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RESUMEN En esta investigación se analiza los impactos de la aplicación del Marco Normativo para Entidades de Gobierno en las cifras contables de los departamentos de Colombia, y la afectación generada en los indicadores financieros. Para esto, se realiza el estudio de las variaciones en la muestra de la información financiera de los 32 departamentos para los años 2017 y 2018, acompañado de un análisis de diferencia de medias elaborado mediante la prueba estadística t - student. Los resultados muestran un aumento de los activos en forma general, sin embargo, se evidencia un mayor aumento en los pasivos totales, ocasionando un efecto negativo en indicadores de endeudamiento y propiedad. Este estudio es exploratorio ya que hasta 2019 se están empezando a reflejar en las cifras de los estados financieros dichos impactos, lo que genera gran utilidad para los entes reguladores y responsables de establecer parámetros legales para su aplicación. ABSTRACT This research analyzes the impacts of the application of the Regulatory Framework for Government Entities in the accounting results of the departments of Colombia, and the impact generated in the financial ratios. The study of the variations in the sample of the financial information of the 32 departments for the years 2017 and 2018 is carried out, accompanied by an analysis of difference of means prepared by means of the t-student statistical test. The results show an increase in assets in general, however there is a greater increase in total liabilities, causing a negative effect on debt and property ratios. This study is exploratory since until 2019 they are beginning to reflect in the figures of the financial statements such impacts, which generates great utility for the regulatory entities and responsible for establishing legal parameters for their application. RESUMO Esta pesquisa analisa os impactos da aplicação da estrutura regulatória para entidades governamentais nas cifras contábeis dos departamentos da Colômbia e o impacto gerado nos indicadores financeiros. Para isso, realizou-se o estudo das variações na amostra das informações financeiras dos 32 departamentos para os anos de 2017 e 2018, acompanhadas de uma análise da diferença de médias preparada pelo teste t-student. Os resultados mostram um aumento dos ativos em geral, no entanto, um aumento maior no passivo total é evidente, causando um efeito negativo nos indicadores de dívida e propriedade. Este estudo é exploratório, pois até 2019 esses impactos começam a refletir-se nas cifras das demonstrações financeiras, o que gera grande utilidade para as entidades reguladoras e responsáveis pelo estabelecimento de parâmetros legais para sua aplicação.

Resumen A lo largo de todas las etapas evolutivas, las personas con discapacidad intelectual pueden presentar trastornos psiquiatricos comorbidos, que a menudo son secundarios a sus deficits intelectivos y a las dificultades en sus capacidades adaptativas a los diferentes entornos que forman parte de sus vidas. Estas comorbilidades psiquiatricas cursan en ocasiones con alteraciones de conducta de dificil manejo, tanto con psicoterapia como con tratamientos farmacologicos. La medicacion puede ser esencial para el control de alteraciones de conducta y otros sintomas asociados. Actualmente carecemos de guias clinicas especificas, de recomendaciones farmacologicas con la suficiente evidencia cientifica y de medicamentos con indicaciones expresas para abordar estos sintomas en pacientes con discapacidad intelectual. Este articulo de revision tiene como objetivo resumir un conjunto de recomendaciones relacionadas con el uso de psicofarmacos en este grupo poblacional.

