Chromosome imbalances in syndromic hearing loss

The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2-q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14-27%), and the use of aCGH for defining disease etiology is recommended.

Clinical and molecular delineation of the 17q21.31 microdeletion syndrome

Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. Results: We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p< 10(25)). Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2 in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb, and FISH analysis on three patients demonstrated a tandem orientation. Although eight of the 32 breakpoint regions coincide with low-copy repeats, none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared with control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization analysis demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements.

Genomic imbalances associated with mullerian aplasia

Background: Aplasia of the mullerian ducts leads to absence of the uterine corpus, uterine cervix, and upper (superior) vagina. Patients with mullerian aplasia (MA) often exhibit additional clinical features such as renal, vertebral and cardiac defects. A number of different syndromes have been associated with MA, and in most cases its aetiology remains poorly understood. Objective and methods: 14 syndromic patients with MA and 46, XX G-banded karyotype were screened for DNA copy number changes by similar to 1 Mb whole genome bacterial artificial chromosome (BAC) array based comparative genomic hybridisation (CGH). The detected alterations were validated by an independent method and further mapped by high resolution oligo-arrays. Results: Submicroscopic genomic imbalances affecting the 1q21.1, 17q12, 22q11.21, and Xq21.31 chromosome regions were detected in four probands. Presence of the alterations in the normal mother of one patient suggests incomplete penetrance and/or variable expressivity. Conclusion: 4 of the 14 patients (29%) were found to have cryptic genomic alterations. The imbalances on 22q11.21 support recent findings by us and others that alterations in this chromosome region may result in impairment of mullerian duct development. The remaining imbalances indicate involvement of previously unknown chromosome regions in MA, and point specifically to LHX1 and KLHL4 as candidate genes.

Mutagenicity and DNA adduct formation of PAH, nitro-PAH, and oxy-PAH fractions of atmospheric particulate matter from Sao Paulo, Brazil

Urban particulate matter (UPM) contributes to lung cancer incidence. Here, we have studied the mutagenic activity and DNA adduct-forming ability of fractionated UPM extractable organic matter (EOM). UPM was collected with a high-volume sampler in June 2004 at two sites, one at street level adjacent to a roadway and the other inside a park within the urban area of the city of Sao Paulo, Brazil. UPM was extracted using dichloromethane, and the resulting EOM was separated by HPLC to obtain PAH, nitro-PAH, and oxy-PAH fractions which were tested for mutagenicity with the Salmonella strains TA98 and YG1041 with and without S9 metabolic activation. The PAH fraction from both sites showed negligible mutagenic activity in both strains. The highest mutagenic activity was found for the nitro-PAH fraction using YG1041 without metabolic activation; however, results were comparable for both sites. The nitro-PAH and oxy-PAH fractions were incubated with calf thymus DNA under reductive conditions appropriate for the activation of nitro aromatic compounds, then DNA adduct patterns and levels were determined with thin-layer chromatography (TLC) (32)p-postlabeling method using two enrichment procedures-nuclease PI digestion and butanol extraction. Reductively activated fractions from both sites produced diagonal radioactive zones (DRZ) of putative aromatic DNA adducts on thin layer plates with both enrichment procedures. No such DRZ were observed in control experiments using fractions from unexposed filters or from incubations without activating system. Total adduct levels produced by the nitro-PAH fractions were similar for both sites ranging from 30 to 45 adducts per 10(8) normal nucleotides. In contrast, the DNA binding of reductively activated oxy-PAH fractions was three times higher and the adduct pattern consisted of multiple discrete spots along the diagonal line on the thin layer plates. However, DNA adduct levels were not significantly different between the sampling sites. Both samples presented the same levels of mutagenic activity. The response in the Salmonella assay was typical of nitroaromatics. Although, more mutagenic activity was related to the nitro-PAH fraction in the Salmonella assay, the oxy-PAH fractions showed the highest DNA adduct levels. More studies are needed to elucidate the nature of the genotoxicants occurring in Sao Paulo atmospheric samples. (C) 2008 Elsevier B.V. All rights reserved.

Underkuvade kunskaper och genealogins möjligheter

Subjugated knowledges and the possibilities of genealogy The article explores the possibilities of “voicing” marginalized subjects by analyzing letters written by female mental patients in the beginning of the twentieth century. Following Michel Foucault, genealogy is here used as a means to explore and reclaim subjugated knowledges, i.e. knowledges that have been dismissed, distorted, disqualified and put aside by more powerful and ultimately victorious knowledge claims, in this case the psychiatric discourse. Historically oriented research on madness has often explored medical and cultural discourses and representations, as these correspond to sources that can be easily found in archives. This also means that mental patients’ own narratives and texts have been more difficult to trace, partly due to the paucity of available documentation. Herein lies a challenge: how can we represent these subjects, whose stories are inevitably always already captured and filtered by authorities, without portraying them either as passive victims or reducing them to effects of power networks? The article thus ponders research ethics, the question of Otherness and the power of representations. The difficulties in representing female patients’ “own”voices are discussed, yet the article points to the necessity of taking voices that are simultaneously in the margins and in the centre of more powerful discourses, seriously as objects of knowledge. The article argues that “the insurrection of subjugated knowledges”, i.e. bringing back such knowledges as represented here by mental patients’ narratives, opens us otherpossibilities of knowledge. Hence, mental patients’ letters are seen as important “fractures” in the official and legitimized knowledge of madness, offering alternative understandings of both committed individuals and the psychiatric discourse itself.

