Thromboembolic and neurologic sequelae of discontinuation of an antihyperlipidemic drug during ongoing warfarin therapy

Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit warfarin deactivation via the hepatic cytochrome P450 system. Therefore, antihyperlipidemic discontinuation has been hypothesized to result in underanticoagulation, as warfarin metabolism is no longer inhibited. We quantified the risk of venous thromboembolism (VTE) and ischemic stroke (IS) due to statin and fibrate discontinuation in warfarin users, in which warfarin was initially dose-titrated during ongoing antihyperlipidemic therapy. Using 1999-2011 United States Medicaid claims among 69 million beneficiaries, we conducted a set of bidirectional self-controlled case series studies-one for each antihyperlipidemic. Outcomes were hospital admissions for VTE/IS. The risk segment was a maximum of 90 days immediately following antihyperlipidemic discontinuation, the exposure of interest. Time-varying confounders were included in conditional Poisson models. We identified 629 study eligible-persons with at least one outcome. Adjusted incidence rate ratios (IRRs) for all antihyperlipidemics studied were consistent with the null, and ranged from 0.21 (0.02, 2.82) for rosuvastatin to 2.16 (0.06, 75.0) for gemfibrozil. Despite using an underlying dataset of millions of persons, we had little precision in estimating IRRs for VTE/IS among warfarin-treated persons discontinuing individual antihyperlipidemics. Further research should investigate whether discontinuation of gemfibrozil in warfarin users results in serious underanticoagulation

Constellations: A New Paradigm for Earth Observations

The last decade has seen a significant increase in the number and the capabilities of remote sensing satellites launched by the international community. A relatively new approach has been the launching of satellites into heterogeneous constellations. Constellations provide the scientists a capability to acquire science data, not only from specific instruments on a single satellite, but also from instruments on other satellites that fly in the same orbit. Initial results from the A-Train (especially following the CALIPSO/CloudSat launch) attest to the tremendous scientific value of constellation flying. This paper provides a history of the constellations (particularly the A-Train) and how the A-Train mission design was driven by science requirements. The A-Train has presented operational challenges which had not previously been encountered. Operations planning had to address not only how the satellites of each constellation operate safely together, but also how the two constellations fly in the same orbits without interfering with each other when commands are uplinked or data are downlinked to their respective ground stations. This paper discusses the benefits of joining an on-orbit constellation. When compared to a single, large satellite, a constellation infrastructure offers more than just the opportunities for coincidental science observations. For example, constellations reduce risks by distributing observing instruments among numerous satellites; in contrast, a failed launch or a system failure in a single satellite would lead to loss of all observations. Constellations allow for more focused, less complex satellites. Constellations distribute the development, testing, and operations costs among various agencies and organizations for example, the Morning and Afternoon Constellations involve several agencies within the U.S. and in other countries. Lastly, this paper addresses the need to plan for the long-term evolution of a constellation. Agencies need to have a replenishment strategy as some satellites age and eventually leave the constellation. This will ensure overlap of observations, thus providing continuous, calibrated science data over a much longer time period. Thoughts on the evolution of the A-Train will also be presented

Determination of copper in tap water using solid-phase spectrophotometry

A new application of ion exchange films is presented. The films are used in a simple analytical method of directly determining low concentrations of Cu(2+) in aqueous solutions, in particular, drinking water. The basis for this new test method is the color and absorption intensity of the ion when adsorbed onto the film. The film takes on the characteristic color of the adsorbed cation, which is concentrated on the film by many orders of magnitude. The linear relationship between absorbance (corrected for variations in film thickness) and solution concentration makes the determinations possible. These determinations agree well with flame atomic absorption determinations

Gene expression in Leishmania is regulated predominantly by gene dosage

ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy

Limits on the star formation rates of z>2 damped Ly-alpha systems from H-alpha spectroscopy

We present the results of a long-slit K-band spectroscopic search with CGS4 on UKIRT for H-alpha emission from the objects responsible for high-redshift (z > 2) damped Ly-alpha absorption systems. The objective was to measure the star-formation rates in these systems. However, no H-alpha emission was detected above our 3-sigma limits of f < 10E-19 W/m**2, corresponding to star formation rates < 10 M_sun/yr/h**2 (q_0=0.5). These upper limits are more meaningful than those from searches for Ly-alpha emission because the H-alpha line is unaffected by resonant scattering. For q_0=0.5 our limits are in conflict with the star formation rates predicted under the assumption that the high-z DLAs are the fully-formed galactic-disk counterparts of today's massive spiral galaxies. Deeper spectroscopy is needed to test this picture for q_0=0.0. A programme of NICMOS imaging observations currently underway, combined with VLT spectroscopy, will provide a detailed picture of the link between DLAs and young galaxies.Comment: 5 pages, LaTex, includes 1 encapsulated postscript figure. To appear in the proceedings of the workshop on "NICMOS and the VLT: A New Era of High Resolution Near Infrared Imaging and Spectroscopy", held in Pula, Sardinia (26-27 May 1998), eds. Wolfram Freudling et al. Uses aspconf.sty and epsf.st

The Global Stratotype Section and Point (GSSP) for the base of the Katian Stage of the Upper Ordovician Series at Black Knob Ridge, Southeastern Oklahoma, USA

The International Subcomission on Ordovician Stratigraphy (ISOS) of the International Commission on Stratigraphy (ICS) recently defined the base of the global Upper Ordovician Series to be at the first appearance datum (FAD) of the graptolite species Nemagraptus gracilis in the Fågelsång GSSP in southern Sweden. This designation recognized the tremendous utility for global correlation of the first appearance of a cosmopolitan taxon that occurs within a consistent succession of other first appearance datums (e.g., Finney and Bergström, 1986; Bergström et al., 2000). Current efforts by the ISOS have focused on subdividing the Upper Ordovician into three stages and choosing appropriate levels and stratotypes for the bases of the middle and upper of these stages. The purpose of the present report is to describe the GSSP of the middle stage, for which the name Katian Stage was approved by the ISOS and ratified by the ICS in 2006 (Bergström et al., 2006). For a recent review of the long process of developing the new subdivisions of the Ordovician, see Finney (2005)

A Novel Flow-Perfusion Bioreactor Supports 3D Dynamic Cell Culture

Background. Bone engineering requires thicker three-dimensional constructs than the maximum thickness supported by standard cell-culture techniques (2 mm). A flow-perfusion bioreactor was developed to provide chemotransportation to thick (6 mm) scaffolds. Methods. Polyurethane scaffolds, seeded with murine preosteoblasts, were loaded into a novel bioreactor. Control scaffolds remained in static culture. Samples were harvested at days 2, 4, 6, and 8 and analyzed for cellular distribution, viability, metabolic activity, and density at the periphery and core. Results. By day 8, static scaffolds had a periphery cell density of 67% ± 5.0%, while in the core it was 0.3% ± 0.3%. Flow-perfused scaffolds demonstrated peripheral cell density of 94% ± 8.3% and core density of 76% ± 3.1% at day 8. Conclusions. Flow perfusion provides chemotransportation to thick scaffolds. This system may permit high throughput study of 3D tissues in vitro and enable prefabrication of biological constructs large enough to solve clinical problems