Impact of Incremental Perfusion Loss on Oxygen Transport in a Capillary Network Mathematical Model.

OBJECTIVES: To quantify how incremental capillary perfusion loss, such as that seen in experimental models of sepsis, affects tissue oxygenation using a computation model of oxygen transport. METHODS: A computational model was applied to capillary networks with dimensions 84x168x342 (NI) and 70x157x268 (NII) μm, reconstructed in vivo from rat skeletal muscle. Functional capillary density (FCD) loss was applied incrementally up to ~40% and combined with high tissue oxygen consumption to simulate severe sepsis. RESULTS: A loss of ~40% FCD loss decreased median tissue PO2 to 22.9 and 20.1 mmHg in NI and NII compared to 28.1 and 27.5 mmHg under resting conditions. Increasing red blood cell supply rate (SR) to baseline levels returned tissue PO2 to within 5% of baseline. High consumption combined with a 40% FCD loss, resulted in tissue anoxia in both network volumes and median tissue PO2 of 11.5 and 8.9 mmHg in NI and NII respectively; median tissue PO2 was recovered to baseline levels by increasing total SR 3 - 4 fold. CONCLUSIONS: These results suggest a substantial increase in total SR is required in order to compensate for impaired oxygen delivery as a result of loss of capillary perfusion and increased oxygen consumption during sepsis. This article is protected by copyright. All rights reserved

Nonperturbative Gauge Fixing and Perturbation Theory

We compare the gauge-fixing approach proposed by Jona-Lasinio and Parrinello, and by Zwanziger (JPLZ) with the standard Fadeev-Popov procedure, and demonstrate perturbative equality of gauge-invariant quantities, up to irrelevant terms induced by the cutoff. We also show how a set of local, renormalizable Feynman rules can be constructed for the JPLZ procedure.Comment: 9 pages, latex, version to appear in Phys. Rev.

Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles

Background: There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes. Methods: Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-gamma ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl beta-galactosidase assay with primary isolates of HIV-1. Results: This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody response. However, the antibodies did not neutralise primary isolates of HIV-1 or the V3-sensitive isolate SF162 using the TZM-bl b-galactosidase assay. Conclusions: MVA and FP9 are ideal replication-deficient viral vectors for HIV-1 vaccines due to their excellent safety profile for use in humans. This study shows this novel prime-boost-boost regimen was poorly immunogenic in Chinese cynomolgus macaques

Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis.

The microcirculation during sepsis fails due to capillary plugging involving microthrombosis. We demonstrated that intravenous injection of ascorbate reduces this plugging, but the mechanism of this beneficial effect remains unclear. We hypothesize that ascorbate inhibits the release of the antifibrinolytic plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and platelets during sepsis. Microvascular endothelial cells and platelets were isolated from mice. Cells were cultured and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα), or thrombin (agents of sepsis), with/without ascorbate for 1-24 h. PAI-1 mRNA was determined by quantitative PCR. PAI-1 protein release into the culture medium was measured by ELISA. In platelets, PAI-1 release was measured after LPS, TNFα, or thrombin stimulation, with/without ascorbate. In endothelial cells, LPS and TNFα increased PAI-1 mRNA after 6-24 h, but no increase in PAI-1 release was observed; ascorbate did not affect these responses. In platelets, thrombin, but not LPS or TNFα, increased PAI-1 release; ascorbate inhibited this increase at low extracellular pH. In unstimulated endothelial cells and platelets, PAI-1 is released into the extracellular space. Thrombin increases this release from platelets; ascorbate inhibits it pH-dependently. The data suggest that ascorbate promotes fibrinolysis in the microvasculature under acidotic conditions in sepsis

Stability and BPS branes

We define the concept of Pi-stability, a generalization of mu-stability of vector bundles, and argue that it characterizes N=1 supersymmetric brane configurations and BPS states in very general string theory compactifications with N=2 supersymmetry in four dimensions.Comment: harvmac, 18 p