Shared decision-making in mental health care : a user perspective on decisional needs in community-based services

BACKGROUND: Shared decision-making (SDM) is an emergent research topic in the field of mental health care and is considered to be a central component of a recovery-oriented system. Despite the evidence suggesting the benefits of this change in the power relationship between users and practitioners, the method has not been widely implemented in clinical practice. OBJECTIVE: The objective of this study was to investigate decisional and information needs among users with mental illness as a prerequisite for the development of a decision support tool aimed at supporting SDM in community-based mental health services in Sweden. METHODS: Three semi-structured focus group interviews were conducted with 22 adult users with mental illness. The transcribed interviews were analyzed using a directed content analysis. This method was used to develop an in-depth understanding of the decisional process as well as to validate and conceptually extend Elwyn et al.'s model of SDM. RESULTS: The model Elwyn et al. have created for SDM in somatic care fits well for mental health services, both in terms of process and content. However, the results also suggest an extension of the model because decisions related to mental illness are often complex and involve a number of life domains. Issues related to social context and individual recovery point to the need for a preparation phase focused on establishing cooperation and mutual understanding as well as a clear follow-up phase that allows for feedback and adjustments to the decision-making process. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The current study contributes to a deeper understanding of decisional and information needs among users of community-based mental health services that may reduce barriers to participation in decision-making. The results also shed light on attitudinal, relationship-based, and cognitive factors that are important to consider in adapting SDM in the mental health system.

Double stranded DNA-binding studies of potential Rhodium(ll) antitumor complexes

In 1952, Dwyer and coworkers began testing a series of metal complexes for potential inhibition of cancer cell proliferation in animals.[l] The complexes tested were unsuitable for such studies due to their high toxicity. Therefore, no further work was done on the project. However, in 1965, Rosenberg and coworkers revisited the possibility of potential metal-based drugs. Serendipitously, they discovered that cis-diamminedichloroplatinum(lI) (cisplatin) inhibits cell division in E. coli.[2] Further studies of this and other platinum compounds revealed inhibition of tumor cell lines sarcoma 180 and leukemia LI2l0 in mice.[l] Cisplatin was approved by the Food and Drug Administration in 1970 as a chemical chemotherapeutic agent in the treatment of cancer. The drug has primarily been used in the treatment of testicular and ovarian cancers, although the powerful chemotherapeutic properties of the compound indicate use against a variety of other cancers.[3] The toxicity of this compound, however, warrants the development of other metal-based potential antitumor agents. The success of cisplatin, a transition-metal-based chemotherapeutic, opened the doors to a host of research on the antitumor effects of other transition-metal complexes. Beginning in the 1970s, researchers looked to rhodium for potential use in antitumor complexes. Dirhodium complexes with bridging equatorial ligands (Figure I) were the primary focus for this research. The overwhelming majority of these complexes were dirhodium(II) carboxylate complexes, containing two rhodium(II) centers, four equatorial ligands in a lantero formation around the metal center, and an axial ligand on either end. The family of complexes in Figure 1 will be referred to as dirhodium(II) carboxylate complexes. The dirhodium centers are each d? with a metal-metal bond between them. Although d? atoms are paramagnetic, the two unpaired electrons pair to make the complex diamagnetic. The basic formula of the dirhodium(lI) carboxylate complexes is Rh?(RCOO)?(L)? with R being methyl, ethyl, propyl, or butyl groups and L being water or the solvent in which the complex was crystalized. Of these dirbodium(II) carboxylate complexes, our research focuses on Rb la and two other similar complexes Rh2 and Rh3 (Figure 2). Rh2 is an activated form of Rhla, with four acetonitrile groups in place of two of the bidentate acetate ligands. Rh3 is similar to Rhla, with trifluoromethyl groups in place of the methyl groups on the acetate ligands.