Neurodevelopmental disorders are challenging to study in the laboratory, and despite a large investment, few novel treatments have been developed in the last decade. While animal models have been valuable in elucidating disease mechanisms and in providing insights into the function of specific genes, the predictive validity of preclinical models to test potential therapies has been questioned. In the last two decades, diverse new murine models of Down syndrome (DS) have been developed and numerous studies have demonstrated neurobiological alterations that could be responsible for the cognitive and behavioral phenotypes found in this syndrome. In many cases, similar alterations were found in murine models and in individuals with DS, although several phenotypes shown in animals have yet not been confirmed in the human condition. Some of the neurobiological alterations observed in mice have been proposed to account for their changes in cognition and behavior, and have received special attention because of being putative therapeutic targets. Those include increased oxidative stress, altered neurogenesis, overexpression of the Dyrk1A gene, GABA-mediated overinhibition and Alzheimer's disease-related neurodegeneration. Subsequently, different laboratories have tested the efficacy of pharmacotherapies targeting these alterations. Unfortunately, animal models are limited in their ability to mimic the extremely complex process of human neurodevelopment and neuropathology. Therefore, the safety and efficacy identified in animal studies are not always translated to humans, and most of the drugs tested have not demonstrated any positive effect or very limited efficacy in clinical trials. Despite their limitations, though, animal trials give us extremely valuable information for developing and testing drugs for human use that cannot be obtained from molecular or cellular experiments alone. This chapter reviews some of these therapeutic approaches and discusses some reasons that could account for the discrepancy between the findings in mouse models of DS and in humans, including: (i) the incomplete resemble of the genetic alterations of available mouse models of DS and human trisomy 21, (ii) the lack of evidence that some of the phenotypic alterations found in mice (e.g., GABA-mediated overinhibition, and alterations in adult neurogenesis) are also present in DS individuals, and (iii) the inaccuracy and/or inadequacy of the methods used in clinical trials to detect changes in the cognitive and behavioral functions of people with DS. Despite the shortcomings of animal models, animal experimentation remains an invaluable tool in developing drugs. Thus, we will also discuss how to increase predictive validity of mouse models.

Metodologicamente esta investigacion hizo uso de los instrumentales proporcionados por la investigacion bibliografica, la cual consiste en una investigacion cientifica donde se exploro lo que han escrito los diferentes teologos biblistas latinoamericanos. La investigacion cientifica empirica que nos propusimos se dividio en tres fases: a) la primera contiene la compilacion y analisis de datos por pais, revista y temas, b) la segunda, desarrolla la interrelacion de la informacion mediante el software ATLAS.ti, buscando comprender el objeto de estudio en familias a saber: teologia sistematica, teologia eclesial, teologia del dialogo y teologia practica y, c) la tercera, interpreta los resultados obtenidos en la fase dos organizados en campos semanticos.

A mediados de los anos sesenta, a la luz del Concilio Vaticano ii, comienza a dar sus primeros pasos la Teologia de la Liberacion en America Latina y seguidamente se gestan importantes aportes teologicos en centros de formacion teologica de tradicion y otros que a la luz de este acontecimiento emergen (Silva, 2009). Es importante anotar, que muchos de estos centros de formacion y reflexion teologica, no comparten ampliamente los intereses y logros de esta teologia que en un ambiente de crisis mundial, presenta novedades en la manera como se percibia la teologia en su momento.

La metodologia de la investigacion tiene como rasgo principal el analisis documental, con la obligada necesidad de realizar una curaduria de documentos virtuales, asi como la utilizacion del software ATLAS.ti para el analisis cualitativo de los datos recopilados por los investigadores; desde esta organizacion de la informacion que el software arrojo, se realizo la interpretacion de contenidos teologicos producidos en el periodo escogido, ello permitio sistematizar las lineas desde las que se esta socializando la produccion en teologia en los paises elegidos.

Un sincero examen de la situacion actual de la teologia, permitira reconocer que la teologia academica no goza del mismo aprecio ahora, del que gozaba hace algunos anos en la Iglesia, en la sociedad y en la Universidad. ?Que ha sucedido? ?Por que la teologia no es aceptada hoy en dia en muchas partes, como la necesaria autorreflexion critica de la fe cristiana ni como una asignatura academica importante en la Universidad? ?Por que los institutos teologicos y universidades se van convirtiendo cada vez mas en centros de ciencias de las religiones? ?Habra pasado la moda de la teologia como dilucidacion autocritica de la fe cristiana?

