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Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments
Kimberly B. Zumbrennen-Bullough, Lore Becker, Lillian Garrett, Sabine M. H?lter, Julia Calzada-Wack, Ilona Mossbrugger, Leticia Quintanilla-Fend, Ildiko Racz, Birgit Rathkolb, Thomas Klopstock, Wolfgang Wurst, Andreas Zimmer, Eckhard Wolf, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Steven J. Romney, Elizabeth A. Leibold
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098072
Abstract: Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2?/? mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2?/? mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments.
Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System
John F. Staropoli, Larissa Haliw, Sunita Biswas, Lillian Garrett, Sabine M. H?lter, Lore Becker, Sergej Skosyrski, Patricia Da Silva-Buttkus, Julia Calzada-Wack, Frauke Neff, Birgit Rathkolb, Jan Rozman, Anja Schrewe, Thure Adler, Oliver Puk, Minxuan Sun, Jack Favor, Ildikó Racz, Raffi Bekeredjian, Dirk H. Busch, Jochen Graw, Martin Klingenspor, Thomas Klopstock, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Edith Lopez, Hayat Harati, Eric Hill, Daniela S. Krause, Jolene Guide, Ella Dragileva, Evan Gale, Vanessa C. Wheeler, Rose-Mary Boustany, Diane E. Brown, Sylvie Breton, Klaus Ruether, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Susan L. Cotman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038310
Abstract: Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development.
Evidence of Dopaminergic Processing of Executive Inhibition
Rajendra D. Badgaiyan, David Wack
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028075
Abstract: Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand (11C-raclopride) after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites) and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.
Welfare program organization and legitimacy. A comparison of eleven OECD countries
Calzada, Inés
Revista Internacional de Sociologia , 2012,
Abstract: The main objective of this paper is to analyze the relationship between the institutionalisation of the Welfare State (WS) and its legitimacy, that is, until what extent the way of organising welfare programs have an impact on citizen’s perceptions of these programs and, hence, on the size and composition of the legitimacy basis of the WS. In order to comply with this objective the paper is organised as follows: first we will present data showing the cross-country variation in support for three main welfare programs (health care, old-age pensions, unemployment benefits); then we will analyse until what extent high levels of legitimacy are achieved through cross-class coalitions or cross-ideology coalitions. Finally we evaluate the impact of different program characteristics on the aggregate level of popular support each program achieves. El objetivo principal de este artículo es analizar la relación entre la institucionalización del estado del bienestar (eb) y su legitimidad, es decir, hasta qué punto la forma de organizar el eb afecta a las percepciones que los ciudadanos desarrollan sobre el mismo y, de esta manera, modifica el tama o y composición de sus bases de apoyo. A fin de cumplir con este objetivo el artículo se estructura de la siguiente forma: en primer lugar presentamos un panorama de la variación internacional en las actitudes hacia tres programas de bienestar (sanidad, pensiones y desempleo). Seguidamente estudiaremos de dónde proviene el apoyo extra que algunos programas consiguen, centrándonos específicamente en comprobar si una alta legitimidad se logra mediante la construcción de consensos inter-clases o inter-ideologías. terminaremos evaluando qué características organizativas concretas son las que correlacionan con el nivel de apoyo popular que un programa recibe.
Adaptive High Order Sliding Mode Observer Based Fault Reconstruction for a Class of Nonlinear Uncertain Systems: Application to PEM Fuel Cell System
Jianxing Liu,Salah Laghrouche,Maxime Wack
Mathematics , 2013,
Abstract: This paper focuses on observer based fault reconstruction for a class of nonlinear uncertain systems with Lipschitz nonlinearities. An adaptive-gain Super-Twisting (STW) observer is developed for observing the system states, where the adaptive law compensates the uncertainty in parameters. The inherent equivalent output error injection feature of STW algorithm is then used to reconstruct the fault signal. The performance of the proposed observer is validated through a Hardware-In-Loop (HIL) simulator which consists of a commercial twin screw compressor and a real time Polymer Electrolyte Membrane fuel cell emulation system. The simulation results illustrate the feasibility and effectiveness of the proposed approach for application to fuel cell systems.
