The Effect of Chronic Hypertension on Neuropathology in the TGSWDI Mouse Model of Alzheimer\u27s Disease

Numerous epidemiological studies link vascular disorders, such as hypertension, diabetes and stroke, with Alzheimer’s disease. Hypertension, specifically, is an important modifiable risk factor for late onset Alzheimer’s disease. Despite the abundance of clinical data connecting these conditions, animal studies investigating the connection between the two are lacking. To examine the link between midlife hypertension and the onset of Alzheimer’s disease later in life, chronic hypertension was induced in the TgSwDI mouse model of Alzheimer’s disease in early adulthood using long-term administration of the eNOS inhibitor, N ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). L-NAME treatment accelerated cognitive deficits, microvascular deposition of the amyloidbeta peptide, vascular inflammation, blood brain barrier leakage, and pericyte loss in these mice. Though lysosomal markers were increased in hypertensive TgSwDI mice relative to all other groups, autophagic structures appeared to be increased in both hypertensive TgSwDI mice, as well as hypertensive WT mice. The increased presence of these structures altered cellular morphology at the neurovascular unit and compromised the blood brain barrier in hypertensive mice. Additionally, midlife hypertension induced hippocampal neurodegeneration at an early age in TgSwDI mice. Neuronal loss is a defining characteristic of pathology in Alzheimer’s disease, but is not replicated in many mouse models of the disease. Therefore, this may be a useful research model of Alzheimer’s disease with mixed vascular and amyloid pathologies and may display classical features of the disease missing in more canonical mouse models

Percepción de la Calidad del Servicio de la Institución Educativa N° 40159 Ejército “Arequipa”, Nivel Secundario, Arequipa 2015

Se realizó un estudio de campo y descriptivo, cuyo objetivo fue determinar la percepción de calidad de servicio de la institución educativa Nº 40159 Ejército “Arequipa”, nivel secundario, evaluado en la ciudad de Arequipa durante el 2015; además de determinar una calificación para indicadores como los elementos tangibles, la fiabilidad, la capacidad de respuesta, la seguridad, y la empatía. La hipótesis a comprobar: Es probable que los clientes internos de la institución Nº 40159 Ejército “Arequipa” tengan mejor percepción que los clientes externos sobre la calidad de servicio de dicha institución; debido a que, dentro de los indicadores de calidad de servicio se evalúa la percepción de los clientes internos conformada por el personal administrativo. Materiales y Métodos: Fue una investigación descriptiva, con metodología cuantitativa, donde se utilizó la técnica de la encuesta Ad Hoc mediante el instrumento cuestionario. Estos instrumentos fueron aplicados para obtener información acerca de las 5 dimensiones de la calidad de servicio de la escuela norteamericana, considerando una sola variable que corresponde a la percepción de la calidad del servicio, sobre un universo total de 1024 clientes externos e internos conformado por 490 alumnos, 490 familias, y 44 administrativos; de los cuales se evaluó a 215, 215, y 44 elementos de muestra, respectivamente. La segmentación por sexo, sección, o tipo de personal, fue la siguiente: 1. Grupo alumnos: 115 hombres y 100 mujeres, distribuidos en: 1er grado: 24 hombres y 21 mujeres; 2do grado: 19 hombres y 16 mujeres; 3er grado: 22 hombres y 19 mujeres; 4to grado: 25 hombres y 22 mujeres; 5to grado: 25 hombres y 22 mujeres. 2. Grupo familias: 101 padres y 114 madres, distribuidos en: 1er grado: 18 padres y 27 madres; 2do grado: 16 padres y 19 madres; 3er grado: 23 padres y 18 madres; 4to grado: 24 padres y 23 madres; 5to grado: 20 padres y 27 madres. 3. Grupo administrativos: 20 hombres y 24 mujeres, distribuidos en: Personal directo: 1 hombre y 2 mujeres; asistencia administrativa: 0 hombres y 4 mujeres; personal auxiliar: 1 hombre y 3 mujeres; personal de apoyo: 3 hombres y 3 mujeres; personal militar: 5 hombres y 0 mujeres; personal de servicio: 1 hombre y 1 mujer; profesores de secundaria: 9 hombres y 11 mujeres. Resultados: Promediando a los 3 grupos se tiene que los mejor percibidos son los elementos tangibles con 14.69 de calificación y una σ de 2.06; seguidos de la capacidad de respuesta, con 14.45 y σ de 2.37; seguridad, con 14.41 y σ de 2.25; fiabilidad, con 14.29 y σ de 1.95; y la percibida con menor nivel es la empatía con 13.85 y una σ de 1.94. Conclusiones: Para los alumnos, la fiabilidad es el factor mejor percibido; mientras que para la familia son los elementos tangibles; y, para los administrativos, la capacidad de respuesta. Si bien, en los 3 grupos, se aprecia una relación similar percibida entre los indicadores; se tienen opiniones diferentes en cuanto el valor de los mismos, siendo las más distanciadas las de familia. Para las familias, la calidad del servicio es muy baja; considerándola con un promedio de 12.02. Esto puede deberse a la falta de comunicación, entre las familias y la institución, sobre las mejores prácticas realizadas; ya que, para los administrativos y alumnos, de promedio 16.09 y 14.90 respectivamente, la calificación tiene un valor cualitativo de “Bueno”, considerándolo un buen servicio. Además, se observa que las mujeres tienen una percepción más baja que los hombres sobre la calidad del servicio de la institución educativa N° 40159 Ejército Arequipa; de igual forma, tanto los alumnos como las familias del 5to grado, califican con una baja percepción la calidad del servicio.Tesi