Neurodevelopmental disorders are challenging to study in the laboratory, and despite a large investment, few novel treatments have been developed in the last decade. While animal models have been valuable in elucidating disease mechanisms and in providing insights into the function of specific genes, the predictive validity of preclinical models to test potential therapies has been questioned. In the last two decades, diverse new murine models of Down syndrome (DS) have been developed and numerous studies have demonstrated neurobiological alterations that could be responsible for the cognitive and behavioral phenotypes found in this syndrome. In many cases, similar alterations were found in murine models and in individuals with DS, although several phenotypes shown in animals have yet not been confirmed in the human condition. Some of the neurobiological alterations observed in mice have been proposed to account for their changes in cognition and behavior, and have received special attention because of being putative therapeutic targets. Those include increased oxidative stress, altered neurogenesis, overexpression of the Dyrk1A gene, GABA-mediated overinhibition and Alzheimer's disease-related neurodegeneration. Subsequently, different laboratories have tested the efficacy of pharmacotherapies targeting these alterations. Unfortunately, animal models are limited in their ability to mimic the extremely complex process of human neurodevelopment and neuropathology. Therefore, the safety and efficacy identified in animal studies are not always translated to humans, and most of the drugs tested have not demonstrated any positive effect or very limited efficacy in clinical trials. Despite their limitations, though, animal trials give us extremely valuable information for developing and testing drugs for human use that cannot be obtained from molecular or cellular experiments alone. This chapter reviews some of these therapeutic approaches and discusses some reasons that could account for the discrepancy between the findings in mouse models of DS and in humans, including: (i) the incomplete resemble of the genetic alterations of available mouse models of DS and human trisomy 21, (ii) the lack of evidence that some of the phenotypic alterations found in mice (e.g., GABA-mediated overinhibition, and alterations in adult neurogenesis) are also present in DS individuals, and (iii) the inaccuracy and/or inadequacy of the methods used in clinical trials to detect changes in the cognitive and behavioral functions of people with DS. Despite the shortcomings of animal models, animal experimentation remains an invaluable tool in developing drugs. Thus, we will also discuss how to increase predictive validity of mouse models.

La hepatitis isquémica o hipóxica es una entidad clínica caracterizada por una importante elevación de las aminotransferasas de forma aguda y reversible que ocurre en aquellas situaciones que pueden ocasionar una reducción del flujo sanguíneo hepático, especialmente la insuficiencia cardiaca, sin embargo, se trata de un diagnóstico de exclusión ya que deben descartar previamente otras causas potencialmente responsables de una hepatitis aguda, especialmente víricas y farmacológicas. Histológicamente se caracteriza por una necrosis centrolobulillar. Se presenta un caso ingresado en el servicio de medicina interna durante un período de dos meses.

Esta investigacion tuvo como objetivo sistematizar e interpretar la produccion teologica de las revistas indexadas de las Facultades de Teologia de Colombia, Mexico, Peru, Chile, Argentina y Brasil, con el fin de elaborar un diagnostico epistemologico de lo que han producido entre 2007 y 2014; de ello se podra identificar la existencia o no de una epistemologia teologica propiamente latinoamericana. Este ejercicio academico, entre otras cosas, no tiene la pretension de decir la ultima palabra, lo que si se quiere es interpelar nuestro quehacer academico y motivar a los futuros egresados de las Facultades de Teologia a responder criticamente a las necesidades de su entorno. Al mismo tiempo, llamar la atencion a los docentes e investigadores en esta area a tomar conciencia del tipo de investigacion que estamos produciendo, pues al parecer, hay una distancia en cuanto a lo que se produce desde el piso teologico latinoamericano y a lo que se da en las aulas de clase, pues se sigue privilegiando una educacion monocultural. Esto quiere decir, que la fuente de insumo principal en las Facultades de Teologia no es la reflexion teologica que se produce al interior de la misma, por lo que se prioriza es el estudio del racionamiento teologico eurocentrico antes que la que emana de los propios contextos.

Down syndrome (DS) is the most common chromosomal abnormality in humans. DS is characterized by a number of phenotypes, including the development of Alzheimer's disease-like pathology and immunological, hematological and cardiovascular alterations. Apoptosis or programmed cell death is physiologically involved in development and aging, as well as in numerous pathological processes. Altered apoptosis has been proposed as a putative mechanism underlying many DS phenotypes. Evidence from human and animal studies indicates that apoptosis does not have a prominent role in the disturbances found in brain development in trisomy 21. However, alterations in apoptosis have been associated with neurodegeneration in the aging DS brain, with impairments in general growth and with immunological, cardiovascular and oncological alterations. Altered apoptosis in DS is likely to be the result of the interplay between several chromosome 21 (Hsa21) and non-Hsa21 genes. The interplay between these genes may affect physiological programmed cell death either directly, by modifying the activity of the apoptotic pathways, or indirectly, by inducing degeneration and rendering the cell more vulnerable to apoptosis-inducing factors.

