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    Myeloablative Cord Blood Transplantation in Adults with Acute Leukemia: Comparison of Two Different Transplant Platforms

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    AbstractWe compared the clinical outcomes of adults with acute leukemia that received single-unit umbilical cord blood transplantation (sUCBT) after conditioning with a busulfan/antithymocyte globulin (BU-ATG)–based regimen at University Hospital La Fe (n = 102) or double-unit UCBT (dUCBT) after conditioning with a total body irradiation (TBI)–based regimen at the University of Minnesota (n = 91). Nonrelapse mortality, relapse and disease-free survival were similar in the 2 groups. Multivariate analyses, showed more rapid neutrophil (hazard ratio [HR], .6; 95% confidence interval [CI], .45 to .80; P = .0006) and platelet recovery (HR, .59; 95% CI, .43 to.83; P = .002) after the BU-ATG-based conditioning and sUCBT. Although there was a lower risk of acute graft-versus-host disease (GVHD) grade II to IV (HR, 2.81; 95% CI, 1.75 to 4.35; P < .001) after BU-ATG and sUCBT, the incidences of grade III to IV acute and chronic GVHD were similar between the 2 groups. Regarding disease-specific outcomes, disease-free survival in both acute myeloid leukemia and acute lymphoblastic leukemia (ALL) patients were not significantly different; however, a significantly lower relapse rate was found in patients with ALL treated with TBI and dUCBT (HR, .3; 95% CI, .12 to .84; P = .02). In the context of these specific treatment platforms, our study demonstrates that sUCB and dUCBT offer similar outcomes

    The Wall-stress Footprint of Blood Cells Flowing in Microvessels

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    AbstractIt is well known that mechanotransduction of hemodynamic forces mediates cellular processes, particularly those that lead to vascular development and maintenance. Both the strength and space-time character of these forces have been shown to affect remodeling and morphogenesis. However, the role of blood cells in the process remains unclear. We investigate the possibility that in the smallest vessels blood’s cellular character of itself will lead to forces fundamentally different than the time-averaged forces usually considered, with fluctuations that may significantly exceed their mean values. This is quantitated through the use of a detailed simulation model of microvessel flow in two principal configurations: a diameter D=6.5 μm tube—a model for small capillaries through which red blood cells flow in single-file—and a D=12 μm tube—a model for a nascent vein or artery through which the cells flow in a confined yet chaotic fashion. Results in both cases show strong sensitivity to the mean flow speed U. Peak stresses exceed their means by greater than a factor of 10 when U/D≲10 s−1, which corresponds to the inverse relaxation time of a healthy red blood cell. This effect is more significant for smaller D cases. At faster flow rates, including those more commonly observed under normal, nominally static physiological conditions, the peak fluctuations are more comparable with the mean shear stress. Implications for mechanotransduction of hemodynamic forces are discussed

    Changes of intracellular Ca++ as measured by arsenazo III in relation to the K permeability of human erythrocyte ghosts

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    A Ca-sensitive dye, arsenazo III, has been incorporated into resealed human erythrocyte ghosts and calibrated to monitor continuously micromolar concentrations of intracellular ionized Ca ([Ca++]i). When the external concentration of Ca is much greater than [Ca++]i, [Ca++]i increases because of a net balance between Ca influx and efflux. Dynamic changes in [Ca++]i regulate K efflux, which in turn may influence the rate of Ca influx. A procedure for purifying arsenazo III is also described

    The role of altered [Ca2+]i regulation in apoptosis, oncosis, and necrosis

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    AbstractUnderstanding the processes and events that occur when a cell undergoes a prelethal injury or that lead the cell to death following a lethal injury has been the aim of our research for a number of years. Throughout this period much has been learned, recently at rapid rates, not only by us but my many other investigators as well. Based on the data gathered, we proposed a working hypothesis over a decade ago and have since continually updated it as new experimentation is performed. Our laboratory has focused particularly on the role of cytoplasmic ionized calcium ([Ca2+]i) and the effects of its deregulation on prelethal events, including oncosis and apoptosis, and lethal events (necrosis) following cell death. [Ca2+]i appears to be a major link and signalling event. Understanding the mechanisms involved by using a variety of in vivo and in vitro models, coupled with state-of-the-art methodologies, should now allow us to prevent cell death by killing cells when necessary through gene therapy and cancer chemotherapy

    Why Can’t Protons Move through Water Channels?

