Effect of anticoagulants on fibrin clot structure: a comparison between vitamin K antagonists and factor Xa inhibitors

Background Abnormal clot structure has been identified in patients with thrombotic disorders. Anticoagulant therapy offers clear benefits for thrombosis prevention and treatment by reducing blood clot formation and size; nevertheless, there are limited data on the effects of different anticoagulants, where clotting is initiated with different triggers, on clot structure. Objectives Our aim was to investigate the effects of vitamin K antagonists and factor Xa inhibitors on clot structure. Methods Clots from pooled plasma spiked with rivaroxaban, apixaban, or enoxaparin, as well as plasma from patients on warfarin, were compared to plasma without anticoagulation. The kinetic profile of polymerizing clots was obtained by turbidity, fiber density was determined by confocal microscopy, clot pore size was investigated by permeation, and fiber size was analyzed using scanning electron microscopy. Clotting agonist was either tissue factor or thrombin. Results Following clotting with tissue factor, all anticoagulated clots had a significantly increased lag time, with the exception of enoxaparin. Rivaroxaban additionally led to significantly less dense and more permeable clots, with thicker fibers. In contrast, turbidity analysis following initiation with thrombin showed few effects of anticoagulation, with only enoxaparin leading to a prolonged lag time. Enoxaparin clots made with thrombin were less dense and more permeable. Conclusion Our results show that anticoagulants modulate clot structure particularly when induced by tissue factor, most likely due to reduction of thrombin generation. We propose that the effects of different anticoagulants could be assessed with a global clot structure measurement such as permeation or turbidity, providing information on clot phenotype

Can the Pioneer anomaly be of gravitational origin? A phenomenological answer

In order to satisfy the equivalence principle, any non-conventional mechanism proposed to gravitationally explain the Pioneer anomaly, in the form in which it is presently known from the so-far analyzed Pioneer 10/11 data, cannot leave out of consideration its impact on the motion of the planets of the Solar System as well, especially those orbiting in the regions in which the anomalous behavior of the Pioneer probes manifested itself. In this paper we, first, discuss the residuals of the right ascension \alpha and declination \delta of Uranus, Neptune and Pluto obtained by processing various data sets with different, well established dynamical theories (JPL DE, IAA EPM, VSOP). Second, we use the latest determinations of the perihelion secular advances of some planets in order to put on the test two gravitational mechanisms recently proposed to accommodate the Pioneer anomaly based on two models of modified gravity. Finally, we adopt the ranging data to Voyager 2 when it encountered Uranus and Neptune to perform a further, independent test of the hypothesis that a Pioneer-like acceleration can also affect the motion of the outer planets of the Solar System. The obtained answers are negative.Comment: Latex2e, 26 pages, 6 tables, 2 figure, 47 references. It is the merging of gr-qc/0608127, gr-qc/0608068, gr-qc/0608101 and gr-qc/0611081. Final version to appear in Foundations of Physic

Complementary approaches to understanding the plant circadian clock

Circadian clocks are oscillatory genetic networks that help organisms adapt to the 24-hour day/night cycle. The clock of the green alga Ostreococcus tauri is the simplest plant clock discovered so far. Its many advantages as an experimental system facilitate the testing of computational predictions. We present a model of the Ostreococcus clock in the stochastic process algebra Bio-PEPA and exploit its mapping to different analysis techniques, such as ordinary differential equations, stochastic simulation algorithms and model-checking. The small number of molecules reported for this system tests the limits of the continuous approximation underlying differential equations. We investigate the difference between continuous-deterministic and discrete-stochastic approaches. Stochastic simulation and model-checking allow us to formulate new hypotheses on the system behaviour, such as the presence of self-sustained oscillations in single cells under constant light conditions. We investigate how to model the timing of dawn and dusk in the context of model-checking, which we use to compute how the probability distributions of key biochemical species change over time. These show that the relative variation in expression level is smallest at the time of peak expression, making peak time an optimal experimental phase marker. Building on these analyses, we use approaches from evolutionary systems biology to investigate how changes in the rate of mRNA degradation impacts the phase of a key protein likely to affect fitness. We explore how robust this circadian clock is towards such potential mutational changes in its underlying biochemistry. Our work shows that multiple approaches lead to a more complete understanding of the clock

