Haemostatic alterations and management of haemostasis in patients with cirrhosis

Patients with cirrhosis frequently acquire complex changes in their haemostatic system including a decreased platelet count and decreased levels of various haemostatic proteins. Although historically patients with cirrhosis were thought to have a haemostasis-related bleeding tendency, it is now widely accepted that the haemostatic system of patients with cirrhosis remains in balance as a result of simultaneous changes in pro- and anti-haemostatic systems. The concept of rebalanced haemostasis has led to changes in clinical management, although firm evidence from well-designed clinical studies is largely lacking. For example, many invasive procedures in patients with cirrhosis and a prolonged prothrombin time are now performed without prophylaxis with fresh frozen plasma. Conversely, clinicians have become more aware of the need for anti-thrombotic therapy, even in those patients with abnormal routine coagulation tests. This paper will outline recent advances in pathogenesis, prevention and treatment of both bleeding and thrombotic complications in patients with cirrhosis. Among other topics, we will discuss the haemostatic status of acutely ill patients with cirrhosis, the various causes of bleeding in patients with cirrhosis, and how best to prevent or treat bleeding. In addition, we will discuss the hypercoagulable features of patients with cirrhosis, new insights into the pathogenesis of portal vein thrombosis, and how best to prevent or treat thromboses

Effects of restoring portal flow with anticoagulation and partial splenorenal shunt embolization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110757/1/hep27241.pd

Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats.

OBJECTIVE Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats. RESEARCH DESIGN AND METHODS Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies. RESULTS Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake. CONCLUSIONS Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight

Precision asteroseismology of the pulsating white dwarf GD 1212 using a two-wheel-controlled Kepler spacecraft

We present a preliminary analysis of the cool pulsating white dwarf GD 1212, enabled by more than 11.5 days of space-based photometry obtained during an engineering test of the two-reaction-wheel-controlled Kepler spacecraft. We detect at least 19 independent pulsation modes, ranging from 828.2-1220.8 s, and at least 17 nonlinear combination frequencies of those independent pulsations. Our longest uninterrupted light curve, 9.0 days in length, evidences coherent difference frequencies at periods inaccessible from the ground, up to 14.5 hr, the longest-period signals ever detected in a pulsating white dwarf. These results mark some of the first science to come from a two-wheel-controlled Kepler spacecraft, proving the capability for unprecedented discoveries afforded by extending Kepler observations to the ecliptic.Comment: 8 pages, 4 figures, accepted for publication in The Astrophysical Journa

Interaction of Muscle and Brain Sodium Channels with Multiple Members of the Syntrophin Family of Dystrophin-Associated Proteins

Syntrophins are cytoplasmic peripheral membrane proteins of the dystrophin-associated protein complex (DAPC). Three syntrophin isoforms, alpha1, beta1, and beta2, are encoded by distinct genes. Each contains two pleckstrin homology (PH) domains, a syntrophin-unique (SU) domain, and a PDZ domain. The name PDZ comes from the first three proteins found to contain repeats of this domain (PSD-95, Drosophila discs large protein, and the zona occludens protein 1). PDZ domains in other proteins bind to the C termini of ion channels and neurotransmitter receptors containing the consensus sequence (S/T)XV-COOH and mediate the clustering or synaptic localization of these proteins. Two voltage-gated sodium channels (NaChs), SkM1 and SkM2, of skeletal and cardiac muscle, respectively, have this consensus sequence. Because NaChs are sarcolemmal components like syntrophins, we have investigated possible interactions between these proteins. NaChs copurify with syntrophin and dystrophin from extracts of skeletal and cardiac muscle. Peptides corresponding to the C-terminal 10 amino acids of SkM1 and SkM2 are sufficient to bind detergent-solubilized muscle syntrophins, to inhibit the binding of native NaChs to syntrophin PDZ domain fusion proteins, and to bind specifically to PDZ domains from alpha1-, beta1-, and beta2-syntrophin. These peptides also inhibit binding of the syntrophin PDZ domain to the PDZ domain of neuronal nitric oxide synthase, an interaction that is not mediated by C-terminal sequences. Brain NaChs, which lack the (S/T)XV consensus sequence, also copurify with syntrophin and dystrophin, an interaction that does not appear to be mediated by the PDZ domain of syntrophin. Collectively, our data suggest that syntrophins link NaChs to the actin cytoskeleton and the extracellular matrix via dystrophin and the DAPC

The Next Generation Virgo Cluster Survey. VI. The Kinematics of Ultra-compact Dwarfs and Globular Clusters in M87

