Exploring the use of dimethyl fumarate as microglia modulator for neurodegenerative diseases treatment

The maintenance of redox homeostasis in the brain is critical for the prevention of the development of neurodegenerative diseases. Drugs acting on brain redox balance can be promising for the treatment of neurodegeneration. For more than four decades, dimethyl fumarate (DMF) and other derivatives of fumaric acid ester compounds have been shown to mitigate a number of pathological mechanisms associated with psoriasis and relapsing forms of multiple sclerosis (MS). Recently, DMF has been shown to exert a neuroprotective effect on the central nervous system (CNS), possibly through the modulation of microglia detrimental actions, observed also in multiple brain injuries. In addition to the hypothesis that DMF is linked to the activation of NRF2 and NF-kB transcription factors, the neuroprotective action of DMF may be mediated by the activation of the glutathione (GSH) antioxidant pathway and the regulation of brain iron homeostasis. This review will focus on the role of DMF as an antioxidant modulator in microglia processes and on its mechanisms of action in the modulation of different pathways to attenuate neurodegenerative disease progression

Leaf Fragment Identification of Subtropical Native Grass Species

The present study was carried out to characterise leaf fragments of important plant species of a subtropical native sward in the southernmost state of Brazil. Thirteen important grass species were collected from April to May 1999. Both sides of the leaves were observed using a stereomicroscope. In addition, two approaches were tested to provide a clearer characterisation of the leaves of each species: the leaves were either dried or frozen. The kind and number of veins, the kind and number of hair, and the arrangements and number of stomates on both sides of each leaf are the most useful characteristics to differentiate fragments of native grass species’ leaves. These characteristics can be more easily observed when the plant material is dried

Dinámica lateral de una dupla ferroviaria articulada

Las duplas ferroviarias articuladas son vehículos modulares conformados por dos coches y una unidad motriz (UM) situada entre ellos. Cada coche exhibe la particularidad de poseer sólo un bogie en un extremo y estar apoyado sobre la UM. Estos tipos de vehículos presentan condiciones particulares de inestabilidad debido a la naturaleza propia de la configuración utilizada. Todo fenómeno producido en la dinámica del sistema es magnificado por la complejidad de la distribución de la formación analizada. El módulo de propulsión (UM) constituye el componente con mayor influencia sobre la dinámica de los coches conducidos, generando así, el interés de su estudio. El objetivo general es identificar la gama de parámetros de prueba necesarios para la evaluación del rendimiento del vehículo y determinar las condiciones críticas que limitan la velocidad longitudinal de desplazamiento, lo cual produce la reducción del confort de marcha y afectan la seguridad frente al descarrilamiento. Una limitación importante en el transporte ferroviario es el producido por las vibraciones laterales como respuesta al contacto con la vía. Dichas vibraciones en los coches de pasajeros reducen el confort de marcha, y son capaces de generar un severo desgaste tanto de los rieles como en las ruedas del bogie. Bajo condiciones extremas, estas oscilaciones pueden dar lugar al descarrilamiento de la formación. Existen dos conceptos básicos a considerar en el comportamiento dinámico lateral de vehículos ferroviarios: es el fenómeno conocido como hunting, y la velocidad crítica. El primero de ellos, refiere a la utilización de una sección cónica variable en los perfiles de ruedas, es un movimiento armónico, periódico y oscilante. El segundo, es la velocidad crítica, la cual puede definirse como la velocidad a partir de la cual el vehículo presenta un cambio considerable en su comportamiento dinámico. A bajas velocidades (< 30 km/h), el fenómeno se observa como una oscilación del coche, de gran amplitud, baja frecuencia, a velocidades más elevadas (> 70 km/h), aumenta la probabilidad de producirse una oscilación de aparición violenta, alta frecuencia, generando el peligro de un eventual descarrilamiento. En el presente estudio, se ha realizado el análisis dinámico de la dupla articulada denominada “Alerce”, de la empresa EMEPA. Dicha dupla se encuentra actualmente en funcionamiento como transporte de pasajeros en la línea Belgrano Norte, en el área metropolitana

Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer’s disease patients, possible biomarkers for early diagnosis

Alzheimer's disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid-beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure; therefore, the actual challenge is to define new biomarkers and non-invasive technologies to measure neuropathological changes in vivo at pre-symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non-invasive rapid detection of AD biomarkers. Here, we report the presence of amyloid beta plaques, tau tangles, neurodegeneration and detrimental astrocyte and microglia activation according to a disease associated microglia phenotype (DAM). Thus, we propose the human retina as a useful site for the detection of cellular and molecular changes associated with Alzheimer's disease

Effect of sodium intake on blood pressure, serum levels and renal excretion of sodium and potassium in normotensives with and without familial predisposition to hypertension

