X-linked myoclonic epilepsy with spasticity and intellectual disability - Mutation in the homeobox gene ARX

Objective: To describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder. Methods: The authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach. Results: All six affected boys had myoclonic seizures and TCS; two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2-22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX). Conclusions: XMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX; MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.

Genetic heterogeneity in familial acute myelogenous leukemia: Evidence for a second locus at chromosome 16q21-23.2

The identification of genes responsible for the rare cases of familial leukemia may afford insight into the mechanism underlying the more common sporadic occurrences. Here we test a single family with 11 relevant meioses transmitting autosomal dominant acute myelogenous leukemia (AML) and myelodysplasia for linkage to three potential candidate loci. In a different family with inherited AML, linkage to chromosome 21q22.1-22.2 was recently reported; we exclude linkage to 21q22.1-22.2, demonstrating that familial AML is a heterogeneous disease. After reviewing familial leukemia and observing anticipation in the form of a declining age of onset with each generation, we had proposed 9p21-22 and 16q22 as additional candidate loci. Whereas linkage to 9p21-22 can be excluded, the finding of a maximum two-point LOD score of 2.82 with the microsatellite marker D16S522 at a recombination fraction theta = 0 provides evidence supporting linkage to 16q22. Haplotype analysis reveals a 23.5-cM (17.9-Mb) commonly inherited region among all affected family members extending from D16S451 to D1GS289, In order to extract maximum linkage information with missing individuals, incomplete informativeness with individual markers in this interval, and possible deviance from strict autosomal dominant inheritance, we performed nonparametric linkage analysis (NPL) and found a maximum NPL statistic corresponding to a P-value of .00098, close to the maximum conditional probability of linkage expected for a pedigree with this structure. Mutational analysis in this region specifically excludes expansion of the AT-rich minisatellite repeat FRA16B fragile site and the CAG trinucleotide repeat in the E2F-4 transcription factor. The ''repeat expansion detection'' method, capable of detecting dynamic mutation associated with anticipation, more generally excludes large CAG repeat expansion as a cause of leukemia in this family.

Understanding the practical sense of health actions: contributions of Philosophical Hermeneutics

Health actions have a powerful tech no-scientific armory invested in their instrumental success. Conversely, they have a fragile conceptual basis for the understanding and transformation of the practical sense of health-disease-care processes that especifically take place nowadays. This essay intends to identify the potential contributions of philosophical hermeneutics to overcome such fragility. With this purpose and through contemporary hermeneutics, the recovery of the aristotelian distinction between theory, technique and praxis and its repercussions is discussed, for a systematic treatment of the practical reason of health actions. Against this backdrop, the following stands out: the dialogic essence of understanding-interpreting human acts; the fusion of horizons as the movement of realization of those processes of understanding; and happiness projects, existential guide to everyday life, as the impulse and the possibility of openness of the reason to the practical sense of health actions.

Stem cell transplants for patients with relapsed/refractory leukaemia

Purpose of review Today the indication for allogeneic stem cell transplantation for a high-risk leukaemia in first remission is well defined by most centres. In patients with primary refractory leukaemia the indication is controversially discussed. Similarly patients with relapse and advanced disease have a poor prognosis with chemotherapy, but also with transplantation. Finally more elderly patients with comorbidities seek help from transplantation, most of them in advanced and otherwise refractory disease. The results are reviewed. Recent findings The role of alloimmunity in the control of leukaemia has been defined and pretransplant conditioning treatment could be reduced to less intensive protocols. Graft-versus-leukaemia reactions have been demonstrated with the transfusion of donor lymphocytes. Using nonmyeloablative regimens allogeneic stem cell transplantation could be offered to elderly patients, the majority of patients with acute myeloid leukaemia and myelodysplastic syndromes. The use of antibodies and radio-immunotherapy has improved the treatment of lymphoid malignancies. Cord blood transplants have shown improved results with double transplants. The superiority of maternal donors indicates a role of the donor`s immune repertoire. Summary Taking advantage of alloimmune reactions and reduced intensity conditioning allogeneic stem cell transplantation has become successful even in elderly and fragile patients. The combination of molecular monitoring, targeted therapy and transplantation as a form of immunotherapy may improve the results of leukaemia treatment further.

