Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, heritable condition typified by progression of extensive ossification within skeletal muscle, ligament and tendon together with defects in skeletal development. The condition is easily diagnosed by the presence of shortened great toes and there is severe advancement of disability with age. FOP has been shown to result from a point mutation (c.617G>A) in the ACVR1 gene in almost all patients reported. Very recently two other mutations have been described in three FOP patients. We present here evidence for two further unique mutations (c.605G>T and c.983G>A) in this gene in two FOP patients with some atypical digit abnormalities and other clinical features. The observation of disparate missense mutations mapped to the GS and kinase domains of the protein supports the disease model of mild kinase activation and provides a potential rationale for phenotypic variation. © 2009 Petrie et al.

A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant condition, classically characterised by heterotopic ossification beginning in childhood and congenital great toe malformations; occurring in response to a c.617 G>A ACVR1 mutation in the functionally important glycine/serine-rich domain of exon 6. Here we describe a novel c.587 T>C mutation in the glycine/serine-rich domain of ACVR1, associated with delayed onset of heterotopic ossification and an exceptionally mild clinical course. Absence of great toe malformations, the presence of early ossification of the cervical spine facets joints, plus mild bilateral camptodactyly of the 5th fingers, together with a novel ACVR1 mutation, are consistent with the 'FOP-variant' syndrome. The c.587 T>C mutation replaces a conserved leucine with proline at residue 196. Modelling of the mutant protein reveals a steric clash with the kinase domain that will weaken interactions with FKBP12 and induce exposure of the glycine/serine-rich repeat. The mutant receptor is predicted to be hypersensitive to ligand stimulation rather than being constitutively active, consistent with the mild clinical phenotype. This case extends our understanding of the 'FOP-variant' syndrome.

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G→A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

Fibrodysplasia ossificans progressiva-like in a cat

Fibrodisplasia ossificante progressiva (FOP)-like foi diagnosticada em um felino brasileiro jovem com claudicação progressiva, atrofia, incapacidade de extensão e dor a manipulação dos membros pélvicos. em razão de insuficiência nas respostas aos medicamentos observados na literatura foi preconizado apenas orquiectomia e confinamento do paciente. Apesar de a maioria dos relatos de FOP-like indicar eutanásia, o presente caso está sendo acompanhado há quatro anos, desde o diagnóstico, e apesar de o paciente manter-se com restrições de deambulação, encontra em condições satisfatórias.

Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified (“gene activated”) tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible.

The revolution in human monogenic disease mapping

The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease genes for monogenic disorders; however, the limitations of this approach were particularly evident for identifying causative genes in rare genetic disorders affecting lifespan and/or reproductive fitness, such as skeletal dysplasias. In this review, we illustrate the challenges of mapping disease genes in such conditions through the ultra-rare disorder fibrodysplasia ossificans progressiva (FOP) and we discuss the advances that are being made through current massively parallel (“next generation”) sequencing (MPS) technologies.

Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2

In metazoans, bone morphogenetic proteins (BMPS) direct a myriad of developmental and adult homeostatic evens through their heterotetrameric type I and type II receptor complexes. We examined 3 existing and 12 newly generated mutations in the Drosophila type I receptor gene, saxophone (sax), the ortholog of the human Activin Receptor-Like. Kinasel and -2 (ALK1/ACVR1 and ALK2/ACVR1) genes. Our genetic analyses identified two distinct classes of sax alleles. The first class consists of homozygous viable gain-of-function (GOF) alleles that exhibit (1) synthetic lethality in combination with mutations in BMP pathway components, and (2) significant maternal effect lethality that can be rescued by an increased dosage of the BMP encoding gene, dpp(+). In contrast, the second class consists of alleles that are recessive lethal and do not exhibit lethality in combination with mutations in other BMP pathway components. The alleles in this second class are clearly loss-of-function (LOF) with both complete and partial loss-of-function mutations represented. We find that one allele in the second class of recessive lethals exhibits dominant-negative behavior, albeit distinct from the GOF activity of the first class of viable alleles. On the basis of the fact that the first class of viable alleles can be reverted to lethality and on our ability to independently generate recessive lethal sat mutations, our analysis demonstrates that sax is an essential gene. Consistent with this conclusion, we find that a normal sax transcript is produced by sax(P), a viable allele previously reported to be mill, and that this allele can be reverted to lethality. Interestingly, we determine that two mutations in the first: class of sax alleles show the same amino acid substitutions as mutations in the human receptors ALK1/ACVR1-1 and ACVR1/ALK2, responsible for cases of hereditary hemorrhagic telangiectasia type 2 (HHT2) and fibrodysplasia ossificans progressiva (FOP), respectively. Finally, the data presented here identify different functional requirements for the Sax receptor, support the proposal that Sax participates in a heteromeric receptor complex, and provide a mechanistic framework for future investigations into disease states that arise from defects in BMP/TGF-beta signaling.