Nucleon superfluidity versus thermal states of isolated and transiently accreting neutron stars

The properties of superdense matter in neutron star (NS) cores control NS thermal states by affecting the efficiency of neutrino emission from NS interiors. To probe these properties we confront the theory of thermal evolution of NSs with observations of their thermal radiation. Our observational basis includes cooling isolated NSs (INSs) and NSs in quiescent states of soft X-ray transients (SXTs). We find that the data on SXTs support the conclusions obtained from the analysis of INSs: strong proton superfluidity with T_{cp,max} >= 10^9 K should be present, while mild neutron superfluidity with T_{cn,max} =(2*10^8 -- 2*10^9) K is ruled out in the outer NS core. Here T_{cn,max} and T_{cp,max} are the maximum values of the density dependent critical temperatures of neutrons and protons. The data on SXTs suggest also that: (i) cooling of massive NSs is enhanced by neutrino emission more powerful than the emission due to Cooper pairing of neutrons; (ii) mild neutron superfluidity, if available, might be present only in inner cores of massive NSs. In the latter case SXTs would exhibit dichotomy, i.e. very similar SXTs may evolve to very different thermal states

A Roadmap to Rural Residency Program Development

Rural communities face a pressing need for primary care, behavioral health, and obstetrical care services, yet rural hospitals around the country are closing, and the gap between mortality rates in rural and urban areas is widening. While there is some debate about whether the nation faces a shortage of physicians, there is general consensus that the workforce is maldistributed. Estimates suggested we face a shortfall of 14 164 practitioners in primary care health professional shortage areas. While efforts to address rural workforce shortages need to be targeted along multiple points in a physician’s career trajectory, exposure to rural and underserved settings during training has been shown to increase physicians’ sense of preparedness for rural practice and retention in rural communities. Despite this evidence, graduate medical education (GME) in rural areas remains very limited, and the US Government Accountability Office estimates that only 1% of residents across all specialties train in rural areas. This is due in part to the unique challenges that face rural health organizations in the United States, which often operate on thin financial margins with limited providers and staff. Rural hospitals and federally qualified health centers (FQHCs) often lack the capacity and resources to design, develop, start-up, and maintain rural residency training programs in their communities. The small size and remoteness of rural programs make them susceptible to unique challenges such as inadequate patient volumes, lack of sustained funding after start-up grants, frequent leadership turnover, limited educational resources, difficulty recruiting residents, and insufficient support for faculty development and protected teaching time

The influence of gene expression time delays on Gierer-Meinhardt pattern formation systems

There are numerous examples of morphogen gradients controlling long range signalling in developmental and cellular systems. The prospect of two such interacting morphogens instigating long range self-organisation in biological systems via a Turing bifurcation has been explored, postulated, or implicated in the context of numerous developmental processes. However, modelling investigations of cellular systems typically neglect the influence of gene expression on such dynamics, even though transcription and translation are observed to be important in morphogenetic systems. In particular, the influence of gene expression on a large class of Turing bifurcation models, namely those with pure kinetics such as the Gierer–Meinhardt system, is unexplored. Our investigations demonstrate that the behaviour of the Gierer–Meinhardt model profoundly changes on the inclusion of gene expression dynamics and is sensitive to the sub-cellular details of gene expression. Features such as concentration blow up, morphogen oscillations and radical sensitivities to the duration of gene expression are observed and, at best, severely restrict the possible parameter spaces for feasible biological behaviour. These results also indicate that the behaviour of Turing pattern formation systems on the inclusion of gene expression time delays may provide a means of distinguishing between possible forms of interaction kinetics. Finally, this study also emphasises that sub-cellular and gene expression dynamics should not be simply neglected in models of long range biological pattern formation via morphogens