Observer-Based High Order Sliding Mode Control of Unity Power Factor in Three-Phase AC/DC Converter for Hybrid Electric Vehicle Applications
Jianxing Liu,Salah Laghrouche,Maxime Wack
Mathematics , 2013,
Abstract: In this paper, a full-bridge boost power converter topology is studied for power factor control, using output high order sliding mode control. The AC/DC converters are used for charging the battery and super-capacitor in hybrid electric vehicles from the utility. The proposed control forces the input currents to track the desired values, which can controls the output voltage while keeping the power factor close to one. Super-twisting sliding mode observer is employed to estimate the input currents and load resistance only from the measurement of output voltage. Lyapunov analysis shows the asymptotic convergence of the closed loop system to zero. Simulation results show the effectiveness and robustness of the proposed controller.
Dermatología pediátrica: ?qué hay de nuevo en el acné?
Gilaberte Calzada,Y.;
Pediatría Atención Primaria , 2009, DOI: 10.4321/S1139-76322009000700002
Abstract: acne is one of the most prevalent skin diseases among young people and affects more than 85% of teenagers. this article reviews what is new in acne therapy. the update also includes a new way of looking at acne as a chronic disease, a discussion on the changing role of antibiotics in acne management as a result of concerns about microbial resistance, combined treatments, photodynamic therapy and factors that affect adherence to acne treatments. all these developments are based on a new understanding of the pathophysiology of acne: the role of p. acnes biofilm in the genesis of comedones and inflammation as a key phenomenon in the onset of acne lesions are some of the more recent contributions. the aim of the treatment is to avoid scars and the psychological sequelae of acne.
Algunos aspectos de interés sobre la violencia y el maltrato infantil
Calzada Reyes,Ana;
Revista Cubana de Medicina General Integral , 2004,
Abstract: a bibliographic review of aspects of interest related to the topic of violence, which are of great value in the comprehensive training of the physcian at the primary health care level, is carried out. considerations are made concerning child abuse, one of the diverse forms of expression of violence that is important at present for the medical knowledge and daily practice.
The Nuclear Imperative in Russia’s Security Strategy
J. Oscar Alvarez Calzada
Revista CIDOB d'Afers Internacionals , 2005,
Abstract: The process which culminated in the disappearance of the USSR was heavily influenced by that Soviet Union’s inability to maintain the level of technology reached by the US in the arms race. Under the circumstances of deteriorating Russian power which have been developing since 1991, and given the precariousness that affects its armed forces, nuclear weapons have become the core element of the Russian Federation’s national security strategy. This article explores the causes that have led to this nuclear imperative in Russia’s security strategy; and secondly, it presents the most relevant, and worrying, consequence that this dependence has generated, which is the lowering of the threshold necessary forthe use of nuclear weapons.
Drawing the Caspian Sea: The defining of its legal status in the uncertain post-soviet scenario
J. Oscar álvarez Calzada
Revista CIDOB d'Afers Internacionals , 2003,
Abstract: With the disappearance of the USSR, the Caspian Sea ceased to be an inland sea controlled by the USSR and Iran, to become the object of desire of the new states bordering on it which see in it, and concretely in its extraordinary natural resources, the great hope ofeconomic salvation for their uncertatin future. If we add to this the interests of the great regional actors, Russia and Iran, and those of the United States and the large multinational energy corporations, we get one of the post-Soviet scenarios that arouses the most interestin international public opinion. In this context, the article analyses the unstable situation created in the area in the face of the impossibility of the states bordering on this sea to arrive at a unanimous agreement on the method to follow for dividing up its waters and, therefore, to settle the question of access to the vast natural resources that lie beneath its floor.
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