MicroRNAs Differentially Expressed in ACTH-Secreting Pituitary Tumors

Context: MicroRNAs (miRNAs) are small noncoding RNAs, functioning as antisense regulators of gene expression by targeting mRNA and contributing to cancer development and progression. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites of the genome. Objective: The aim of the study was to analyze the differential expression of let-7a, miR-15a, miR-16, miR-21, miR-141, miR-143, miR-145, and miR-150 in corticotropinomas and normal pituitary tissue and verify whether their profile of expression correlates with tumor size or remission after treatment. Material and Methods: ACTH-secreting pituitary tumor samples were obtained during transphenoidal surgery from patients with Cushing disease and normal pituitary tissues from autopsies. The relative expression of miRNAs was measured by real-time PCR using RNU44 and RNU49 as endogenous controls. Relative quantification of miRNA expression was calculated using the 2(-Delta Delta Ct) method. Results: We found underexpression of miR-145 (2.0-fold; P = 0.04), miR-21 (2.4-fold; P = 0.004), miR-141 (2.6-fold; P = 0.02), let-7a (3.3-fold; P = 0.003), miR-150 (3.8-fold; P = 0.04), miR-15a (4.5-fold; P = 0.03), miR-16 (5.0-fold; P = 0.004), and miR-143 (6.4-fold; P = 0.004) in ACTH-secreting pituitary tumors when compared to normal pituitary tissues. There were no differences between miRNA expression and tumor size as well as miRNA expression and ratio of remission after surgery, except in patients presenting lower miR-141 expression who showed a better chance of remission. Conclusion: Our results support the possibility that altered miRNA expression profile might be involved in corticotrophic tumorigenesis. However, the lack of knowledge about miRNA target genes postpones full understanding of the biological functions of down-regulated or up-regulated miRNAs in corticotropinomas. (J Clin Endocrinol Metab 94: 320-323, 2009)

The genetic and environmental relationship between the interpersonal sensitivity measure (IPSM) and the personality dimensions of Eysenck and Cloninger

A shortened version of the Interpersonal Sensitivity Measure (IPSM) developed to predict depression prone personalities was administered in a self-report questionnaire to a community-based sample of 3269 Australian twin pairs aged 18-28 years, along with Eysenck's EPQ and Cloninger's TPQ. The IPSM included four sub-scales: Separation Anxiety (SEP); Interpersonal Sensitivity (INT); Fragile Inner-Self (FIS); and Timidity (TIM). Univariate analysis revealed that individual differences in the IPSM sub-scale scores were best explained by additive genetic and specific environmental effects. Confirming previous research findings, familial aggregation for the EPQ and TPQ personality dimensions was entirely due to additive genetic effects. In the multivariate case, a model comprising additive genetic and specific environmental effects best explained the covariation between the latent factors for male and female twin pairs alike. The EPQ and TPQ dimensions accounted for moderate to large proportions of the genetic variance (40-76%) in the IPSM sub-scales, while most of the non-shared environment variance was unique to the IPSM sub-scales. (C) 2001 Elsevier Science Ltd. All rights reserved.

Development of ligase-assisted spacer addition for the measurement of microsatellites

Conventional methods for detecting differences in microsatellite repeat lengths rely on electrophoretic fractionation on long denaturing polyacrylamide gels, a time-consuming and labor-intensive method. Therefore, there is a need for the development of new and rapid approaches to routinely detect such length polymorphisms. The advent of techniques allowing the coupling of DNA molecules to solid surfaces has provided new prospects in the area of mutation. We describe here the development and optimization of the ligase-assisted spacer addition (LASA) method, a novel and rapid procedure based on an ELISA format to measure microsatellite repeat lengths. The LASA assay was successfully applied to a set of 11 bird samples to assess its capability as a genotyping method.

Healthy ageing - Adults with intellectual disabilities: Physical health issues

This report has been prepared by the Ageing Special Interest Research Group of the International Association for the Scientific Study of Intellectual Disabilities (IASSID) in collaboration with the Department of Mental Health and Substance Dependence and the Programme on Ageing and Health, World Health Organization (WHO), Geneva, Switzerland, and all rights are reserved by the above mentioned organization. The document may, however, be freely reviewed, abstracted, reproduced or translated in part, but not for sale or use in conjunction with commercial purposes. It may also be reproduced in full by non-commercial entities for information or for educational purposes with prior permission from WHO/IASSID. The document is likely to be available in other languages also.