The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. Partial display of DS phenotypes in mice harboring a single trisomy of Kcnj6 provides compelling evidence for a functional role of increased channel expression in some of the abnormal neurological phenotypes found in DS. Notably, the antiepileptic drug (AED) ethosuximide (ETH), but not other AEDs such as gabapentin (GAB), is known to inhibit KCNJ6 channels in mice. Here, we report the effect of chronic ETH and GAB on the behavioral and cognitive phenotypes of TS and disomic control (CO) mice. Neither drug significantly affected sensorimotor abilities, motor coordination or spontaneous activity in TS and CO mice. Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects.

Si bien en el ámbito nacional y, en particular, en el sector comunicativo de las escuelas de formación policial, ya se han desarrollado investigaciones concernientes a la problemática de la seguridad de la información, la actual permite validar y/o refutar datos obtenidos que pueden haber sufrido transformaciones, toda vez que la especificidad y particularidad del ambiente comunicativo que contiene la Escuela de Formación Policial Carlos Eugenio Restrepo exige unos análisis de la temática igualmente diferenciados y particulares. La profundización en esta temática permite que la Institución conozca las realidades de las cuales hace parte su personal, consiguiendo de esta forma adoptar políticas encaminadas a fortalecer y prevenir deficiencias en la dinámica comunicativa y laboral. La presente investigación consiste entonces en realizar un estudio básico de los factores influyentes en la importancia que tiene la seguridad física y lógica en el manejo de la información policial; tema que se ha buscado absolver de la manera más sencilla y clara en lo que al tema se refiere. Esta temática presenta gran interés institucional por la falta de seguridad en el manejo de la información y las comunicaciones detectadas en las escuelas de formación policial del país, y dicha falta de seguridad de la información representa un gasto considerable de recursos tanto en lo económico como en lo administrativo.

Individuals with Down syndrome (DS) present cognitive deficits that can be improved by early implementation of special care programs. However, they showed limited and temporary cognitive effects. We previously demonstrated that postnatal environmental enrichment (EE) improved clearly, though temporarily, the execution of visuospatial memory tasks in Ts65Dn mice, a DS model bearing a partial trisomy of murine chromosome 16; but in contrast to wild-type littermates, there was a lack of structural plasticity in pyramidal cell structure in the trisomic cerebral cortex. In the present study, we have investigated the impact of EE on the function of adenylyl cyclase and phospholipase C as a possible mechanism underlying the time-limited improvements observed. Basal production of cyclic adenosine monophosphate (cAMP) was not affected, but responses to GTPγS, isoprenaline, noradrenaline, SKF 38393 and forskolin were depressed in the Ts65Dn hippocampus. In EE conditions, cAMP accumulation was not significantly modified in control animals with respect to nonenriched controls. However, EE had a marked effect in Ts65Dn mice, in which cAMP production was significantly increased. Similarly, EE increased phospholipase C activity in Ts65Dn mice, in response to carbachol and calcium. We conclude that EE restores the G-protein-associated signal transduction systems that are altered in Ts65Dn mice.

The Ts65Dn (TS) mouse is the most widely used model of Down syndrome (DS). This mouse shares many phenotypic characteristics with the human condition including cognitive and neuromorphological alterations. In this study the effects of physical exercise on hippocampal neurogenesis and behavior in TS mice were assessed. 10-12 month-old male TS and control (CO) mice were submitted to voluntary physical exercise for 7 weeks and the effects of this protocol on hippocampal morphology, neurogenesis and apoptosis were evaluated. Physical exercise improved performance in the acquisition sessions of the Morris water maze in TS but not in CO mice. Conversely, it did not have any effect on anxiety or depressive behavior in TS mice but it did reduce the cognitive components of anxiety in CO mice. TS mice presented a reduced dentate gyrus (DG) volume, subgranular zone area and number of granule neurons. Hippocampal neurogenesis was reduced in TS mice as shown by the reduced number of 5-bromo-2-deoxyuridine (BrdU) positive cells. Voluntary physical exercise did not rescue these alterations in TS mice but it did increase the number of doublecortin (DCX)-and phospho histone 3 (PH3)-positive neurons in CO mice. It is concluded that physical exercise produced a modest anxiolytic effect in CO mice and that this was accompanied by an increased number of immature cells in the hippocampal DG. On the other hand, voluntary physical exercise exerted a positive effect on TS mice learning of the platform position in the Morris water maze that seems to be mediated by a neurogenesis-independent mechanism. © 2010 IBRO.

