Experience with daptomycin daily dosing in ICU patients undergoing continuous renal replacement therapy

Purpose: For critically ill patients undergoing continuous renal replacement therapy (CRRT), daptomycin dosing recommendations are scarce. We, therefore, retrospectively assessed routinely measured daptomycin plasma concentrations, daptomycin dose administered and microbiological data in 11 critically ill patients with Gram-positive infections that had received daptomycin once daily. Methods: The retrospective analysis included critically ill patients treated at the intensive care unit (ICU) who had daptomycin plasma concentrations measured. Results: Daptomycin dose ranged from 3 to 8mg/kg/q24h in patients undergoing CRRT (n=7) and 6 to 10mg/kg/q24h in patients without CRRT (n=4). Peak and trough concentrations showed a high intra- and inter-patient variability in both groups, independent of the dosage per kg body weight. No drug accumulation was detected in CRRT patients with once-daily daptomycin dosing. Causative pathogens were Enterococcus faecium (n=6), coagulase-negative Staphylococcus (n=2), Staphylococcus aureus (n=2) and unknown in one patient. Microbiological eradication was successful in 8 of 11 patients. Two of three patients with unsuccessful microbiological eradication and fatal outcome had an Enterococcus faecium infection. Conclusion: In critically ill patients undergoing CRRT, daptomycin exposure with once-daily dosing was similar to ICU patients with normal renal function, but lower compared to healthy volunteers. Our data suggest that daptomycin once-daily dosing is appropriate in patients undergoing CRR

Discussion of the Electromotive Force Terms in the Model of Parker-unstable Galactic Disks with Cosmic Rays and Shear

We analyze the electromotive force (EMF) terms and basic assumptions of the linear and nonlinear dynamo theories in our three-dimensional (3D) numerical model of the Parker instability with cosmic rays and shear in a galactic disk. We also apply the well known prescriptions of the EMF obtained by the nonlinear dynamo theory (Blackman & Field 2002 and Kleeorin et al. 2003) to check if the EMF reconstructed from their prescriptions corresponds to the EMF obtained directly from our numerical models. We show that our modeled EMF is fully nonlinear and it is not possible to apply any of the considered nonlinear dynamo approximations due to the fact that the conditions for the scale separation are not fulfilled.Comment: 15 pages, 12 figure

The inverse cascade and nonlinear alpha-effect in simulations of isotropic helical hydromagnetic turbulence

A numerical model of isotropic homogeneous turbulence with helical forcing is investigated. The resulting flow, which is essentially the prototype of the alpha^2 dynamo of mean-field dynamo theory, produces strong dynamo action with an additional large scale field on the scale of the box (at wavenumber k=1; forcing is at k=5). This large scale field is nearly force-free and exceeds the equipartition value. As the magnetic Reynolds number R_m increases, the saturation field strength and the growth rate of the dynamo increase. However, the time it takes to built up the large scale field from equipartition to its final super-equipartition value increases with magnetic Reynolds number. The large scale field generation can be identified as being due to nonlocal interactions originating from the forcing scale, which is characteristic of the alpha-effect. Both alpha and turbulent magnetic diffusivity eta_t are determined simultaneously using numerical experiments where the mean-field is modified artificially. Both quantities are quenched in a R_m-dependent fashion. The evolution of the energy of the mean field matches that predicted by an alpha^2 dynamo model with similar alpha and eta_t quenchings. For this model an analytic solution is given which matches the results of the simulations. The simulations are numerically robust in that the shape of the spectrum at large scales is unchanged when changing the resolution from 30^3 to 120^3 meshpoints, or when increasing the magnetic Prandtl number (viscosity/magnetic diffusivity) from 1 to 100. Increasing the forcing wavenumber to 30 (i.e. increasing the scale separation) makes the inverse cascade effect more pronounced, although it remains otherwise qualitatively unchanged.Comment: 21 pages, 26 figures, ApJ (accepted

Gulp1 controls Eph/ephrin trogocytosis and is important for cell rearrangements during development