The origin of ultra-compact dwarfs (UCDs)--objects larger and more massive than typical globular clusters (GCs), but more compact than typical dwarf galaxies--has been hotly debated in the 15 years since their discovery. Even whether UCDs should be considered galactic in origin, or simply the most extreme GCs, is not yet settled. We present the dynamical properties of 97 spectroscopically confirmed UCDs (rh >~10 pc) and 911 GCs associated with central cD galaxy of the Virgo cluster, M87. Our UCDs, of which 89% have M_star > ~2X10^6 M_sun and 92% are as blue as the classic blue GCs, nearly triple the sample of previous confirmed Virgo UCDs, providing by far the best opportunity for studying the global dynamics of a UCD system. We found that (1) UCDs have a surface number density profile that is shallower than that of the blue GCs in the inner ~ 70 kpc and as steep as that of the red GCs at larger radii; (2) UCDs exhibit a significantly stronger rotation than the GCs, and the blue GCs seem to have a velocity field that is more consistent with that of the surrounding dwarf ellipticals than with that of UCDs; (3) UCDs have a radially increasing orbital anisotropy profile, and are tangentially-biased at radii < ~ 40 kpc and radially-biased further out. In contrast, the blue GCs become more tangentially-biased at larger radii beyond ~ 40 kpc; (4) GCs with M_star > 2X10^6 M_sun have rotational properties indistinguishable from the less massive ones, suggesting that it is the size, instead of mass, that differentiates UCDs from GCs as kinematically distinct populations. We conclude that most UCDs in M87 are not consistent with being merely the most luminous and extended examples of otherwise normal GCs. The radially-biased orbital structure of UCDs at large radii is in general agreement with the "tidally threshed dwarf galaxy" scenario.Comment: 27 pages, 21 figures. To appear in The Astrophysical Journa

Validation of Kepler's Multiple Planet Candidates. III: Light Curve Analysis & Announcement of Hundreds of New Multi-planet Systems

The Kepler mission has discovered over 2500 exoplanet candidates in the first two years of spacecraft data, with approximately 40% of them in candidate multi-planet systems. The high rate of multiplicity combined with the low rate of identified false-positives indicates that the multiplanet systems contain very few false-positive signals due to other systems not gravitationally bound to the target star (Lissauer, J. J., et al., 2012, ApJ 750, 131). False positives in the multi- planet systems are identified and removed, leaving behind a residual population of candidate multi-planet transiting systems expected to have a false-positive rate less than 1%. We present a sample of 340 planetary systems that contain 851 planets that are validated to substantially better than the 99% confidence level; the vast majority of these have not been previously verified as planets. We expect ~2 unidentified false-positives making our sample of planet very reliable. We present fundamental planetary properties of our sample based on a comprehensive analysis of Kepler light curves and ground-based spectroscopy and high-resolution imaging. Since we do not require spectroscopy or high-resolution imaging for validation, some of our derived parameters for a planetary system may be systematically incorrect due to dilution from light due to additional stars in the photometric aperture. None the less, our result nearly doubles the number of verified exoplanets.Comment: 138 pages, 8 Figures, 5 Tables. Accepted for publications in the Astrophysical Journa

Discovery and Validation of Kepler-452b: A 1.6-Re Super Earth Exoplanet in the Habitable Zone of a G2 Star

We report on the discovery and validation of Kepler-452b, a transiting planet identified by a search through the 4 years of data collected by NASA's Kepler Mission. This possibly rocky 1.63$^{+0.23}_{-0.20}$ R$_\oplus$ planet orbits its G2 host star every 384.843$^{+0.007}_{0.012}$ days, the longest orbital period for a small (R$_p$ < 2 R$_\oplus$) transiting exoplanet to date. The likelihood that this planet has a rocky composition lies between 49% and 62%. The star has an effective temperature of 5757$\pm$85 K and a log g of 4.32$\pm$0.09. At a mean orbital separation of 1.046$^{+0.019}_{-0.015}$ AU, this small planet is well within the optimistic habitable zone of its star (recent Venus/early Mars), experiencing only 10% more flux than Earth receives from the Sun today, and slightly outside the conservative habitable zone (runaway greenhouse/maximum greenhouse). The star is slightly larger and older than the Sun, with a present radius of 1.11$^{+0.15}_{-0.09}$ R$_\odot$ and an estimated age of 6 Gyr. Thus, Kepler-452b has likely always been in the habitable zone and should remain there for another 3 Gyr.Comment: 19 pages, 16 figure

The Rapid-Sampling Vertical Profiler : test cruise, July 1982

In this report we describe a preliminary version of a temperature/conductivity profiler that combines the calibration accuracy of a CTD with the vertical resolution of a microstructure instrument and the ease of deployment of an XBT. We also describe the results of a test of this version on a month-long cruise from Honolulu to 42 N and back in July 1982. This instrument system, which we call the Rapid-Sampling Vertical Profiler, has two versions. One uses a Neil Brown conductivity transducer and a fast-tip thermistor as sensors, and has a vertical resolution of 3 cm in salinity and temperature. The other has a micro-scale conductivity sensor, with a fast-tip thermistor. It has a resolution of less than one millimeter in conductivity,·but only 3 cm in the thermistor signal so that density information can still only be acquired on the 3-cm scale