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    Transbilayer organization of membrane cholesterol at low concentrations: Implications in health and disease

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    AbstractCholesterol is an essential and representative lipid in higher eukaryotic cellular membranes and is often found distributed nonrandomly in domains in biological membranes. A large body of literature exists on the organization of cholesterol in plasma membranes or membranes with high cholesterol content. However, very little is known about organization of cholesterol in membranes containing low amounts of cholesterol such as the endoplasmic reticulum or inner mitochondrial membranes. In this review, we have traced the discovery and subsequent development of the concept of transbilayer cholesterol dimers (domains) in membranes at low concentrations. We have further discussed the role of membrane curvature and thickness on the transbilayer organization of cholesterol. Interestingly, this type of cholesterol organization could be relevant in cellular sorting and trafficking, and in pathological conditions

    A method to compute absolute free energies or enthalpies of fluids

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    AbstractWe propose a new method to compute the free energy or enthalpy of fluids or disordered solids by computer simulation. The main idea is to construct a reference system by freezing one representative configuration, and then carry out a thermodynamic integration. We present a strategy and an algorithm which allows to sample the thermodynamic integration path even in the case of liquids, despite the fact that the particles can diffuse freely through the system. The method is described in detail and illustrated with applications to hard sphere fluids and solids with mobile defects

    Neutron Strain Scanning of Fibre and Diode Laser Welds in Stainless Steel and Ti6Al4V

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    AbstractFibre lasers provide an unprecedented combination of high beam quality, brightness and low cost. Fibre laser beams can provide an exceptionally high power density beam with a relatively large depth of focus. Compared to more established laser welding technologies such as diode laser welding, fibre laser welding produces exceptionally narrow weld beads. As with all types of welding, fibre laser welding produces residual stresses in the material forming and adjacent to the weld. The SALSA instrument at the Institut Laue Langevin (ILL) has been used to make neutron diffraction measurements for both fibre and diode laser welded stainless steel 304 and Ti6Al4V. Clear diffraction peaks are obtained from stainless steel 304 and residual stress distributions are obtained. Little variation in residual stress distribution with welding parameters is seen. Ti6Al4V diffraction peaks are complicated by phase transformations on cooling. Transformed beta phase peaks in Ti6Al4V allow the extent of the heat affected zone to be determined

    The influence of the alpha grain size on internal fatigue crack initiation in drawn Ti-6Al-4V wires

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    AbstractIn the very high cycle fatigue regime, the location of crack initiation in titanium alloys is known to shift from the surface towards the bulk of the material. This internal fatigue crack initiation results in faceted features on the fracture surface. These facets are in fact alpha grains that have been broken in a planar manner. Typically, a cluster of many facets is observed either just below the surface or deeper inside the bulk. In this study, uniaxial tension-tension fatigue tests are performed on Ti-6Al-4V wires which have been subjected to different heat treatments in order to vary the alpha grain size. Four different microstructures are obtained, with average alpha grain sizes of approximately 1, 2, 5 and 10 µm. The fatigue life is found to decrease with increasing grain size. Electrochemical polishing of the wires prior to fatigue testing is applied in order to promote internal crack initiation at higher stresses and consequently shorter testing durations. Four samples broke due to an internal crack: three samples with average alpha grain size 5 µm, which failed after 2.6 x 107, 5.7 x 107 and 9.6 x 107 cycles, and one sample with average alpha grain size 10 µm, which failed after only 7.6 x 106 cycles. The threshold stress intensity factor range, which is calculated from the size of the facet-containing area, is between 5 and 6 MPa.m1/2 for all four samples. Fractographic examination of the facets reveals that they are not smooth, but show roughness at the nanoscale. This roughness has a linear appearance for nearly all facets, except for one anomalous facet in the sample with the largest grain size, which shows a fan-shaped pattern. From electron backscatter diffraction measurements on cross-sections of the fracture surfaces obtained by focused ion beam milling, it is also found that nearly all the facets coincide with a prismatic plane, and the linear markings are parallel to the prismatic slip direction. Only the anomalous facet has a near-basal orientation. These observations suggest the possibility that facets are formed by either a slip-based mechanism or a cleavage-based mechanism, and that the alpha grain size is one of the parameters that controls which mechanism occurs
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