Factor VIII:C concentrate purified from plasma using monoclonal antibodies: human studies

Conventional clotting factor concentrates have, until recently, been of intermediate purity, containing less than 1% of the coagulation factor, and greater than 99% extraneous plasma proteins such as fibrinogen, fibronectin, gamma globulins, and traces of many others. We report here the results of a new factor VIII concentrate that is purified from human plasma using a mouse monoclonal antibody to factor VIII:vWF in an affinity chromatography system. The resultant concentrate has an activity of between 3,000 and 5,000 U/mg protein before albumin is added as a stabilizer. Seven patients with severe hemophilia A and no inhibitor who were positive for antibody to human immunodeficiency virus (HIV) have been treated solely with this concentrate for over 24 months. Factor usage in these patients has ranged from 611 U/kg/yr to 2,022 U/kg/yr. These patients have infused approximately once per week on the average, most often for joint hemorrhages. The efficacy of the concentrate is excellent. No allergic reactions have occurred and no factor VIII antibodies have developed. In these seven patients mean CD4 counts stabilized (856 +/- 619 at screen v 778 +/- 686 at 24 months) and there was reversal of skin test anergy. In a comparison group on conventional intermediate purity concentrate chosen retrospectively decreases in mean CD4 cell counts similarly did not occur. However, the number of the comparison patients who were anergic increased over the course of the study. These observations indicate the possibility that more highly purified concentrates may stabilize immune function in HIV seropositive patients

Antigenic specificity of antibody-dependent cell-mediated cytotoxicity directed against human immunodeficiency virus in antibody-positive sera

Antibody-dependent cell-mediated cytotoxicity (ADCC) specific for human immunodeficiency virus (HIV) has been described for HIV-infected individuals. To determine the antigenic specificity of this immune response and to define its relationship to the disease state, an ADCC assay was developed using Epstein-Barr virus-transformed lymphoblastoid cell line targets infected with vaccinia virus vectors expressing HIV proteins. The vaccinia virus vectors induced appropriate HIV proteins (envelope glycoproteins gp160, gp120, and gp41 or gag proteins p55, p40, p24, and p17) in infected lymphoblastoid cell lines as demonstrated by radioimmunoprecipitation and syncytia formation with c8166 cells. Killer cell-mediated, HIV-specific ADCC was found in sera from HIV-seropositive but not HIV-seronegative hemophiliacs. This HIV-specific response was directed against envelope glycoprotein but was completely absent against target cells expressing the HIV gag proteins. The ADCC directed against gp160 was present at serum dilutions up to 1/316,000. There was no correlation between serum ADCC titer and the stage of HIV-related illness as determined by T-helper-cell numbers. These experiments clearly implicated gp160 as the target antigen of HIV-specific ADCC activity following natural infection. Vaccines which stimulate antibodies directed against gp160, which are capable of mediating ADCC against infected cells, could be important for protection against infection by cell-associated virus

Detection of major histocompatibility complex class I-restricted, HIV-specific cytotoxic T lymphocytes in the blood of infected hemophiliacs

Major histocompatibility (MHC)-restricted, human immunodeficiency virus type one (HIV-1)-specific, cytotoxic T lymphocytes (CTLs) were detected in the peripheral blood mononuclear cells (PBMCs) of HIV-1-infected individuals. Using a system of autologous B and T lymphoblastoid cell lines infected with recombinant vaccinia vectors (VVs) expressing HIV-1 gene products, we were able to detect HIV-1-specific cytolytic responses in the PBMCs of 88% of HIV-1-seropositive hemophiliac patients in the absence of in vitro stimulation. These cytolytic responses were directed against both HIV-1 envelope and gag gene products. The responses were resistant to natural killer (NK) cell depletion and were inhibited by monoclonal antibodies (MoAbs) to the T cell receptor, CD8 surface antigens, and MHC class I antigens, suggesting a classical MHC class I restricted, virus-specific CTL response

AXTAR: Mission Design Concept

The Advanced X-ray Timing Array (AXTAR) is a mission concept for X-ray timing of compact objects that combines very large collecting area, broadband spectral coverage, high time resolution, highly flexible scheduling, and an ability to respond promptly to time-critical targets of opportunity. It is optimized for submillisecond timing of bright Galactic X-ray sources in order to study phenomena at the natural time scales of neutron star surfaces and black hole event horizons, thus probing the physics of ultradense matter, strongly curved spacetimes, and intense magnetic fields. AXTAR's main instrument, the Large Area Timing Array (LATA) is a collimated instrument with 2-50 keV coverage and over 3 square meters effective area. The LATA is made up of an array of supermodules that house 2-mm thick silicon pixel detectors. AXTAR will provide a significant improvement in effective area (a factor of 7 at 4 keV and a factor of 36 at 30 keV) over the RXTE PCA. AXTAR will also carry a sensitive Sky Monitor (SM) that acts as a trigger for pointed observations of X-ray transients in addition to providing high duty cycle monitoring of the X-ray sky. We review the science goals and technical concept for AXTAR and present results from a preliminary mission design study.Comment: 19 pages, 10 figures, to be published in Space Telescopes and Instrumentation 2010: Ultraviolet to Gamma Ray, Proceedings of SPIE Volume 773

