novo mutations in developmental disorders.
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year
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