Systhema de medidas adoptaveis para a progressiva e total extincção do trafico, e da escravatura no Brasil

Proposta da Sociedade ao Governo Imperial para a gradual e total extinção da escravatura no Brasil.

Systhema de medidas adaptaveis para a progressiva e total extincção do trafico, e da escravatura no Brasil / confeccionado e aprovado pela Sociedade Contra o Trafico de Africanos, e Promotora da Colonisação, e da Civilisação dos Indigenas

Proposta da Sociedade ao Governo Imperial para a gradual e total extinção da escravatura no Brasil.

Avaliação dos níveis de ansiedade e depressão e sua correlação com a intensidade de dor em doentes oncológicos com doença avançada e progressiva

Tese de mestrado, Cuidados Paliativos, Faculdade de Medicina, Universidade de Lisboa, 2015

Otimização do processo de projeto de uma ferramenta progressiva para a estampagem de componentes metálicos

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Mecânica

O regresso da homogeneidade no post Guerra Fria. Uma inversão da tendência histórica de progressiva heterogeneidade na natureza do sistema internacional?

Dissertação apresentada para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Ciência Política e Relações Internacionais (especialização em Relações Internacionais)

Seguretat clínica: La percepció del risc assistencial pels malalts amb insuficiència renal crònica progressiva

La seguretat del pacient es considera una prioritat en l’assistència sanitària, activitat cada cop més complexa que comporta riscos potencials i en la que no existeix un sistema capaç de garantir l’absència d’efectes adversos, ja que es tracta d’una activitat en la que es combinen factors inherents al sistema com actuacions humanes (8). Els objectius específics s’han dividit en tres apartats segons les variables relacionades amb: la consulta de diàlisi; la satisfacció dels malalts amb el tracte, comunicació i informació rebuda per part dels professionals de la salut que atenen als malalts a la consulta; i amb els errors comesos per part dels professionals metges i infermers : Les dones se senten més satisfetes amb el tracte rebut per la infermera que els homes. Les expectatives dels participants respecte al que esperaven de la consulta superen l’esperada. Els professionals que treballen a la consulta pre diàlisi són persones sensibles respecte a la intimitat. La consulta de nefrologia aporta confiança, seguretat i satisfacció al pacient. Els malalts que no han patit l’experiència d’efectes indesitjables per l’assistència i per la mediació mostren més satisfacció en el tracte infermer que els que l’han patit. Aquesta relació no s’observa en la satisfacció amb el tracte mèdic.: Les dones se senten més satisfetes amb el tracte rebut per la infermera que els homes. Les expectatives dels participants respecte al que esperaven de la consulta superen l’esperada. Els professionals que treballen a la consulta pre diàlisi són persones sensibles respecte a la intimitat. La consulta de nefrologia aporta confiança, seguretat i satisfacció al pacient. Els malalts que no han patit l’experiència d’efectes indesitjables per l’assistència i per la mediació mostren més satisfacció en el tracte infermer que els que l’han patit. Aquesta relació no s’observa en la satisfacció amb el tracte mèdic

A educação e formação de adultos (1999-2010) : a progressiva importância da educação e formação para a competitividade

Neste artigo discuto a política pública de educação e formação de adultos, em resultado da adopção do S@ber+. Programa para Desenvolvimento e Expansão da Educação e Formação de Adultos 1999-2006, após 1999, e da Iniciativa Novas Oportunidades, depois de 2005. Estes documentos são objecto da análise de conteúdo; são igualmente efectuadas referências a Programas de Governo e legislação. A discussão das finalidades da política pública que podem ser encontradas nestes textos é efectuada a partir de três modelos de análise de políticas públicas que incluem dois eixos, um educativo e um político, aqui destacado, que privilegia a intervenção do Estado na educação de adultos. As considerações finais apontam para uma crescente influência da União Europeia na política pública de educação e formação de adultos, nomeadamente para um destaque na relação entre educação/formação e políticas de emprego, no que às prioridades concerne, o que denota a valorização de princípios de educação e formação para a competitividade, a retracção do Estado neste campo de práticas e a responsabilização dos adultos pelas suas opções e percursos de aprendizagem.