The aetiology of idiopathic Parkinson's disease

Agents potentially involved in the aetiology of idiopathic Parkinson's disease are discussed. These include factors regulating dopaminergic neurogenesis (Nurr 1, Ptx-3, and Lmx1b) and related proteins, together with genes involved in familial Parkinson's disease (α synuclein, parkin, and ubiquitin carboxy terminal hydroxylase L1), and endogenous and environmental agents.published_or_final_versio

Role of mitochondrial uncoupling protein-4 in energy supply during neuronal differentiation

OBJECTIVES: Neuronal differentiation is involved in brain development. Stimulation of all-trans-retinoic acid (RA) in neuroblastoma cells results in growth inhibition, increased neuron-specific enolase (NSE) activity, and promoted axonal growth. Mitochondrial uncoupling protein-4 (UCP4) is ...published_or_final_versionThe 16th Medical Research Conference (MRC), Department of Medicine, the University of Hong Kong, Hong Kong, 22 January 2011. In Hong Kong Medical Journal, 2011, v. 17 suppl. 1, p. 31, abstract no. 4

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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Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson's disease (PD). Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation, but as an integral part of this process, superoxides and other reactive oxygen species are also produced. Excessive free radical production contributes to oxidative stress. Cells have evolved to handle such stress via various endogenous anti-oxidant proteins. One such family of proteins is the mitochondrial uncoupling proteins (UCPs), which are anion carriers located in the mitochondrial inner membrane. There are five known homologues (UCP1 to 5), of which UCP4 and 5 are predominantly expressed in neural cells. In a series of previous publications, we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium (MPP+; toxic metabolite of MPTP) and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential, and reducing oxidative stress. We also showed how their expression can be influenced by nuclear factor kappa-B (NF-kappaB) signaling pathway specifically in UCP4. Furthermore, we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin (hormone produced by adipocytes) acting via UCP2 against MPP+-induced toxicity. There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD. Their expression, which can be induced, may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.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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Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease

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Glycine Receptor Complex Analysis Using Immunoprecipitation-Blue Native Gel Electrophoresis-Mass Spectrometry.

The pentameric glycine receptor (GlyR), comprising the α1 and β subunits, is a major inhibitory ionotropic receptor in brainstem and spinal cord. GlyRs interact with gephyrin (GPHN), a scaffold protein that anchors the GlyR in the plasma membrane and enables it to form clusters in glycinergic postsynapses. Using an interaction proteomics approach, we provide evidence of the ArfGEFs IQ motif and Sec7 domain 3 (IQSEC3) and IQ motif and Sec7 domain 2 (IQSEC2) as two novel synaptic proteins interacting with GlyR complexes. When the affinity‐isolated GlyR complexes were fractionated by blue native gel electrophoresis and characterized by mass spectrometry, GlyR α1β‐GPHN appeared as the most abundant complex with a molecular weight of approximately 1 MDa, and GlyR α1β‐GPHN‐IQSEC3 as a minor protein complex of approximately 1.2 MDa. A third GlyR α1β‐GPHN‐IQSEC2 complex existed at the lowest amount with a mass similar to the IQSEC3‐containing complex. Using yeast two‐hybrid we demonstrate that IQSEC3 interacts with the GlyR complex by binding to the GPHN G domain at the N‐terminal of the IQSEC3 IQ‐like domain. Our data provide direct evidence of the interaction of IQSEC3 with GlyR‐GPHN complexes, underscoring a potential role of these ArfGEFs in the function of glycinergic synapses

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

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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