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News Article | September 25, 2017
Site: www.eurekalert.org

A study published in the journal Nature Neuroscience, from Nature publishing group, describes the identification of a novel molecular pathway that can constitute a therapeutic target for cognitive defects in Parkinson's disease. The study coordinated by Portuguese researchers from the Instituto de Medicina Molecular (iMM Lisboa), the University Medical Center Goettingen, Germany and CEDOC - Nova Medical School Lisbon, along with other colleagues from Germany, showed that abnormal forms of Parkinson's disease (PD)-associated protein alpha-synuclein interact with the prion protein (PrP), triggering a cascade of events that culminates in neuronal dysfunction, causing cognitive defects that are reminiscent of those in PD. "This is the follow up of a previous study initiated in my laboratory, where we found that particular forms of the protein alpha-synuclein cause dysfunction of neuronal circuits involved in memory formation. We did not know how this was happening, and in this new study we have detailed the molecular mechanisms involved, which suggests we now have new targets for therapeutic intervention" - explains Tiago Outeiro, a former Group leader of iMM now in Germany and at CEDOC, who coordinated the study together with Luísa Lopes, a Group Leader at iMM. Using pharmacology and genetics, the team has now defined a series of molecular events that explains the memory defects observed in animals that model some important aspects of PD. Luísa Lopes adds: "We used a mouse model of PD in which human alpha-synuclein is produced and found that by blocking this interaction with PrP using a caffeine analogue, reverted the abnormal neuronal activity and memory deficits. This study links nicely with our previous work on Alzheimer's disease, further suggesting that molecules like caffeine may indeed have potential benefits against memory deficits upon neurodegeneration". Parkinson's disease is a devastating disorder affecting millions of people worldwide. Current therapies are only symptomatic, and treat only some of the motor symptoms of the disease. "We now know that PD is much more than just a motor disease, and there is a great demand for novel therapies, especially those capable of modulating disease progression or, ideally, capable of preventing the onset of the disease" - explains Tiago Outeiro. "We are very excited with the findings of our collaboration, and this study demonstrates that when we pull together our complementary expertise we can make important discoveries that can impact the lives of the millions of people (patients and families) affected by these terrible disorders" - concludes Luísa Lopes. Original Publication: Diana G. Ferreira, Mariana Temido-Ferreira, Hugo Vicente Miranda, Vânia L. Batalha, Joana E. Coelho, Éva M. Szegö, Inês Marques-Morgado, Sandra H. Vaz, Jeong Seop Rhee, Matthias Schmitz, Inga Zerr, Luísa V. Lopes* and Tiago F. Outeiro* (2017) α-Synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B. Nature Neuroscience doi: 10.1038/nn.4648 Tiago Fleming Outeiro is full Professor and Director of the Department of Experimental Neurodegeneration at the University Medical Center Goettingen. Tiago graduated in Biochemistry at the University of Porto in 1998. He did his PhD thesis at the Whitehead Institute for Biomedical research - MIT, in the USA, and then was a Postdoctoral Research Fellow in the Department of Neurology of the Massachusetts General Hospital - Harvard Medical School where he focused on the study of Neurodegenerative disorders such as Parkinson's and Alzheimer's disease. Tiago directed the Cell and Molecular Neuroscience Unit at IMM, Lisbon, from 2007 to 2014, and has been Full Professor and the Director of the Department of Experimental Neurodegeneration at the University Medical Center Goettingen, in Germany since October 2010. He is also currently leading the Cell and Molecular Neuroscience Group at CEDOC, Nova Medical School, in Lisbon. Tiago is a world leader in the field of Parkinson's and Alzheimer's disease, and has authored >160 research articles in the field of Parkinson's and Alzheimer's disease. He participates in various international collaborative projects with the aim of identifying the molecular basis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. He has received multiple awards and grants in Germany, from the European Union, and from other leading international funding agencies. Luísa V. Lopes is a Group leader@iMM Lisboa, Portugal since 2013 https:/ . Luísa graduated in Lisbon in 1998 in Biochemistry and then pursued a PhD in Neurosciences being trained in the University of Cambridge, UK and at the Karolinska Institute, Sweden, followed by a postdoc at Nestlé Research Center in Lausanne, Switzerland. Her work focuses on understanding the mechanisms inducing the "early-aging" of the cognitive function. The team has provided evidence for an important contribution of adenosine receptors in pathophysiological context, and their impact in noxious brain conditions such as stress, aging and neurodegeneration. Her team provided crucial evidence of a possible glucocorticoid-adenosine link in Alzheimer's disease (with D. Blum) following previous groundwork suggesting circadian disorders as a trigger for accelerated cognitive loss. Instituto de Medicina Molecular (iMM Lisboa) is a reference biomedical research centre in Portugal, having acquired the special status of Associate Laboratory of the Portuguese Ministry of Science and Technology. iMM's mission is to promote basic, translational and clinical biomedical research, with the aim of understanding the mechanisms of disease and developing new therapeutic approaches. For more information please visit the iMM Lisboa's website: http://www. CEDOC - CHRONIC DISEASES RESEARCH CENTER - is an established institute which aims at excellence in medical research on chronic diseases. The general objectives of CEDOC are to form an internationally-recognized Center of excellence in Biomedical, Translational and Clinical Research on chronic diseases; to stimulate collaborative research between groups within the CEDOC; to strengthen research quality and innovation and to promote multidisciplinary projects within and beyond the Center; to provide an exciting research environment for the training of Postdoctoral Fellows, PhD and Master funding at national and international levels; and to simulate the organization of outreach activities at local and national levels. For more information please visit: http://cedoc.