Rhodes University v Student Representative Council of Rhodes University: The constitutionality of interdicting non-violent disruptive protest

Section 17 of the Constitution of the Republic of South Africa, 1996 enshrines the right to assemble, peacefully and unarmed, and the Regulation of Gatherings Act 205 of 1993 enables the exercise of this right peacefully and with due regard to the rights of others. The recent student protests across South Africa have occasioned litigation seeking to interdict protest action, which the universities claim is unlawful. Overly broad interdicts, which interdict lawful protest action, violate the constitutional right to assembly and have a chilling effect on protests. In a decision of the High Court of South Africa, Eastern Cape Division, Grahamstown, a final interdict was granted interdicting two individuals from, among other things, disrupting lectures and tutorials at Rhodes University and from inciting such disruption. In this note, the constitutionality of interdicting non-violent disruptive protest is discussed and analysed, using Rhodes University v Student Representative Council of Rhodes University and Others (1937/2016) [2016] ZAECGHC 141

Automated detection of GFAP-labeled astrocytes in micrographs using YOLOv5

Astrocytes, a subtype of glial cells with a complex morphological structure, are active players in many aspects of the physiology of the central nervous system (CNS). However, due to their highly involved interaction with other cells in the CNS, made possible by their morphological complexity, the precise mechanisms regulating astrocyte function within the CNS are still poorly understood. This knowledge gap is also due to the current limitations of existing quantitative image analysis tools that are unable to detect and analyze images of astrocyte with sufficient accuracy and efficiency. To address this need, we introduce a new deep learning framework for the automated detection of GFAP-immunolabeled astrocytes in brightfield or fluorescent micrographs. A major novelty of our approach is the applications of YOLOv5, a sophisticated deep learning platform designed for object detection, that we customized to derive optimized classification models for the task of astrocyte detection. Extensive numerical experiments using multiple image datasets show that our method performs very competitively against both conventional and state-of-the-art methods, including the case of images where astrocytes are very dense. In the spirit of reproducible research, our numerical code and annotated data are released open source and freely available to the scientific community.National Science Foundation ; National Institutes of Healt

Hypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia

Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia

Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition

Development of a Design Methodology for Hydraulic Pipelines Carrying Rectangular Capsules

The scarcity of fossil fuels is affecting the efficiency of established modes of cargo transport within the transportation industry. Efforts have been made to develop innovative modes of transport that can be adopted for economic and environmental friendly operating systems. Solid material, for instance, can be packed in rectangular containers (commonly known as capsules), which can then be transported in different concentrations very effectively using the fluid energy in pipelines. For economical and efficient design of such systems, both the local flow characteristics and the global performance parameters need to be carefully investigated. Published literature is severely limited in establishing the effects of local flow features on system characteristics of Hydraulic Capsule Pipelines (HCPs). The present study focuses on using a well validated Computational Fluid Dynamics (CFD) tool to numerically simulate the solid-liquid mixture flow in both on-shore and off-shore HCPs applications including bends. Discrete Phase Modelling (DPM) has been employed to calculate the velocity of the rectangular capsules. Numerical predictions have been used to develop novel semi-empirical prediction models for pressure drop in HCPs, which have then been embedded into a robust and user-friendly pipeline optimisation methodology based on Least-Cost Principle