The most commonly used model of Down syndrome, the Ts65Dn (TS) mouse, is trisomic for most of the region of MMU16 that is homologous to HSA21. This mouse shares many phenotypic characteristics with people with Down syndrome including behavioral and cognitive alterations. The objective of this study was to analyze the ability of two drugs that improve cognition in different experimental models, the acetylcholinesterase inhibitor donepezil and the non-competitive GABA(A) antagonist pentylenetetrazole (PTZ), to improve the cognitive deficits found in TS mice. The drugs were administered p.o. to TS and CO mice for 8 weeks and a behavioral characterization was performed. Sensorimotor abilities, including vision, hearing, strength and motor coordination, as well as locomotor activity in the home cage, were not modified by any chronic treatment in TS and CO mice. TS mice showed altered equilibrium in the aluminium rod, and this effect was larger under PTZ treatment. This result may indicate a potential adverse effect of PTZ in Ts65Dn mice. Learning and memory were evaluated in TS and CO mice after both treatments in the Morris water maze. Donepezil administration did not modify learning and memory in animals of any genotype. On the other hand, PTZ administration rescued TS performance in the Morris water maze.

A direct relation between the rate of adult hippocampal neurogenesis in mice and the immobility time in a forced swim test after living in an enriched environment has been suggested previously. In the present work, young adult mice living in an enriched environment for 2 months developed considerably more immature differentiating neurons (doublecortin-positive, DCX+) than control, non-enriched animals. Furthermore, we found that the more DCX+ cells they possessed, the lower the immobility time they scored in the forced swim test. This DCX+ subpopulation is composed of mostly differentiating dentate neurons independently of the birthdates of every individual cell. However, variations found in this subpopulation were not the result of a general effect on the survival of any newborn neuron in the granule cell layer, as 5-bromo-2-deoxyuridine (BrdU)-labeled cells born during a narrow time window included in the longer lifetime period of DCX+ cells, were not significantly modified after enrichment. In contrast, the survival of the mature population of neurons in the granule cell layer of the dentate gyrus in enriched animals increased, although this did not influence their performance in the Porsolt test, nor did it influence the dentate gyrus volume or granule neuronal nuclei size. These results indicate that the population of immature, differentiating neurons in the adult hippocampus is one factor directly related to the protective effect of an enriched environment against a highly stressful event. © 2007 IBRO.

Ts65Dn mouse is the most widely accepted model for Down syndrome. We previously showed that environmental enrichment improved spatial learning in female but deteriorated it in male Ts65Dn mice. This study analyzed the factors contributing to the disturbed cognition of male Ts65Dn mice after enriched housing, by allocating male control and Ts65Dn mice in four conditions after weaning: small (n = 2-3) and large group (n = 8-10) housing, and enriched housing in small (2-3) and large groups (8-10). Learning, aggressive behavior, anxiety-like behavior and biochemical correlates of stress were evaluated when Ts65Dn and control mice were 4-5 months old. Environmental enrichment in large mixed colonies of Ts65Dn and diploid littermates disturbed behavioral and learning skills of Ts65Dn mice in the Morris water maze. ACTH and testosterone levels were not modified in any group of mice. Ts65Dn and control mice subjected to enriched housing in large groups and Ts65Dn mice housed in large groups showed higher corticosterone levels. Aggressive behavior was evaluated by measuring the number of attacks performed in the presence of an intruder. Ts65Dn mice performed less attacks than controls in all conditions, especially after enriched housing, indicating subordination. In the plus maze, cognitive aspects (i.e. risk assessment) and motor components (open arm avoidance) of anxiety behavior were evaluated; no difference in any condition was found. It is suggested that an excess of social and/or physical stimulation in Ts65Dn mice may affect cognition by disturbing the emotional and behavioral components of the learning process.

Reduced number of neurons is a common feature in Down's syndrome (DS) brains. Since reduced neuronal number also occurs in the dentate gyrus of Ts65Dn mice (TS), a model for DS, hippocampal cell proliferation and survival were analyzed in young and old TS mice. For evaluating proliferation and survival, half of the mice were sacrificed 1 day, and the other half 30 days after the last bromodeoxyuridine injection, respectively. No difference was found in the number of proliferating or surviving cells of young TS and control mice. An age-associated decline in total cell number and density has been found in both genotypes, this decline being more pronounced in TS animals. Thus, aged TS mice showed reduced cell proliferation and density of surviving cells compared to CO mice. Due to the putative involvement of newborn cells in the dentate gyrus in learning processes, the reduced proliferative capacity found in TS mice could be involved in the cognitive problems found in this model of Down syndrome.