Soares P.I.P.,New University of Lisbon | Dias S.J.R.,Instituto Portugues Of Oncologia Of Lisbon | Dias S.J.R.,Instituto Gulbenkian Ciencia | Novo C.M.M.,CEDOC | And 4 more authors.
Mini-Reviews in Medicinal Chemistry | Year: 2012

Osteosarcoma is the most common primary bone tumor in children and adolescents, with a 5-year disease free survival rate of 70%. Current chemotherapy regimens comprise a group of chemotherapeutic agents in which doxorubicin is included. However, tumor resistance to anthracyclines and cardiotoxicity are limiting factors for its usage. Liposomal formulations of doxorubicin improve its anti-cancer effects but are still insufficient. The research in this area has lead to the production of anthracyclines analogues, such as ladirubicin, the leading compound of alkylcyclines. This new anticancer agent has shown promising results in vivo and in vitro, being effective against osteosarcoma cell lines, including those with a multidrug resistant phenotype. In phase I clinical trials, this molecule caused mild side effects and did not induce significant cardiotoxicity at doses ranging from 1 to 16 mg/m2, resulting in a peak plasma concentration (Cmax) ranging from 0.5 to 1.5 μM. The recommended doses for phase II studies were 12 and 14 mg/m2 in heavily and minimally pretreated/non-pretreated patients, respectively. Phase II clinical trials in ovary, breast, colorectal cancer, NSCLC and malignant melanoma are underway. Given the improved molecular targeting efficacy of these new compounds, ongoing approaches have sought to improve drug delivery systems, to improve treatment efficacy while reducing systemic toxicity. The combination of these two approaches may be a good start for the discovery of new treatment for osteosarcoma. © 2012 Bentham Science Publishers.


Sena A.,CEDOC | Sena A.,Centro Hospitalar Of Lisbon Central | Bendtzen K.,Copenhagen University | Cascais M.J.,CEDOC | And 2 more authors.
Journal of Neurology | Year: 2010

Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher's exact tests for categorical data, respectively. Multivariate logistic regression was usedtoevaluate the effectofpotential confounders. Patients who developed NAbs had lower apoE levels before treatment, 67 (47-74) mg/L median (interquartile range), and at the moment of NAb analysis, 53 (50-84) mg/L, in comparison to those who remained NAb-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta. © Springer-Verlag 2010.


Marcelino P.,CEDOC | Reuter D.A.,University of Hamburg
Current Cardiology Reviews | Year: 2011