Long-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model

BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment. OBJECTIVES: This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD. METHODS: TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood-brain barrier (BBB) integrity. RESULTS: Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB. CONCLUSIONS: Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.This work was funded by a Proof-of-Concept Award from the Robertson Therapeutic Development Fund (Dr. Cortes-Canteli), The Rockefeller University; NINDS/NIH grant NIS106668 (Drs. Norris and Strickland); European Union’s Seventh Framework Programme (FP7-PEOPLE-2013-IIF), grant agreement n PIIF-GA-2013-624811 (Drs. Cortes-Canteli and Fuster), CNIC, Madrid, Spain; Miguel Servet type I research contract (CP16/00174 and MS16/00174 [Dr. Cortes-Canteli]), Instituto de Salud Carlos III (ISCIII), CNIC; Iniciativa de Empleo Juvenil (PEJ16/MED/TL-1231 [A. Marcos-Diaz] and PEJ-2018-AI/BMD-11477 [C. Ceron]) from Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid; European Regional Development Funds (FEDER “Una manera de hacer Europa”) and European Social Funds (FSE “El FSE invierte en tu futuro”); and with the support of the Marie Curie Alumni Association (Dr. Cortes-Canteli). The CNIC is supported by the ISCIII, the Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). CIC biomaGUNE is a Maria de Maeztu Unit of Excellence (MDM-2017-0720). Dr. Sanchez-Gonzalez is an employee of Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) and mixed dementia (MxD) comprise the majority of dementia cases in the growing global aging population. MxD describes the coexistence of AD pathology with vascular pathology, including cerebral small vessel disease (SVD). Cardiovascular disease increases risk for AD and MxD, but mechanistic synergisms between the coexisting pathologies affecting dementia risk, progression and the ultimate clinical manifestations remain elusive. To explore the additive or synergistic interactions between AD and chronic hypertension, we developed a rat model of MxD, produced by breeding APPswe/PS1ΔE9 transgenes into the stroke-prone spontaneously hypertensive rat (SHRSP) background, resulting in the SHRSP/FAD model and three control groups (FAD, SHRSP and non-hypertensive WKY rats, n = 8-11, both sexes, 16-18 months of age). After behavioral testing, rats were euthanized, and tissue assessed for vascular, neuroinflammatory and AD pathology. Hypertension was preserved in the SHRSP/FAD cross. Results showed that SHRSP increased FAD-dependent neuroinflammation (microglia and astrocytes) and tau pathology, but plaque pathology changes were subtle, including fewer plaques with compact cores and slightly reduced plaque burden. Evidence for vascular pathology included a change in the distribution of astrocytic end-foot protein aquaporin-4, normally distributed in microvessels, but in SHRSP/FAD rats largely dissociated from vessels, appearing disorganized or redistributed into neuropil. Other evidence of SVD-like pathology included increased collagen IV staining in cerebral vessels and PECAM1 levels. We identified a plasma biomarker in SHRSP/FAD rats that was the only group to show increased Aqp-4 in plasma exosomes. Evidence of neuron damage in SHRSP/FAD rats included increased caspase-cleaved actin, loss of myelin and reduced calbindin staining in neurons. Further, there were mitochondrial deficits specific to SHRSP/FAD, notably the loss of complex II, accompanying FAD-dependent loss of mitochondrial complex I. Cognitive deficits exhibited by FAD rats were not exacerbated by the introduction of the SHRSP phenotype, nor was the hyperactivity phenotype associated with SHRSP altered by the FAD transgene. This novel rat model of MxD, encompassing an amyloidogenic transgene with a hypertensive phenotype, exhibits several features associated with human vascular or "mixed" dementia and may be a useful tool in delineating the pathophysiology of MxD and development of therapeutics