Assessment of Cellular Estrogenic Activity Based on Estrogen Receptor-Mediated Reduction of Soluble-Form Catechol-O-Methyltransferase (COMT) Expression in an ELISA-Based System

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PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion

Background: Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. Methods: As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. Results: Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. Conclusion: Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP. © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.published_or_final_versio

PMCA4 (ATP2B4) Mutation in Familial Spastic Paraplegia

Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. In this study, we identified a novel missense mutation (c.803G.A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP using whole-exome sequencing and confirmed with Sanger sequencing. This mutation co-segregated with the phenotype in the six family members studied and is predicted to be pathogenic when multiple deleteriousness predictions were combined. This novel R268Q mutation was not present in over 7,000 subjects in public databases, and over 1,000 Han Chinese in our database. Prediction of potential functional consequence of R268Q mutation on PMCA4 by computational modeling revealed that this mutation is located in protein aggregation-prone segment susceptible to protein misfolding. Analysis for thermodynamic protein stability indicated that this mutation destabilizes the PMCA4 protein structure with higher folding free energy. As PMCA4 functions to maintain neuronal calcium homeostasis, our result showed that calcium dysregulation may be associated with the pathogenesis of FSP.published_or_final_versio

Clinical and Pathological Findings in Women with Fabry Disease

Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease

The effect of ex-vivo rotenone intoxication on dopamine re-uptake of LRRK2-R1441G mutant mouse

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LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity

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Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease

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Estudo de caso: Gestão do risco operacional ligado às reclamações dos clientes na indústria hoteleira

Cada vez é mais difícil fidelizar os clientes, o desafio para os hotéis continua a ser a diminuição do número de reclamações e a melhoria da satisfação dos hóspedes. A indústria hoteleira já implementou processos para ter uma regularidade na qualidade do serviço. Contudo, no dia a dia os clientes continuam a reclamar quando existe uma falha no serviço. É aqui que entra o conceito do risco operacional, um conceito mais conhecido no setor da banca e pouco estudado na literatura para a indústria do Turismo e da Hotelaria. O relatório de estágio inclui um estudo de caso, criado de maneira a simular as estadias de um casal que vem com regularidade ao Hotel cinco estrelas Penha Longa Ritz-Carlton. Cada reclamação foi resolvida da melhor maneira para satisfazer novamente os hóspedes e o custo associado foi simulado com o objetivo de medir o impacto do risco operacional na rendibilidade. Em conclusão, o risco operacional tem de ser medido com cuidado, mesmo que não seja suposto gerir perdas financeiras significativas, o seu custo tem um impacto na rendibilidade. Existem várias formas de gerir o risco operacional, antecipando processos bem definidos no papel até à gestão das reclamações.As it becomes more complicated to build up customer loyalty, the challenge for hotels continues to be the reduction of customer complaints and the improvement of customer satisfaction. The Hotel industry already implemented processes to assure a regularity in the service quality. However, customers are still complaining on a daily basis when they are victim of a service failure. The operational risk is a concept known in the bank sector and few studies exist for tourism and Hotel industry. The internship report includes a case study, created in a way to simulate various stays of a couple that comes regularly in the five stars Hotel Penha Longa Ritz-Carlton. Each complaint was solved in the best way to satisfy the client and the cost was simulated in order to measure the impact of operational risk on profitability. To conclude, operational risk has to be considered carefully, even if it is not supposed to generate important loss, the cost has impact on profitability. It exists various ways to manage the operational risk, from the anticipation with well-defined processes until the complaints management

Competências não técnicas do enfermeiro instrumentista

Relatório de Estágio apresentado para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Enfermagem PerioperatóriaO presente relatório de estágio enquadra-se no 1º Curso de Mestrado em Enfermagem Perioperatória, da Escola Superior de Saúde do Instituto Politécnico de Setúbal. Foi redigido segundo a metodologia de projeto, focando-se na integração de conhecimentos e competências adquiridas durante o curso, no domínio da enfermagem perioperatória. Tem como objetivos estabelecidos: (1) reflexão crítica acerca das atividades realizadas em contexto de estágio; (2) desenvolvimento de um projeto acerca das competências não técnicas do enfermeiro instrumentista; (3) reflexão crítica acerca do desenvolvimento de competências de mestre em enfermagem perioperatória. De forma a responder aos objetivos propostos organizou-se a estrutura deste relatório por três capítulos distintos: Capítulo I – onde consta o enquadramento concetual, considerando a teoria do autocuidado de Dorothea Elizabeth Orem; e enquadramento teórico, acerca do conceito de competência em enfermagem perioperatória. Capítulo II – corresponde ao enquadramento metodológico, onde é fundamentado o método seguido para a construção do projeto, exposto o tipo de estudo conduzido, o trabalho de campo desenvolvido, bem como os processos de colheita e tratamento de dados, considerando sempre as questões éticas do processo de investigação. Capítulo III – é realizada a reflexão sobre o estágio realizado, assim como a aquisição do perfil de competências de mestre em enfermagem perioperatória. A realização deste relatório de estágio permitiu a aquisição de conhecimentos no domínio da enfermagem perioperatória. Com os contributos da investigação elaborada, foi possível a compreensão e aplicação destes saberes para a resolução de problemas, em ambiente clinico multidisciplinar, consciente das implicações científicas, éticas, deontológicas e jurídicas.This internship report is part of the 1st Master in Perioperative Nursing, taken in Escola Superior de Saúde do Instituto Politécnico de Setúbal. It has been drafted according to project methodology, focusing on the integration of knowledge and skills acquired during the course in the field of perioperative nursing. Its stated objetives are: (1) critical analysis of the activities undertaken in the stage context; (2) project development for scrub nurses non-technical skills; (3) critical assessment on the development master competencies in perioperative nursing. In order to meet the proposed objetives, this report is organized by three chapters: Chapter I – with the conceptual framework, considering the self-care theory of Dorothea Elizabeth Orem; and theoretical framework of competence in perioperative nursing. Chapter II - corresponds to the methodological framework, which is based the method followed for the construction of the project, stated the type of study conducted, the field work and the procedures for collection and processing of data, always considering ethical issues in research process. Chapter III - is held to assess the internship stage, as well as the acquisition of master skills profile in perioperative nursing. The completion of this internship report allowed the acquisition of knowledge in the field of perioperative nursing. With the contributions of elaborate investigation, it was possible the understanding and application of this knowledge to solve problems in a multidisciplinary clinical environment, aware of the scientific, ethical, ethical and legal implications

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS

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