Drug release profile for an ETS-1 inhibitor in ReGel

poste

Modelling ultrasound-induced mild hyperthermia of hyperplasia in vascular grafts

<p>Abstract</p> <p>Background</p> <p>Expanded polytetrafluoroethylene (ePTFE) vascular grafts frequently develop occlusive neointimal hyperplasia as a result of myofibroblast over-growth, leading to graft failure. ePTFE exhibits higher ultrasound attenuation than native soft tissues. We modelled the selective absorption of ultrasound by ePTFE, and explored the feasibility of preventing hyperplasia in ePTFE grafts by ultrasound heating. Specifically, we simulated the temperature profiles of implanted grafts and nearby soft tissues and blood under ultrasound exposure. The goal was to determine whether ultrasound exposure of an ePTFE graft can generate temperatures sufficient to prevent cell growth on the graft without damaging nearby soft tissues and blood.</p> <p>Methods</p> <p>Ultrasound beams from two transducers (1.5 and 3.2 MHz) were simulated in two graft/tissue models, with and without an intra-graft cellular layer mimicking hyperplasia, using the finite-difference time-domain (FDTD) method. The resulting power deposition patterns were used as a heat source for the Pennes bioheat equation in a COMSOL^®Multiphysics heat transfer model. 50°C is known to cause cell death and therefore the transducer powers were adjusted to produce a 13°C temperature rise from 37°C in the ePTFE.</p> <p>Results</p> <p>Simulations showed that both the frequency of the transducers and the presence of hyperplasia significantly affect the power deposition patterns and subsequent temperature profiles on the grafts and nearby tissues. While neither transducer significantly raised the temperature of the blood, the 1.5-MHz transducer was less focused and heated larger volumes of the graft and nearby soft tissues than the 3.2-MHz transducer. The presence of hyperplasia had little effect on the blood's temperature, but further increased the temperature of the graft and nearby soft tissues in response to either transducer. Skin cooling and blood flow play a significant role in preventing overheating of the native tissues.</p> <p>Conclusions</p> <p>Modelling shows that ultrasound can selectively heat ePTFE grafts and produce temperatures that cause cell death on the graft. The temperature increase in blood is negligible and that in the adjacent soft tissues may be minimized by skin cooling and using appropriate transducers. Therefore, ultrasound heating may have the potential to reduce neointimal hyperplasia and failure of ePTFE vascular grafts.</p

Detector modules and spectrometers for the TIME-Pilot [CII] intensity mapping experiment

This proceeding presents the current TIME-Pilot instrument design and status with a focus on the close-packed modular detector arrays and spectrometers. Results of laboratory tests with prototype detectors and spectrometers are discussed. TIME-Pilot is a new mm-wavelength grating spectrometer array under development that will study the Epoch of Reionization (the period of time when the first stars and galaxies ionized the intergalactic medium) by mapping the fluctuations of the redshifted 157:7 μm emission line of singly ionized carbon ([CII]) from redshift z ~ 5:2 to 8:5. As a tracer of star formation, the [CII] power spectrum can provide information on the sources driving reionization and complements 21 cm data (which traces neutral hydrogen in the intergalactic medium). Intensity mapping provides a measure of the mean [CII] intensity without the need to resolve and detect faint sources individually. We plan to target a 1 degree by 0.35 arcminute field on the sky and a spectral range of 199-305 GHz, producing a spatial-spectral slab which is 140 Mpc by 0.9 Mpc on-end and 1230 Mpc in the redshift direction. With careful removal of intermediate-redshift CO sources, we anticipate a detection of the halo-halo clustering term in the [CII] power spectrum consistent with current models for star formation history in 240 hours on the JCMT. TIME-Pilot will use two stacks of 16 parallel-plate waveguide spectrometers (one stack per polarization) with a resolving power R ~ 100 and a spectral range of 183 to 326 GHz. The range is divided into 60 spectral channels, of which 16 at the band edges on each spectrometer serve as atmospheric monitors. The diffraction gratings are curved to produce a compact instrument, each focusing the diffracted light onto an output arc sampled by the 60 bolometers. The bolometers are built in buttable dies of 8 (low freqeuency) or 12 (high frequency) spectral channels by 8 spatial channels and are mated to the spectrometer stacks. Each detector consists of a gold micro-mesh absorber and a titanium transition edge sensor (TES). The detectors (1920 total) are designed to operate from a 250 mK base temperature in an existing cryostat with a photon-noise-dominated NEP of ~2 * 10^(-17) WHz^(-1-2). A set of flexible superconducting cables connect the detectors to a time-domain multiplexing SQUID readout system

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Effects of sickle erythrocytes on metabolism and gene regulation in cultured human endothelial cells under flow conditions