Estilo parental percebido e adaptação psicológica de adolescentes adotados

Nas últimas décadas, diversos autores têm indicado que a condição de ser filho adotivo implica maior risco de desadaptação psicológica. Frente a isto, esta pesquisa investigou as relações existentes entre auto-estima, depressão, estilo parental percebido e adoção. A amostra foi composta por 524 adolescentes entre 14 e 15 anos de idade (68 adotados e 456 criados pelas famílias biológicas). Os instrumentos utilizados foram um questionário demográfico, as Escalas de Responsividade e Exigência Parental, o CDI e a Escala de Auto-Estima de Rosenberg. Análises de Regressão apontaram que as variáveis que apresentaram maior efeito sobre os índices de saúde emocional foram a responsividade parental, o sexo e o tipo de filiação. Os achados indicaram que pais adotivos são significativamente mais indulgentes do que pais biológicos. Em comparação, pais biológicos foram descritos por seus filhos como mais negligentes. Os resultados demonstraram ainda que a adoção isoladamente não resulta em maior depressão entre os jovens, mas a interação da afiliação com diversos outros fatores determina diferenças nestes escores. Os achados corroboraram o efeito transcultural dos estilos parentais sobre a adaptação psicológica e confirmaram a hipótese de que as estratégias de socialização parental moderam o desenvolvimento dos adolescentes adotados.

Mais... ou menos?... : a construção da operação de subtração no campo conceitual das estruturas aditivas

Na perspectiva da Epistemologia Genética, a adição e a subtração são pertencentes a um mesmo gênero de operações, ou seja, às estruturas aditivas e, na Teoria dos Campos Conceituais, a adição e a subtração pertencem ao Campo Conceitual Aditivo. A relação entre elas é abordada dentro do Campo Conceitual Aditivo, trabalhando-se com situações de transformação, de composição parte-todo e de “quanto falta”. Esta pesquisa de Mestrado busca compreender os esquemas que as crianças utilizam na construção da subtração no campo conceitual das estruturas aditivas. Nosso objetivo de pesquisa é descrever os esquemas que expressam avanços no desenvolvimento das crianças na construção da subtração, especificamente nas situações de transformação, de composição parte-todo e de “quanto falta”. Para encontrar esses esquemas, realizamos uma pesquisa microgenética com crianças de 2ª e de 3ª série do Ensino Fundamental, resolvendo situações-problema do campo conceitual aditivo. A subtração é uma operação que leva um tempo maior do que a adição para ser construída e cuja compreensão vai muito além da apropriação da sua linguagem. Entendemos que os significados da adição e da subtração são construídos em conjunto e que, portanto, são partes de um mesmo processo. Verificamos que as crianças, ao construírem os significados dessas operações, vão elaborando esquemas cada vez mais avançados, demonstrando um progresso na compreensão principalmente da subtração.

Hedging options in a garch environment: testing the term structure of stochastic volatility models

This paper develops a methodology for testing the term structure of volatility forecasts derived from stochastic volatility models, and implements it to analyze models of S&P500 index volatility. U sing measurements of the ability of volatility models to hedge and value term structure dependent option positions, we fmd that hedging tests support the Black-Scholes delta and gamma hedges, but not the simple vega hedge when there is no model of the term structure of volatility. With various models, it is difficult to improve on a simple gamma hedge assuming constant volatility. Ofthe volatility models, the GARCH components estimate of term structure is preferred. Valuation tests indicate that all the models contain term structure information not incorporated in market prices.

Perceções acerca do impacto da prática desportiva: um estudo de caso com atletas de competição da escola Dragon Force Madeira

Este estudo inscreve-se no quadro de pesquisa da análise das perceções dos atletas de competição sub 13 da escola Dragon Force acerca do impacto das actividades desportivas sobre o rendimento escolar, relações entre pares e interpessoais, autoestima e autoconceito. Participaram neste estudo 14 atletas do género masculino com idades entre 11 e 13 anos. As metodologias utilizadas foram a quantitativa e a qualitativa. Os instrumentos utilizados foram: notas académicas, Registo de Empenho e Desenvolvimento Educativo (R.E.D.E.), Escala de Autoestima Global de Rosenberg (Rosenberg Self-Esteem Scale, RSES), Questionário de Motivação para as Atividades Desportivas (QMAD), e Escala de Autopercepção de Susan Harter para adolescentes (EAPH-A). Também foi utilizado o focus group. Parte dos dados foi inserida na base de dados do SPSS, versão 19.0, procedendo-se, igualmente, à análise de conteúdo do material resultante do focus group. Embora os resultados revelem que existem algumas diferenças de perceção, a maior parte dos atletas considera que a prática desportiva está associada à alegria e ao divertimento. Também entendem que esta prática influencia o rendimento escolar, a autoestima, o autoconceito, as relações entre pares e interpessoais.