Mental retardation in individuals with Down syndrome (DS) is thought to result from anomalous development and function of the brain; however, the underlying neuropathological processes have yet to be determined. Early implementation of special care programs result in limited, and temporary, cognitive improvements in DS individuals. In the present study, we investigated the possible neural correlates of these limited improvements. More specifically, we studied cortical pyramidal cells in the frontal cortex of Ts65Dn mice, a partial trisomy of murine chromosome 16 (MMU16) model characterized by cognitive deficits, hyperactivity, behavioral disruption and reduced attention levels similar to those observed in DS, and their control littermates. Animals were raised either in a standard or in an enriched environment. Environmental enrichment had a marked effect on pyramidal cell structure in control animals. Pyramidal cells in environmentally enriched control animals were significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. As each dendritic spine receives at least one excitatory input, differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. The present results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development.

The aim of this study was to analyse the biochemical and behavioural consequences of chronic treatment with opioid receptor antagonists in rats. We have evaluated the respiratory depressant and antinociceptive effects of the mu-opioid agonist sufentanil, the density of brain mu-opioid receptors, and the expression of G-protein-coupled receptor kinases and beta-arrestin 2 in cerebral cortex and striatum, following sustained opioid receptor blockade. Our results demonstrate that 24 h after interruption of 7 days chronic infusion of naltrexone (120 microg/h), the respiratory depressant potency of the mu-opioid receptor agonist sufentanil was increased to a similar extent as the antinociceptive potency (about three-fold). This was accompanied by mu-opioid receptor up-regulation in several areas of the rat brain associated with opioid control of pain perception and breathing. Moreover, chronic treatment with either naltrexone (120 microg/h) or naloxone (120 microg/h) caused significant increases in the expression levels of G-protein-coupled receptor kinases types 2, 3, and 6, and of beta-arrestin 2 in brain cortex and striatum. Together our data suggest an increased constitutive receptor activity secondary to mu-opioid receptor up-regulation following chronic antagonist treatment.

© 2014 García-Cerro et al. Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/2) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities., This work was supported by grants from the Jerome Lejeune Foundation (www.fondationlejeune.org/en/) and the Spanish Ministry of Economy and Competitiveness (www.mineco.gob.es/) (Grant numbers: PSI2012-33652 and SAF2010-17004)

Agonist- and guanine-nucleotide-stimulated phospholipase C-β (PLC) activity was characterized in crude plasma membrane preparations from cerebral cortex, hippocampus and cerebellum of Ts65Dn mice, a model for Down syndrome, and their control littermates. The levels of expression of PLC-β(1–4) isoforms and G-protein αq/11 subunits were also quantified by Western blot analysis to establish their contribution to the patterns of PLC functioning. PLC activity regulated by G-proteins and muscarinic and 5-HT2 receptors presented a regional distribution in both control and Ts65Dn mice. In both groups of mice, the intensity of PLC responses to maximal activation by calcium followed the sequence cerebellum > cortex > hippocampus. Both basal and maximal PLC activities, however, were significantly lower in cerebellar membranes of Ts65Dn than in control mice. This difference was mostly revealed in crude plasma membranes prepared from cerebellum at the level of G-protein-dependent-PLC activity because the concentration-response curve to GTPγS showed a reduction of the maximal effect in Ts65Dn mice, with no change in sensitivity (EC50). Western blot analysis showed a heterogeneous distribution of PLC-β(1–4) isoforms in both groups of mice. The levels of PLC-β4 isoform, however, were significantly lower in the cerebellum of Ts65Dn than in control mice. We conclude that the cerebellum of Ts65Dn mice has severe deficiencies in PLC activity stimulated by guanine nucleotides, which are specifically related to a lower level of expression of the PLC-β4 isoform, a fact that may account for the neurological phenotype observed in this murine model of Down syndrome. J. Neurosci. Res. 66:540–550, 2001. © 2001 Wiley-Liss, Inc.