Sickle cell anemia is characterized by chronic hemolysis and episodic vasoocclusive crises. There are many factors contributing to vascular occlusion in sickle cell patients, with the enhanced, abnormal adhesion of sickle erythrocytes to endothelial cells being investigated most thoroughly. The vascular endothelium lining on blood vessel walls is in a unique position of direct exposure to these abnormal red blood cells. It is possible that interactions with sickle erythrocytes may modulate endothelial cells to create an environment sensitive to crisis-triggering factors and in favor of adhesion events. However, quantitative information on the metabolic and gene regulatory effects of these interactions on endothelial cells under flow is lacking. In this research, we developed an experimental system that simulates the physiological vascular flow environment to subject cultured human endothelial cell (EC) monolayers to sickle cell perfusion with a well-defined wall shear stress level of 1dyne/cm2 for times up to 24 hours. Effects of sickle erythrocytes on EC production of vasotone mediators (prostacyclin and endothelin-1) and on EC expression of cell adhesion molecules (ICAM-1 and VCAM-1) were examined at the transcription and/or protein levels. The production of prostacyclin and endothelin-1 both increased in ECs after exposure to sickle cell perfusion, in comparison to perfusion with normal red cells. The altered levels of prostacyclin and endothelin-1 may disturb the delicate balance of vasoactive materials, leading to vasotone instability in sickle cell patients. Gene expression and cell surface expression of ICAM-1 in ECs were profoundly elevated by perfusion with sickle erythrocytes. The elevation in membrane-bound ICAM-1 levels may increase the interactions between blood cells and ECs, especially leukocyte endothelium adhesion. This may lead to the entrapment of red cells in regions of low oxygen tension in the microcirculation and trigger the polymerization of sickle hemoglobin. VCAM-1 mRNA, but not membrane-bound VCAM-1, was also significantly increased by perfusion with sickle erythrocytes. The presence of VCAM-1 on ECs may enhance the adhesion of erythrocytes via binding to integrin VLA-4( a 4 b 1) expressed on sickle cell membranes, but not on normal red cell membranes. The release of soluble ICAM-1 and soluble VCAM-1 both increased in ECs after exposure to sickle cell perfusion, and may serve as an indicator of injury and/or activation of ECs. The presence of IL-1 b in the perfusion system, as a model of inflammatory cytokine effects, synergistically increased the production of prostacyclin, ICAM-1 and VCAM-1 in endothelial cells. This is consistent with the close association of inflammation and vasoocclusive crises observed in sickle cell anemia patients

Transcription Factor ETS-1 and Reactive Oxygen Species: Role in Vascular and Renal Injury

The E26 avian erythroblastosis virus transcription factor-1 (ETS-1) is a member of the ETS family and regulates the expression of a variety of genes including growth factors, chemokines and adhesion molecules. Although ETS-1 was discovered as an oncogene, several lines of research show that it is up-regulated by angiotensin II (Ang II) both in the vasculature and the glomerulus. While reactive oxygen species (ROS) are required for Ang II-induced ETS-1 expression, ETS-1 also regulates the expression of p47phox, which is one of the subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and a major source of ROS in the kidney and vasculature. Thus, there appears to be a positive feedback between ETS-1 and ROS. ETS-1 is also upregulated in the kidneys of rats with salt-sensitive hypertension and plays a major role in the development of end-organ injury in this animal model. Activation of the renin angiotensin system is required for the increased ETS-1 expression in these rats, and blockade of ETS-1 or haplodeficiency reduces the severity of kidney injury in these rats. In summary, ETS-1 plays a major role in the development of vascular and renal injury and is a potential target for the development of novel therapeutic strategies to ameliorate end-organ injury in hypertension

High resolution hemodynamic profiling of murine arteriovenous fistula using magnetic resonance imaging and computational fluid dynamics

Abstract Background Arteriovenous fistula (AVF) maturation failure remains a major cause of morbidity and mortality in hemodialysis patients. The two major etiologies of AVF maturation failure are early neointimal hyperplasia development and persistent inadequate outward remodeling. Although hemodynamic changes following AVF creation may impact AVF remodeling and contribute to neointimal hyperplasia development and impaired outward remodeling, detailed AVF hemodynamics are not yet fully known. Since murine AVF models are valuable tools for investigating the pathophysiology of AVF maturation failure, there is a need for a new approach that allows the hemodynamic characterization of murine AVF at high resolutions. Methods This methods paper presents a magnetic resonance imaging (MRI)-based computational fluid dynamic (CFD) method that we developed to rigorously quantify the evolving hemodynamic environment in murine AVF. The lumen geometry of the entire murine AVF was reconstructed from high resolution, non-contrast 2D T2-weighted fast spin echo MRI sequence, and the flow rates of the AVF inflow and outflow were extracted from a gradient echo velocity mapping sequence. Using these MRI-obtained lumen geometry and inflow information, CFD modeling was performed and used to calculate blood flow velocity and hemodynamic factors at high resolutions (on the order of 0.5 μm spatially and 0.1 ms temporally) throughout the entire AVF lumen. We investigated both the wall properties (including wall shear stress (WSS), wall shear stress spatial gradient, and oscillatory shear index (OSI)) and the volumetric properties (including vorticity, helicity, and Q-criterion). Results Our results demonstrate increases in AVF flow velocity, WSS, spatial WSS gradient, and OSI within 3 weeks post-AVF creation when compared to pre-surgery. We also observed post-operative increases in flow disturbances and vortices, as indicated by increased vorticity, helicity, and Q-criterion. Conclusions This novel protocol will enable us to undertake future mechanistic studies to delineate the relationship between hemodynamics and AVF development and characterize biological mechanisms that regulate local hemodynamic factors in transgenic murine AVF models