1. Seventeen normal volunteers aged 19 to 22 were randomly subjected, in a trial of crossover design, to three distinct regimens of sodium chloride intake : high (16 to 20 g), normal (8 to 12 g) and low (0 .5 to 1 g). Each regimen lasted nine days, with determination of blood pressure and heart rate (in the supine position and after sudden rising), body weight, and urinary output of creatinine, sodium and potassium on the third, sixth and ninth days. 1n addition, plasma levels of creatinine, sodium and potassium were determined on the ninth day so that sodium and potassium clearance and fractional excretion could be calculated. 2. Eleven of the volunteers had a family history of hypertension. Compared to the' six without such a history, these subjects showed : 1) higher supirie systolic blood pressure on the third day of sodium overload (124 .7 ± 3.0 vs 112.3 ± 2.9 mmHg, P <o;02); 2) higher supine diastolic blood pressure on ·the third day of sodium overload (76 .5 ·± 2.8 vs 64.5 ± 4.3 mmHg; P < 0.05); 3) higher supine diastolic blood pressure on the sixth day of sodium overload (73 .7 ± 2.3 vs 63 .8 ± 3.2 mmHg, P < 0 .05); 4) lower supine heart rate on the ninth day of sodium overload (6 LO ± 3.1 vs 72.7 ± 4.6: P< 0.05), and 5) lower plasma potassium on the ninth day of sodium overload (4.10 ±0.05 vs 4-28 ± 0.06 mEq/1, P <0.05). 3. These results suggest that normal individuals whose familial history places them at risk for the development of hypertension differ from those not at risk during their adaptation to sodium load by suffering a transient elevation of blood pressure within a few days of the increase in load. The low levels of plasma potassium observed in these volunteers after a period of sodium load may be due to the operation of different renal mechanisms of sodium excretion in this group, leading to increased kaliuresis, and may explain the high vascular reactivity of such individuals

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses

Proliferation Index: A Continuous Model to Predict Prognosis in Patients with Tumours of the Ewing's Sarcoma Family

The prognostic value of proliferation index (PI) and apoptotic index (AI), caspase-8, -9 and -10 expression have been investigated in primary Ewing's sarcoma family of tumours (ESFT). Proliferating cells, detected by immunohistochemistry for Ki-67, were identified in 91% (91/100) of tumours with a median PI of 14 (range 0–87). Apoptotic cells, identified using the TUNEL assay, were detected in 96% (76/79) of ESFT; the median AI was 3 (range 0–33). Caspase-8 protein expression was negative (0) in 14% (11/79), low (1) in 33% (26/79), medium (2) in 38% (30/79) and high (3) in 15% (12/79) of tumours, caspase-9 expression was low (1) in 66% (39/59) and high (3) in 34% (20/59), and caspase-10 protein was low (1) in 37% (23/62) and negative (0) in 63% (39/62) of primary ESFT. There was no apparent relationship between caspase-8, -9 and -10 expression, PI and AI. PI was predictive of relapse-free survival (RFS; p = 0.011) and overall survival (OS; p = <0.001) in a continuous model, whereas AI did not predict outcome. Patients with tumours expressing low levels of caspase-9 protein had a trend towards a worse RFS than patients with tumours expressing higher levels of caspase-9 protein (p = 0.054, log rank test), although expression of caspases-8, -9 and/or -10 did not significantly predict RFS or OS. In a multivariate analysis model that included tumour site, tumour volume, the presence of metastatic disease at diagnosis, PI and AI, PI independently predicts OS (p = 0.003). Consistent with previous publications, patients with pelvic tumours had a significantly worse OS than patients with tumours at other sites (p = 0.028); patients with a pelvic tumour and a PI≥20 had a 6 fold-increased risk of death. These studies advocate the evaluation of PI in a risk model of outcome for patients with ESFT

Combined use of expression and CGH arrays pinpoints novel candidate genes in Ewing sarcoma family of tumors

<p>Abstract</p> <p>Background</p> <p>Ewing sarcoma family of tumors (ESFT), characterized by t(11;22)(q24;q12), is one of the most common tumors of bone in children and young adults. In addition to <it>EWS/FLI1 </it>gene fusion, copy number changes are known to be significant for the underlying neoplastic development of ESFT and for patient outcome. Our genome-wide high-resolution analysis aspired to pinpoint genomic regions of highest interest and possible target genes in these areas.</p> <p>Methods</p> <p>Array comparative genomic hybridization (CGH) and expression arrays were used to screen for copy number alterations and expression changes in ESFT patient samples. A total of 31 ESFT samples were analyzed by aCGH and in 16 patients DNA and RNA level data, created by expression arrays, was integrated. Time of the follow-up of these patients was 5–192 months. Clinical outcome was statistically evaluated by Kaplan-Meier/Logrank methods and RT-PCR was applied on 42 patient samples to study the gene of the highest interest.</p> <p>Results</p> <p>Copy number changes were detected in 87% of the cases. The most recurrent copy number changes were gains at 1q, 2, 8, and 12, and losses at 9p and 16q. Cumulative event free survival (ESFT) and overall survival (OS) were significantly better (P < 0.05) for primary tumors with three or less copy number changes than for tumors with higher number of copy number aberrations. In three samples copy number imbalances were detected in chromosomes 11 and 22 affecting the <it>FLI1 </it>and <it>EWSR1 </it>loci, suggesting that an unbalanced t(11;22) and subsequent duplication of the derivative chromosome harboring fusion gene is a common event in ESFT. Further, amplifications on chromosomes 20 and 22 seen in one patient sample suggest a novel translocation type between <it>EWSR1 </it>and an unidentified fusion partner at 20q. In total 20 novel ESFT associated putative oncogenes and tumor suppressor genes were found in the integration analysis of array CGH and expression data. Quantitative RT-PCR to study the expression levels of the most interesting gene, <it>HDGF</it>, confirmed that its expression was higher than in control samples. However, no association between <it>HDGF </it>expression and patient survival was observed.</p> <p>Conclusion</p> <p>We conclude that array CGH and integration analysis proved to be effective methods to identify chromosome regions and novel target genes involved in the tumorigenesis of ESFT.</p