Dehydration converts DsbG crystal diffraction from low to high resolution

Diffraction quality crystals are essential for crystallographic studies of protein structure, and the production of poorly diffracting crystals is often regarded as a dead end in the process. Here we show a dramatic improvement of poorly diffracting DsbG crystals allowing high-resolution diffraction data measurement. Before dehydration, the crystals are fragile and the diffraction pattern is streaky, extending to 10 Angstrom resolution. After dehydration, there is a spectacular improvement, with the diffraction pattern extending to 2 Angstrom resolution. This and other recent results show that dehydration is a simple, rapid, and inexpensive approach to convert poor quality crystals into diffraction quality crystals.

O modelo organiza????es sociais: li????es e oportunidades de melhoria

As Organiza????es Sociais (OS) s??o organiza????es sem fins lucrativos, ???qualificadas??? para absorver atividades executadas por organiza????es p??blicas, nos termos e condi????es estabelecidas em contratos de gest??o firmados entre organiza????es e o governo. Este artigo relata os principais resultados do semin??rio ???O modelo OS: li????es e oportunidades de melhorias???, realizado em outubro de 2001, do qual participaram gestores e t??cnicos da Secretaria de Gest??o (SEGES), de OS, de ??rg??os supervisores dessas organiza????es, de ??rg??os intervenientes, e especialistas em gest??o p??blica. Com rela????o ??s OS analisadas, pode-se perceber que: a) h?? controv??rsias e ambig??idades quanto ?? sua natureza jur??dica e quanto ao processo de avalia????o dessas organiza????es; b) a gest??o de recursos humanos ?? afetada pela exist??ncia de grupos submetidos a distintos regimes de trabalho, isto ??, Estatuto dos Funcion??rios P??blicos e Consolida????o das Leis do Trabalho; c) a gest??o de recursos financeiros ?? marcada pela irregularidade no fluxo dos referidos recursos; e d) o controle dos bens p??blicos ocorre de forma fr??gil e o processo de compra est?? sendo realizado sem problemas. Com base nessas considera????es, o documento prop??e algumas sugest??es de aperfei??oamento do modelo OS.

A reforma do Estado, a emerg??ncia da descentraliza????o e as pol??ticas ambientais

No contexto da reforma do Estado brasileiro, a descentraliza????o das compet??ncias pol??ticas e administrativas na arena ambiental tem se mostrado um processo din??mico. Muitas inst??ncias locais j?? respondem pela quest??o ambiental. No entanto, isso n??o significa mais compet??ncia administrativa, sustentabilidade institucional, tampouco participa????o democr??tica. Dois casos de pol??tica ambiental s??o retratados no texto: o licenciamento industrial pelos munic??pios brasileiros e o a gest??o florestal pelo Estado do Mato Grosso. A descentraliza????o do licenciamento ambiental para o ??mbito municipal ainda parece fr??gil em munic??pios menores, em um processo que parece ser induzido pelo Estado e n??o pelo controle social local. Em rela????o ?? pol??tica florestal, o caso do Mato Grosso ?? emblem??tico. Ele mostra que a coopera????o com o poder p??blico federal e, em determinados momentos, sua coordena????o s??o de suma import??ncia para que as pol??ticas p??blicas ambientais n??o fiquem ?? merc?? de governos estaduais, que podem envies??-las em favor do ???desenvolvimentismo???, nem percam a legitimidade adiante da fragilidade financeira e institucional dos ??rg??os ambientais locais.

Sa??de do trabalhador: um (n??o) olhar sobre o servidor p??blico

O presente artigo pretende tecer algumas considera????es a respeito dos discursos e pr??ticas da ??rea da sa??de do trabalhador em rela????o aos trabalhadores dos servi??os p??blicos. Na primeira parte, demarca a constru????o do campo da Sa??de do Trabalhador enquanto pol??tica p??blica no Brasil, identificando como as Confer??ncias Nacionais de Sa??de do Trabalhador trataram o tema da sa??de do servidor p??blico. Em seguida, analisa entrevistas realizadas com profissionais da Per??cia M??dica de um estado brasileiro. Ao final, conclui que a????es voltadas ?? aten????o da sa??de do servidor p??blico n??o integram uma pol??tica p??blica, mas ficam ?? merc?? dos diferentes governos, sendo que os enunciados sobre a sa??de do trabalhador t??m uma fr??gil penetra????o em um campo ainda hegem??nico da medicina do trabalho. A sa??de do servidor p??blico n??o tem merecido investimento, apenas controle, em conson??ncia com um longo hist??rico de desvaloriza????o do setor p??blico.