Dynamics of solar coronal loops II. Catastrophic cooling and high-speed downflows

This work addresses the problem of plasma condensation and ``catastrophic cooling'' in solar coronal loops. We have carried out numerical calculations of coronal loops and find several classes of time-dependent solutions (static, periodic, irregular), depending on the spatial distribution of a temporally constant energy deposition in the loop. Dynamic loops exhibit recurrent plasma condensations, accompanied by high-speed downflows and transient brightenings of transition region lines, in good agreement with features observed with TRACE. Furthermore, these results also offer an explanation for the recent EIT observations of De Groof et al. (2004) of moving bright blobs in large coronal loops. In contrast to earlier models, we suggest that the process of catastrophic cooling is not initiated by a drastic decrease of the total loop heating but rather results from a loss of equilibrium at the loop apex as a natural consequence of heating concentrated at the footpoints of the loop, but constant in time.Comment: 13 pages, 15 figure

Safety, Immunogenicity, and Transmissibility of Single-Dose Live Oral Cholera Vaccine Strain CVD l03-HgR in 24- to 59-Month-Old Indonesian Children

Recombinant A-B+ Vibrio cholerae O1 strain CVD 103-HgR is a safe, highly immunogenic, single-dose live oral vaccine in adults in industrialized countries, Safety, excretion, immunogenicity, vaccine transmissibility, and environmental introduction ofCVD 103-HgR were investigated among 24- to 59-month-old children in Jakarta. In 81 households, 1 child was randomly allocated a single dose of vaccine (5 x 109 cfu) and another, placebo. Additionally, 139 unpaired children were randomly allocated vaccine or placebo. During 9 days of follow-up, diarrhea or vomiting did not occur more often among vaccinees than controls. Vaccine was minimally excreted and was isolated from no controls and from 1 (0.6%) of 177 unvaccinated family contacts. A 4-fold or higher rise in serum vibriocidal antibody was observed in 75% of vaccinees (10-fold rise in geometric mean titer over baseline). Of 135 paired placebo recipients or household contacts, 5 had vibriocidal seroconversions. Moore swabs placed in sewers and latrines near 97 households failed to detect vaccine. These observations pave the way for a large-scale field trial of efficac

UAS-based high resolution mapping of evapotranspiration in a Mediterranean tree-grass ecosystem

Este artículo está sujeto a una licencia CC BY 4.0Understanding the impact of land use and land cover change on surface energy and water budgets is increasingly important in the context of climate change research. Eddy covariance (EC) methods are the gold standard for high temporal resolution measurements of water and energy fluxes, but cannot resolve spatial heterogeneity and are limited in scope to the tower footprint (few hundred meter range). Satellite remote sensing methods have excellent coverage, but lack spatial and temporal resolution. Long-range unmanned aerial systems (UAS) can complement these other methods with high spatial resolution over larger areas. Here we use UAS thermography and multispectral data as inputs to two variants of the Two Source Energy Balance Model to accurately map surface energy and water fluxes over a nutrient manipulation experiment in a managed semi-natural oak savanna from peak growing season to senescence. We use energy flux measurements from 6 EC stations to evaluate the performance of our method and achieve good accuracy (RMSD ≈ 60 W m− 2 for latent heat flux). We use the best performing latent heat estimates to produce very high-resolution evapotranspiration (ET) maps, and investigate the drivers of ET change over the transition to the senescence period. We find that nitrogen and nitrogen plus phosphorus treatments lead to significant increases in ET (P < 0.001) for both trees (4 and 6%, respectively) and grass (12 and 9%, respectively) compared to the control. These results highlight that the high sensitivity and spatial and temporal resolution of a UAS system allows the precise estimation of relative water and energy fluxes over heterogeneous vegetation cover.This research was supported by the DAAD/BMBF program Make Our Planet Great Again – German Research Initiative Project MONSOON (grant number 57429870).Peer reviewe

Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and-unexpectedly-lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractant

Down Syndrome: Age-Dependence of PiB Binding in Postmortem Frontal Cortex Across the Lifespan

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS) with subsequent development into Alzheimer disease neuropathology, typically by 40 years of age. In vivo imaging using the Pittsburgh Compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro 3H-PiB binding in the frontal cortex of autopsy cases with DS compared to non-DS controls. Tissue from 64 cases included controls (N=25) and DS (N=39). In DS, 3H-PiB binding was significantly associated with age. After age 40 years in DS, 3H-PiB binding rose dramatically along with increasing individual variability. 3H-PiB binding correlated with the amount of Aβ42. Using fixed frontal tissue and fluorescent 6-CN-PiB, neuritic and cored plaques along with extensive cerebral amyloid angiopathy (CAA) showed 6-CN-PiB binding. These results suggest that cortical PiB binding as shown by positron emission tomography imaging reflects plaques and CAA in DS brain