Associação dos níveis de motivação e autoestima na aderência à prática de atividade física de universitários

A aderência à prática da atividade física se constitui na maior dificuldade encontrada pelos profissionais da área da saúde. É importante ter conhecimento de determinantes que podem influenciar na aderência. Os objetivos do presente estudo foram o de elaborar, desenvolver e validar uma escala para avaliar a Autoestima referenciada na aderência da prática da atividade física e verificar a associação da Motivação e Autoestima à prática de atividade física. A Escala de Autoestima proposta para validação é uma escala de auto-resposta com dezesseis itens, cinco dimensões e com respostas com três níveis de concordância. Os participantes no estudo de validação são 312 universitários de ambos os sexos, com idades compreendidas entre 18 e 35 anos. Metade deles é praticante regular de atividade física. A Análise Fatorial dos itens mostra cinco dimensões: Introspecção, Imagem Física, Satisfação com a vida, Aceitação e Confiança. As propriedades psicométricas são aceitáveis, com Alfa de Cronbach igual a 0,75. O estudo de validação baseado nas correlações entre esta escala e a de Rosenberg, segundo o teste Qui-quadrado de Pearson, com sig. p < 0, 001 nas classificações e na correlação sugere que a escala pode ser utilizada em estudos de investigação e programas de promoção da saúde. As escalas de Autoestima e de Motivação (MPAM-R) foram aplicadas a um grupo de 110 universitários, 65% do sexo feminino e 35% do sexo masculino, com idade média compreendida entre 18 e 35 anos. Segmentados em dois grupos de praticantes regulares e não regulares de atividade física. Foram controladas as variáveis demográficas, ambientais e antropométricas. Verificou-se associação significativa entre as variáveis Autoestima e Motivação pelo teste Qui-Quadrado, e que denotam que a dimensão da Autoestima Imagem Física, quando cruzada com as dimensões da Motivação, mostra-se em alto grau discricionário e associação direta. Motivação Diversão (sig.p = 0,002), Competência (sig.p = 0.007) e Social (sig.p = 0.016). Ainda, no cruzamento do Escore Total da dimensão Autoestima e a dimensão Diversão da variável Motivação, apresenta associação diretas e significativas (sig.p = 0.020). A síntese dos resultados denota ações combinadas de estímulo na melhora da percepção positiva da Imagem Física do indivíduo, tendo como plano de fundo, ambiente divertido, desafiador (competência) e social (interação com os pares), traduz em aderência a prática da Atividade Física

Autoestima e qualidade de vida de pessoas com úlcera venosa atendidas na atenção primária

Venous ulcers (VU) is a chronic injury of the lower extremities and because of its high incidence and recurrence implies long and complex treatments, damaging the quality of life (QOL) and self-esteem (SE) of the people. This study aimed to analyze the association between self-esteem with the quality of life of people with venous ulcers treated in primary care. Cross sectional analytical study with a quantitative approach conducted with 44 people met with VU at 13 primary care units 2 and Mixed units in Natal/RN. The study was approved by the Ethics Committee in Research of the Federal University of Rio Grande do Norte (UFRN), CAAE: 07556312.0.0000.5537. Held data collection from February to April 2014 and used three instruments: a structured form covering sociodemographic, health care and clinical variables, the Rosenberg Self-Esteem Scale and the SF-36. The collected data were entered into a database and processed on computerized software for descriptive and inferential analyzes. The results showed a predominance of people with UV females (65,9%), with more than 60 years (59,1%), married or in a stable relationship (52,3%), low education (86,4%) without occupation (68,2%) and less than one minimum wage income (81,8%). Regarding assistance characteristics was observed that most patients performed the dressing with appropriate material (72,7%), professional or trained caregiver (61,4%) did not use compression therapy (81,8%), treating the injury for more than 6 months (77,3%), lack of guidelines for the use of compression therapy, elevation of legs, and regular exercise (77,3%) and consulting the angiologist last year (52,3% ). Regarding clinical features of the lesion was found that most of the recurrent lesions are (77,3%), over one year of current lesion (52,3%) medium to large lesions (54,8%), without signs of infection (61,3%) and pain (79,5%). The mean SE of respondents was 9,3 (± 5,1). The relations between the SE and the sociodemographic variables, health care and clinics showed that individuals without a partner (a) (p = 0,01), who did not wear compression therapy (p = 0,04), with more 6 months of treatment (p = 0,01) and larger lesions (p = 0,01) had a lower SE. The mean domain and the dimensions of the SF-36 were lower emphasizing the functional capacity 36.5 (± 27,6) and the physical aspects of 15.3 (± 30,6). There were significant correlations between AE people with VU and the domains and dimensions of the SF-36: physical functioning (r = -0,432), general health (r = -0,415), vitality (r = -0,573), aspects social (r = -0,517), mental health (r = -0,612) and mental health dimensions (r = -0,612) and physical health (r = -0,473). Based on these results it is concluded by rejecting the null hypothesis and accept the alternative proposed in the study in which it was found that there is a negative correlation between the SE and the QOL of people with venous ulcers