Trogocytosis, in which cells nibble away parts of neighboring cells, is an intercellular cannibalism process conserved from protozoa to mammals. Its underlying molecular mechanisms are not well understood and are likely distinct from phagocytosis, a process that clears entire cells. Bi-directional contact repulsion induced by Eph/ephrin signaling involves transfer of membrane patches and full-length Eph/ephrin protein complexes between opposing cells, resembling trogocytosis. Here, we show that the phagocytic adaptor protein Gulp1 regulates EphB/ephrinB trogocytosis to achieve efficient cell rearrangements of cultured cells and during embryonic development. Gulp1 mediates trogocytosis bi-directionally by dynamic engagement with EphB/ephrinB protein clusters in cooperation with the Rac-specific guanine nucleotide exchange factor Tiam2. Ultimately, Gulp1's presence at the Eph/ephrin cluster is a prerequisite for recruiting the endocytic GTPase dynamin. These results suggest that EphB/ephrinB trogocytosis, unlike other trogocytosis events, uses a phagocytosis-like mechanism to achieve efficient membrane scission and engulfment

The molecular species responsible for α1-antitrypsin deficiency are suppressed by a small molecule chaperone

The formation of ordered Z (Glu342Lys) α1-antitrypsin polymers in hepatocytes is central to liver disease in α1-antitrypsin deficiency. In vitro experiments have identified an intermediate conformational state (M*) that precedes polymer formation, but this has yet to be identified in vivo. Moreover, the mechanism of polymer formation and their fate in cells have been incompletely characterised. We have used cell models of disease in conjunction with conformation-selective monoclonal antibodies and a small molecule inhibitor of polymerisation to define the dynamics of polymer formation, accumulation and secretion. Pulse-chase experiments demonstrate that Z α1-antitrypsin accumulates as short-chain polymers that partition with soluble cellular components and are partially secreted by cells. These precede the formation of larger, insoluble polymers with a longer half-life (10.9 ± 1.7 h and 20.9 ± 7.4 h for soluble and insoluble polymers, respectively). The M* intermediate (or a by-product thereof) was identified in the cells by a conformation-specific monoclonal antibody. This was completely abrogated by treatment with the small molecule, which also blocked the formation of intracellular polymers. These data allow us to conclude that the M* conformation is central to polymerisation of Z α1-antitrypsin in vivo; preventing its accumulation represents a tractable approach for pharmacological treatment of this condition; polymers are partially secreted; and polymers exist as two distinct populations in cells whose different dynamics have likely consequences for the aetiology of the disease

Thermal Equilibrium Curves and Turbulent Mixing in Keplerian Accretion Disks

We consider vertical heat transport in Keplerian accretion disks, including the effects of radiation, convection, and turbulent mixing driven by the Balbus-Hawley instability, in astronomical systems ranging from dwarf novae (DNe), and soft X-ray transients (SXTs), to active galactic nuclei (AGN). We propose a modified, anisotropic form of mixing-length theory, which includes radiative and turbulent damping. We also include turbulent heat transport, which acts everywhere within disks, regardless of whether or not they are stably stratified, and can move entropy in either direction. We have generated a series of vertical structure models and thermal equilibrium curves using the scaling law for the viscosity parameter $\alpha$ suggested by the exponential decay of the X-ray luminosity in SXTs. We have also included equilibrium curves for DNe using an $\alpha$ which is constant down to a small magnetic Reynolds number ($\sim 10^4$). Our models indicate that weak convection is usually eliminated by turbulent radial mixing. The substitution of turbulent heat transport for convection is more important on the unstable branches of thermal equilibrium S-curves when $\alpha$ is larger. The low temperature turnover points $\Sigma_{max}$ on the equilibrium S-curves are significantly reduced by turbulent mixing in DNe and SXT disks. However, in AGN disks the standard mixing-length theory for convection is still a useful approximation when we use the scaling law for $\alpha$, since these disks are very thin at the relevant radii. In accordance with previous work, we find that constant $\alpha$ models give almost vertical S-curves in the $\Sigma-T$ plane and consequently imply very slow, possibly oscillating, cooling waves.Comment: 43 pages, 12 figures, 6 tables, to be published in Ap

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan

Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging.

Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy

The case for a distributed solar dynamo shaped by near-surface shear

Arguments for and against the widely accepted picture of a solar dynamo being seated in the tachocline are reviewed and alternative ideas concerning dynamos operating in the bulk of the convection zone, or perhaps even in the near-surface shear layer, are discussed. Based on the angular velocities of magnetic tracers it is argued that the observations are compatible with a distributed dynamo that may be strongly shaped by the near-surface shear layer. Direct simulations of dynamo action in a slab with turbulence and shear are presented to discuss filling factor and tilt angles of bipolar regions in such a model.Comment: 10 pages, 6 figures, Astrophys. J. 625 (scheduled for the 1 June 2005 issue