On the spectral density from instantons in quenched QCD

We investigate the contribution of instantons to the eigenvalue spectrum of the Dirac operator in quenched QCD. The instanton configurations that we use have been derived, elsewhere, from cooled SU(3) lattice gauge fields and, for comparison, we also analyse a random `gas' of instantons. Using a set of simplifying approximations, we find a non-zero chiral condensate. However we also find that the spectral density diverges for small eigenvalues, so that the chiral condensate, at zero quark mass, diverges in quenched QCD. The degree of divergence decreases with the instanton density, so that it is negligible for the smallest number of cooling sweeps but becomes substantial for larger number of cools. We show that the spectral density scales, that finite volume corrections are small and we see evidence for the screening of topological charges. However we also find that the spectral density and chiral condensate vary rapidly with the number of cooling sweeps -- unlike, for example, the topological susceptibility. Whether the problem lies with the cooling or with the identification of the topological charges is an open question. This problem needs to be resolved before one can determine how important is the divergence we have found for quenched QCD.Comment: 33 pages, 16 figures (RevTex), substantial revisions; to appear in Phys.Rev.

Searching for chiral logs in the static-light decay constant

Using the clover fermion action in unquenched QCD with pion masses as low as 420 MeV, we look for evidence for chiral logs in the static-light decay constant. There is some evidence for a chiral log term, if the original static theory of Eichten and Hill is used. However, the more precise data from the static action of the ALPHA collaboration do not show any evidence for non-linear dependence of the static-light decay constant on the light quark mass. We make some comments on the connection between chiral perturbation theory for decay constants of the pion and static-light meson

Lattice Calculation of Heavy-Light Decay Constants with Two Flavors of Dynamical Quarks

We present results for $f_B$, $f_{B_s}$, $f_D$, $f_{D_s}$ and their ratios in the presence of two flavors of light sea quarks ($N_f=2$). We use Wilson light valence quarks and Wilson and static heavy valence quarks; the sea quarks are simulated with staggered fermions. Additional quenched simulations with nonperturbatively improved clover fermions allow us to improve our control of the continuum extrapolation. For our central values the masses of the sea quarks are not extrapolated to the physical $u$, $d$ masses; that is, the central values are "partially quenched." A calculation using "fat-link clover" valence fermions is also discussed but is not included in our final results. We find, for example, $f_B = 190 (7) (^{+24}_{-17}) (^{+11}_{-2}) (^{+8}_{-0})$ MeV, $f_{B_s}/f_B = 1.16 (1) (2) (2) (^{+4}_{-0})$, $f_{D_s} = 241 (5) (^{+27}_{-26}) (^{+9}_{-4}) (^{+5}_{-0})$ MeV, and $f_{B}/f_{D_s} = 0.79 (2) (^{+5}_{-4}) (3) (^{+5}_{-0})$, where in each case the first error is statistical and the remaining three are systematic: the error within the partially quenched $N_f=2$ approximation, the error due to the missing strange sea quark and to partial quenching, and an estimate of the effects of chiral logarithms at small quark mass. The last error, though quite significant in decay constant ratios, appears to be smaller than has been recently suggested by Kronfeld and Ryan, and Yamada. We emphasize, however, that as in other lattice computations to date, the lattice $u,d$ quark masses are not very light and chiral log effects may not be fully under control.Comment: Revised version includes an attempt to estimate the effects of chiral logarithms at small quark mass; central values are unchanged but one more systematic error has been added. Sections III E and V D are completely new; some changes for clarity have also been made elsewhere. 82 pages; 32 figure

Lattice QCD determination of m_b, f_B and f_Bs with twisted mass Wilson fermions

We present a lattice QCD determination of the b quark mass and of the B and B_s decay constants, performed with N_f=2 twisted mass Wilson fermions, by simulating at four values of the lattice spacing. In order to study the b quark on the lattice, two methods are adopted in the present work, respectively based on suitable ratios with exactly known static limit and on the interpolation between relativistic data, evaluated in the charm mass region, and the static point, obtained by simulating the HQET on the lattice. The two methods provide results in good agreement. For the b quark mass in the MSbar scheme and for the decay constants we obtain m_b(m_b)=4.29(14) GeV, f_B=195(12) MeV, f_Bs=232(10) MeV and f_Bs/f_B=1.19(5). As a byproduct of the analysis we also obtain the results for the f_D and f_Ds decay constants: f_D=212(8) MeV, f_Ds=248(6) MeV and f_Ds/f_D=1.17(5).Comment: 23 pages, 10 figures, 2 tables. Added appendix showing the agreement of the data for the ratios with the HQE prediction. Matching JHEP published versio