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Benito-Leon J.,University Hospital 12 Of Octubre | Benito-Leon J.,Research Center Biomedica en Red sobre Enfermedades Neurodegenerativas | Benito-Leon J.,Complutense University of Madrid | Mitchell A.J.,University of Leicester | And 2 more authors.
European Journal of Neurology

Background and purpose: To determine the value of health-related quality of life (HRQOL) in predicting progression of disability in patients with multiple sclerosis (MS) over a period of 2 years. Methods: Patients with MS were recruited in 13 outpatient clinics in Madrid, Spain. Baseline HRQOL was quantified using the Functional Assessment of MS (FAMS) and disability with Kurtzke Expanded Disability Status (EDSS). A clinical meaningful deterioration of disability was defined as an increased of ≥1 point in baseline EDSS scores of ≤5.5 and an increase of ≥0.5 point in baseline EDSS scores of ≥6.0. We dichotomized the change in disability according to clinical meaningful deterioration (dependent variable) and performed a logistic regression analysis with the tertiles of the FAMS scores (the upper tertile [high HRQOL] was the reference) as independent variable, adjusting by socio-demographic and clinical variables. Results: Out of 371 enrolled patients, 61 patients with MS dropped out during the 2-year follow-up. Of the remaining 310, 94 (30.3%) had clinical meaningful deterioration of disability. The odds of clinical meaningful deterioration of disability were higher as HRQOL decreased with a significant dose-dependent effect. Adjusted odds ratios were 2.61 [95% confidence interval (CI) 95% = 1.12-6.09], [middle tertile vs. upper tertile (reference)]; and 3.27 (95% CI = 1.31-8.18), (lower tertile vs. upper tertile). Conclusions: The identification of those patients with MS with poor HRQOL may be important in assessing the risk of future disability progression. Clearly, impaired HRQOL should be one of the primary concerns amongst clinicians who provide treatment to patients affected by MS. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS. Source

Ferre S.,U.S. National Institutes of Health | Casado V.,University of Barcelona | Casado V.,Research Center Biomedica en Red sobre Enfermedades Neurodegenerativas | Devi L.A.,Mount Sinai School of Medicine | And 9 more authors.
Pharmacological Reviews

Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seemto apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and highthroughput screening approaches to the discovery of receptor-heteromer selective compounds. Source

Van Den Berg M.E.L.,Carlos III Institute of Health | Castellote J.M.,Carlos III Institute of Health | Castellote J.M.,Complutense University of Madrid | Mahillo-Fernandez I.,Carlos III Institute of Health | And 2 more authors.

Background: Incidence studies of spinal cord injury (SCI) are important for health-care planning and epidemiological research. This review gives a quantitative update on SCI epidemiology worldwide through a statistical evaluation of incidence rates. Methods: A systematic review was conducted. For each study, the crude rate ratio was calculated and, when possible, age- and gender-adjusted incidence rate ratios with 95% CI were determined by direct adjustment or using Poisson regression. Results: Thirteen studies were included. Annual crude incidence rates in traumatic SCI varied from 12.1 per million in The Netherlands to 57.8 per million in Portugal. Compared to the Portuguese reference study, incidence rates showed a 3-fold variation, with the highest rates in Canada and Portugal. Most traumatic SCI studies showed a bimodal age distribution. The first peak was found in young adults between 15 and 29 years and a second peak in older adults (mostly ≥65 years). Motor vehicle accidents and falls were the most prevalent causes of injury accounting for nearly equal percentages. In contrast, another age pattern in non-traumatic SCI reflected steadily increasing incidence with advancing age. Conclusions: The results show significant variation in SCI incidence with changing epidemiological patterns. A trend towards increased incidence in the elderly was observed, likely due to falls and non-traumatic injury. Copyright © 2010 S. Karger AG, Basel. Source

Simon D.,Autonomous University of Madrid | Garcia-Garcia E.,Autonomous University of Madrid | Royo F.,CIC Biomagune | Falcon-Perez J.M.,CIC Biomagune | And 3 more authors.
FEBS Letters

Increasing amounts of tau protein were expressed in non-neuronal cells. When intracellular amounts reached a threshold level, tau protein was released to the extracellular culture medium in association with membrane vesicles. Hence, we propose that tau might be secreted through membrane vesicles as a cellular mechanism to eliminate the excess of tau protein, thereby avoiding its toxicity. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Source

Rodriguez-Oroz M.C.,San Sebastian University | Rodriguez-Oroz M.C.,Ikerbasque | Rodriguez-Oroz M.C.,Research Center Biomedica en Red sobre Enfermedades Neurodegenerativas | Moro E.,University of Toronto | And 2 more authors.
Movement Disorders

The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L-dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so-called "honeymoon" period in which the disease seemed to be controlled, motor fluctuations and L-dopa-induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short- and medium-term follow-up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long-term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long-term clinical outcomes of surgical PD patients with at least 5-year follow-up, focusing on the long-term motor symptoms that were initially responsive to surgery. © 2012 Movement Disorder Society. Source

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