The goal of hemodynamic monitoring and management during major surgery is to guarantee adequate organ perfusion, a major prerequisite for adequate tissue oxygenation and thus, end-organ function. Further, hemodynamic monitoring should serve to prevent, detect, and to effectively guide treatment of potentially life-threatening hemodynamic events, such as severe hypovolemia due to hemorrhage, or cardiac failure. The ideal monitoring device does not exist, but some conditions must be met: it should be easy and operator-independently to use; it should provide adequate, reproducible information in real time. In this review we discuss in particular the role of intraoperative use of transesophageal echocardiography (TOE). Although TOE has gained special relevance in cardiac surgery, its role in major non cardiac surgery is still to be determined. We particularly focus on its ability to provide measurements of cardiac output (CO), and its role to guide fluid therapy. Within the last decade, concepts oriented on optimizing stroke volume and cardiac output mainly by fluid administration and guided by continuous monitoring of cardiac output or so called functional parameters of cardiac preload gained particular attention. Although they are potentially linked to an increased amount of fluid infusion, recent data give evidence that such pre-emptive concepts of hemodynamic optimization result in a decrease in morbidity and mortality. As TOE allows a real time direct visualization of cardiac structures, other potentially important advantages of its use also outside the cardiac surgery operation room can be postulated, namely the ability to evaluate the anatomical and functional integrity of the left and the right heart chambers. Finally, a practical approach to TOE monitoring is presented, based on a local experience. © 2011 Bentham Science Publishers.


Dias S.S.,CEDOC | Martins M.F.O.,New University of Lisbon
Procedia Computer Science | Year: 2015

Costs with HIV/AIDS hospitalizations are one of the major financial burdens on healthcare systems worldwide. In Portugal, hospitalizations related to HIV infection are some of the most expensive and the second major diagnosis category, and also accounts for the greatest average length of stay. As a result, it is crucial to understand and identify HIV/AIDS hospital length of stay outliers. The objective of this study is to analyse HIV/AIDS length of stay high outliers during five consecutive years (2009-2013) and to identify its determinants for a specific HIV/AIDS diagnosis related group. To attain these objectives we will use a logistic regression model with random effects. © 2015 The Authors. Published by Elsevier B.V.


Capela T.,Hospital Curry Cabral | Tavares I.,Hospital Curry Cabral | Pereira P.,CEDOC | Vigia E.,CEDOC | And 3 more authors.
Transplantation Proceedings | Year: 2014

This study evaluated the relationship between intraoperative hemodynamic instability (IOHI) and the development of calcineurin inhibitor (CNI) toxicity in the early postoperative period after liver transplantation (LT). Eighty-two patients were enrolled during a 1-year period and a 3-month follow-up. IOHI, requiring continuous infusion of vasopressors, was observed in 31 patients (38%, group 1; control group 2, n = 51). Acute kidney injury (AKI) developed in 28 patients (52% in group 1 vs 24% in group 2, P =.02), and CNI-related neurotoxicity (CNI-NT) in 26 (48% in group 1 vs 22% in group 2, P =.03). Group 1 patients received mainly deceased donor grafts (87% vs 57% in group 2, P <.001). An independent association between IOHI and CNI-NT (P =.029) and AKI (P =.016) was observed. The receiver-operator characteristic curve revealed an area under the curve of 0.63 for IHI (sensitivity 56%; specificity 75%) and 0.65 for AKI (sensitivity 56%; specificity 70.2%). In conclusion, patients undergoing LT with IOHI may be more prone to developing CNI-NT and AKI in the early postoperative period. © 2014 by Elsevier Inc. All rights reserved.


Guarino M.P.,CEDOC | Ribeiro M.J.,CEDOC | Sacramento J.F.,CEDOC | Conde S.V.,CEDOC
Age | Year: 2013

The role of caffeine consumption on insulin action is still under debate. The hypothesis that chronic caffeine intake reverses aging-induced insulin resistance in the rat was tested in this work. The mechanism by which caffeine restores insulin sensitivity was also investigated. Six groups of rats were used: 3 months old (3 M), 3 months old caffeine-treated (3MCaf), 12months old (12 M), 12 months old caffeine-treated (12MCaf), 24 months old (24 M), and 24 months old caffeinetreated (24MCaf). Caffeine was administered in drinking water (1 g/l) during 15 days. Insulin sensitivity was assessed by means of the insulin tolerance test. Blood pressure, body weight, visceral and total fat, fasting glycemia and insulinemia, plasma nonesterified fatty acids (NEFA), total antioxidant capacity (TAC), cortisol, nitric oxide, and catecholamines were monitored. Skeletal muscle Glut4 and 5′-AMP activated protein kinase (AMPK) protein expression and activity were also assessed. Aged rats exhibited diminished insulin sensitivity accompanied by hyperinsulinemia and normoglycemia, increased visceral and total fat, decreased TAC and plasma catecholamines, and also decreased skeletal muscle Glut4 and AMPK protein expression. Chronic caffeine intake restored insulin sensitivity and regularized circulating insulin and NEFA in both aging models. Caffeine neither modified skeletal muscle AMPK expression nor activity in aged rats; however, it decreased visceral and total fat in 12 M rats and it restored skeletal muscle Glut4 expression to control values in 24 M rats. We concluded that chronic caffeine intake reverses aging-induced insulin resistance in rats by decreasing NEFA production and also by increasing Glut4 expression in skeletal muscle. © 2012 American Aging Association.