Down's syndrome (DS) is a major cause of mental retardation, hypotonia and delayed development. Murine models of DS carrying large murine or human genomic fragments show motor alterations and memory deficits. The specific genes responsible for these phenotypic alterations have not yet been defined. DYRK1A, the human homolog of the Drosophila minibrain gene, maps to the DS critical region of human chromosome 21 and is overexpressed in DS fetal brain. DYRK1A encodes a serine-threonine kinase, probably involved in neuroblast proliferation. Mutant Drosophila minibrain flies have a reduction in both optic lobes and central brain, showing learning deficits and hypoactivity. We have generated transgenic mice (TgDyrk1A) overexpressing the full-length cDNA of Dyrk1A. TgDyrk1A mice exhibit delayed cranio-caudal maturation with functional consequences in neuromotor development. TgDyrk1A mice also show altered motor skill acquisition and hyperactivity, which is maintained to adulthood. In the Morris water maze, TgDyrk1A mice show a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect turned out to be specifically related to reference memory, whereas working memory was almost unimpaired. These alterations are comparable with those found in the partial trisomy chromosome 16 murine models of DS and suggest a causative role of DYRK1A in mental retardation and in motor anomalies of DS.

Chronic opioid administration induces adaptations in neurones resulting in opioid tolerance and dependence. The changes in dihydropyridine (DHP)-sensitive Ca(2+) channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the micro-opioid receptor agonist sufentanil were analyzed in the central nervous system (CNS) of rats. Autoradiographic assays were performed with [(3)H]PN-200-110 (isopropyl 4-(2,1, 3-benzoxadiazol-4-yl)-1,4-dihydro-2, 6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate). Chronic s.c. infusion of sufentanil (2 microg/h) for 7 days, which has been shown to induce tolerance to the opioid antinociceptive effect, produced an up-regulation of DHP binding sites. The highest increases in density were localized in regions involved in nociceptive transmission and perception, such as the dorsal horn of the spinal cord, the dorsal raphe nucleus, the central grey matter, the thalamic nuclei, and the somatosensory cortex. Animals were rendered supersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 microg/h) and nimodipine (1 microg/h) for 7 days. Under these conditions, a greater increase in the number of DHP binding sites was observed in the spinal cord, central grey matter, dorsal raphe nucleus, and somatosensory neocortex, when compared to the sufentanil group. The role of an increased influx through L-type channels in opioid tolerance is reinforced, whereas their persistent blockade is essential for the expression of opioid supersensitivity.

The ability of nimodipine, a dihydropyridine calcium antagonist, to reduce the daily dose of oral morphine in cancer patients who had developed dose escalation, was tested in 54 patients under randomized, double-blind, placebo-controlled conditions. We selected patients that required at least two successive increments of morphine to maintain pain relief. A possible pharmacokinetic interaction between nimodipine and morphine was also studied in 14 patients by assaying steady-state serum levels of morphine and its 3- and 6-glucuronides. A total of 30 patients completed the study, 14 and 16 in the nimodipine and placebo groups, respectively. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313+/-52 to 174+/-33 mg/day (P0.001) in the nimodipine group, and from 254+/-26 to 218+/-19 mg/day (not significant) in the placebo group. The percentages of reduction in the daily dose of morphine also showed significant differences between both groups (P=0.02). One week after introducing nimodipine or placebo, while the dose of morphine remained similar to that of the pre-test week, the serum levels of morphine and its glucuronides were not modified significantly. We conclude that the introduction of nimodipine in patients chronically treated with morphine may be a safe alternative to reduce the daily requirements of the opioid. It is suggested that interference with Ca2+-related events may attenuate the development and/or expression of tolerance to morphine in a clinically relevant way.

The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of their CNS due to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age-related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration in TS mice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed in TS mice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition in TS mice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampal LTP in trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus of TS mice. These results indicate that the cognitive-enhancing effects of melatonin in adult TS mice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression of DS neuropathology., This work was supported through grants from the Instituto de Formación e Investigación Marqués de Valdecilla (FMV-API 10/19), the Jerome Lejeune Foundation and the Spanish Ministry of Economy and Competitiveness (PSI2012-33652).