Avalia????o da integra????o do programa de erradica????o do trabalho infantil ao programa bolsa fam??lia

O artigo descreve e avalia o novo modelo do Programa de Erradica????o do Trabalho Infantil (PETI) integrado ao Programa Bolsa Fam??lia (PBF). Mostra que o desenho para implementar a integra????o contribuiu para racionaliza????o e aprimoramento dos processos de gest??o do PBF e PETI: pelo Cadastro ??nico, reduziu gastos administrativos, facilitou monitoramento e avalia????o e contribuiu para melhor aplica????o dos recursos do PETI; pelo SISPETI, tornou poss??vel acompanhar a oferta das a????es socioeducativas e de conviv??ncia pelos munic??pios. Argumenta que, como as causas do trabalho infantil v??o al??m da insufici??ncia de renda, ao enfatizar o crit??rio da renda e equalizar o tratamento das fam??lias que possuem crian??as e adolescentes em situa????o de trabalho infantil e as que n??o registram essa pr??tica, o modelo de integra????o adotado pode ter tornado fr??geis os incentivos ?? retirada das crian??as e adolescentes do trabalho infantil. Conseq??entemente, pode ter enfraquecido a pol??tica de combate ao trabalho infantil.

A poesia nos livros didáticos : contribuição para um projeto educativo emancipatório

Este estudo tem por objetivo analisar poemas transcritos em livros didáticos do Ensino Médio adotados por escolas públicas, a partir do ano 2012, o estudo que as obras fazem dos poemas, o conteúdo das obras relacionado à poesia e à literatura e o trabalho que os professores fazem com os poemas em suas aulas, para verificar o possível potencial desestabilizador desses textos, relacionado à orientação dos discentes quanto à desigualdade e à exclusão social, em consonância com a ideologia de um Projeto Educativo Emancipatório sugerido por Boaventura de Sousa Santos. A pesquisa fundamenta-se nos pressupostos do “método crítico” de Bloch e as análises efetivadas possuem aspecto quantitativo e qualitativo. As informações dos docentes foram colhidas por meio de uma entrevista semiestruturada. Foi possível identificar que os poemas, em geral, nas duas obras, ocorrem em grande quantidade, contudo, em um número reduzido, se considerados aqueles que abordam situações de desigualdade e exclusão social; que há fragilidades importantes no estudo que as obras fazem deles, como uma pobre ou inexistente exploração do sentido textual, que dificulta um trabalho educativo crítico com os alunos; que os conteúdos relacionados à poesia e à literatura estão dispostos de forma fragmentada e desarticulada nas obras, comprometendo a aquisição de um conhecimento global pelos alunos; e que há, por parte dos docentes, um significativo trabalho com poemas, em geral, e um considerável trabalho com poemas do livro didático no sentido de orientar os alunos quanto à realidade social. Concluímos, então, que, apesar das inconsistências indicadas, nos poemas e nas obras, se os professores, conforme nos orienta Dalvi, encararem o livro didático como espaço de rasura e construírem novas visões sobre os seus conteúdos, de maneira a “trapacear” a “trapaça” que ele faz, podem torná-lo mais acessível e educativo para os alunos. Afinal, temos a potência da poesia do livro didático e a possibilidade dos docentes, que sinalizam para a possível tarefa de mostrar aos discentes situações de desigualdade e exclusão do passado, com o intuito de desestabilizá-los, no presente, em consonância com a ideia do supracitado Projeto.

Reviewing horizontalization: the challenge of analysis in Brazilian foreign policy

Abstract This article presents the increasing demands over the Brazilian Ministry of Foreign Affairs (Itamaraty) for opening its doors to other actors. This discussion will be followed by relevant theoretical and methodological analysis. We will defend the need to overcome problems related to: 1) conceptual vagueness about what the concept of participation means; 2) lack of clarity in the baseline to which comparisons are made; 3) fragile empirical basis; 4) limitations on the use of sources; and 5) how to understand the impact exerted by systemic forces.