Figueiredo A.,CEDOC | Germano N.,CEDOC | Guedes P.,CEDOC | Marcelino P.,CEDOC
Current Cardiology Reviews | Year: 2011

Echocardiography is a non-invasive tool, aimed towards the anatomical and functional characterization of the heart. In Intensive Care it is considered nowadays as a necessary tool for patient evaluation. However, the information obtained using echocardiography is not the same as provided by other means, namely the invasive ones. In recent years there has been a significant evolution in the general concepts of haemodynamic support for the critically ill patient. In this new environment, echocardiography has gained particular relevance. In this text the new positioning of echocardiography in the light of the new concepts for hemodynamic support is described, as well as, the need for a specific formative program directed towards Intensive Care physicians. A new generation of biomarkers can also add relevant information and start a new era in haemodynamic support. They may help to further characterize the disease process, identifying patients at risk, as well as, characterize specific organ failure as well as monitoring therapy. © 2011 Bentham Science Publishers.


This study evaluated the relationship between intraoperative hemodynamic instability (IOHI) and the development of calcineurin inhibitor (CNI) toxicity in the early postoperative period after liver transplantation (LT). Eighty-two patients were enrolled during a 1-year period and a 3-month follow-up. IOHI, requiring continuous infusion of vasopressors, was observed in 31 patients (38%, group 1; control group 2, n= 51). Acute kidney injury (AKI) developed in 28 patients (52% in group 1 vs 24% in group 2, P= .02), and CNI-related neurotoxicity (CNI-NT) in 26 (48% in group 1 vs 22% in group 2, P= .03). Group 1 patients received mainly deceased donor grafts (87% vs 57% in group 2, P< .001). An independent association between IOHI and CNI-NT (P= .029) and AKI (P= .016) was observed. The receiver-operator characteristic curve revealed an area under the curve of 0.63 for IHI (sensitivity 56%; specificity 75%) and 0.65 for AKI (sensitivity 56%; specificity 70.2%). In conclusion, patients undergoing LT with IOHI may be more prone to developing CNI-NT and AKI in the early postoperative period.


PubMed | CEDOC
Type: Journal Article | Journal: Age (Dordrecht, Netherlands) | Year: 2013

The role of caffeine consumption on insulin action is still under debate. The hypothesis that chronic caffeine intake reverses aging-induced insulin resistance in the rat was tested in this work. The mechanism by which caffeine restores insulin sensitivity was also investigated. Six groups of rats were used: 3 months old (3 M), 3 months old caffeine-treated (3MCaf), 12 months old (12 M), 12 months old caffeine-treated (12MCaf), 24 months old (24 M), and 24 months old caffeine-treated (24MCaf). Caffeine was administered in drinking water (1 g/l) during 15 days. Insulin sensitivity was assessed by means of the insulin tolerance test. Blood pressure, body weight, visceral and total fat, fasting glycemia and insulinemia, plasma nonesterified fatty acids (NEFA), total antioxidant capacity (TAC), cortisol, nitric oxide, and catecholamines were monitored. Skeletal muscle Glut4 and 5-AMP activated protein kinase (AMPK) protein expression and activity were also assessed. Aged rats exhibited diminished insulin sensitivity accompanied by hyperinsulinemia and normoglycemia, increased visceral and total fat, decreased TAC and plasma catecholamines, and also decreased skeletal muscle Glut4 and AMPK protein expression. Chronic caffeine intake restored insulin sensitivity and regularized circulating insulin and NEFA in both aging models. Caffeine neither modified skeletal muscle AMPK expression nor activity in aged rats; however, it decreased visceral and total fat in 12 M rats and it restored skeletal muscle Glut4 expression to control values in 24 M rats. We concluded that chronic caffeine intake reverses aging-induced insulin resistance in rats by decreasing NEFA production and also by increasing Glut4 expression in skeletal muscle.

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