Mice with segmental trisomy 16 (Ts65Dn) which have triplication of a region of mouse chromosome 16 homologous to the Down syndrome critical region in human chromosome 21, are used as a model for Down syndrome. Functioning of the central beta-noradrenergic transmission was studied in Ts65Dn mice. Binding analysis in cerebral cortex revealed no change in the number of beta-adrenoceptors and a slight reduction of affinity. The beta-adrenoceptor transduction was assessed by analyzing cAMP formation in the cerebral cortex, hippocampus and cerebellar cortex under basal conditions and after stimulation with isoprenaline and forskolin. Basal production of cAMP was significantly reduced in hippocampus and cerebellar cortex of Ts65Dn mice compared to control, but not in cerebellum. After phosphodiesterase inhibition, net increments in cAMP accumulation were similar in both groups of mice. Stimulation of cAMP production by isoprenaline (10 microM) and forskolin (10 microM) was much higher in hippocampus than in cerebral cortex of either group. In both areas, but not in cerebellum, the stimulatory responses were consistently and significantly smaller in Ts65Dn than in control mice. Concentration-response curves for isoprenaline and forskolin were generated in the cerebral cortex. Emax responses were lower in trisomic than in control mice; however, in Ts65Dn mice the slope of the response curve to isoprenaline was markedly depressed whereas that to forskolin was similar to control. It is concluded that Ts65Dn mice show severe deficiencies in the synaptic transmission of the central beta-noradrenergic system, which are selective for specific brain areas.

Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1, 5-d][1,4]diazepine), a selective GABAA α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABAA α5 NAMs to treat cognitive dysfunction in DS. © 2013 the authors.

Ts65Dn mice (TS), the most commonly used model of Down syndrome (DS), exhibit phenotypic characteristics of this condition. Both TS mice and DS individuals present cognitive disturbances, age-related cholinergic degeneration, and increased brain expression of β-amyloid precursor protein (AβPP). These neurodegenerative processes may contribute to the progressive cognitive decline observed in DS. Melatonin is a pineal indoleamine that has been reported to reduce neurodegenerative processes and improve cognitive deficits in various animal models. In this study, we evaluated the potentially beneficial effects of long-term melatonin treatment on the cognitive deficits, cholinergic degeneration, and enhanced AβPP and β-amyloid levels of TS mice. Melatonin was administered for 5 months to 5- to 6-month-old TS and control (CO) mice. Melatonin treatment improved spatial learning and memory and increased the number of choline acetyltransferase (ChAT)-positive cells in the medial septum of both TS and CO mice. However, melatonin treatment did not significantly reduce AβPP or β-amyloid levels in the cortex or the hippocampus of TS mice. Melatonin administration did reduce anxiety in TS mice without inducing sensorimotor alterations, indicating that prolonged treatment with this indoleamine is devoid of noncognitive behavioral side effects (e.g., motor coordination, sensorimotor abilities, or spontaneous activity). Our results suggest that melatonin administration might improve the cognitive abilities of both TS and CO mice, at least partially, by reducing the age-related degeneration of basal forebrain cholinergic neurons. Thus, chronic melatonin supplementation may be an effective treatment for delaying the age-related progression of cognitive deterioration found in DS.

Down syndrome (DS) is the most common genetic cause of mental disability. Based on the homology of Hsa21 and the murine chromosomes Mmu16, Mmu17 and Mmu10, several mouse models of DS have been developed. The most commonly used model, the Ts65Dn mouse, has been widely used to investigate the neural mechanisms underlying the mental disabilities seen in DS individuals. A wide array of neuromorphological alterations appears to compromise cognitive performance in trisomic mice. Enhanced inhibition due to alterations in GABAA-mediated transmission and disturbances in the glutamatergic, noradrenergic and cholinergic systems, among others, has also been demonstrated. DS cognitive dysfunction caused by neurodevelopmental alterations is worsened in later life stages by neurodegenerative processes. A number of pharmacological therapies have been shown to partially restore morphological anomalies concomitantly with cognition in these mice. In conclusion, the use of mouse models is enormously effective in the study of the neurobiological substrates of mental disabilities in DS and in the testing of therapies that rescue these alterations. These studies provide the basis for developing clinical trials in DS individuals and sustain the hope that some of these drugs will be useful in rescuing mental disabilities in DS individuals.