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.

The continuum limit in the quenched approximation

Previous work at $6/g^2=5.7$ with quenched staggered quarks is extended with new calculations at 5.85 and 6.15 on lattices up to $32^3\times 64$. These calculations allow a more detailed study of extrapolation in quark mass, finite volume and lattice spacing than has heretofore been possible. We discuss how closely the quenched spectrum approaches that of the real world.Comment: 4 pages, uuencoded compressed PostScript, contribution to Lattice '9

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

Hadron Spectrum with Wilson fermions

We present results of a high statistics study of the quenched spectrum using Wilson fermions at $\beta=6.0$ on $32^3 \times 64$ lattices. We calculate the masses of mesons and baryons composed of both degenerate and non-degenerate quarks. Using non-degenerate quark combinations allows us to study baryon mass splittings in detail. We find significant deviations from the lowest order chiral expansion, deviations that are consistent with the expectations of quenched chiral perturbation theory. We find that there is a $\sim 20$ systematic error in the extracted value of $m_s$, depending on the meson mass ratio used to set its value. Using the largest estimate of $m_s$ we find that the extrapolated octet mass-splittings are in agreement with the experimental values, as is $M_\Delta - M_N$, while the decuplet splittings are 30% smaller than experiment. Combining our results with data from the GF11 collaboration we find considerable ambiguity in the extrapolation to the continuum limit. Our preferred values are $M_N / M_\rho = 1.38(7)$ and $M_\Delta / M_\rho = 1.73(10)$, suggesting that the quenched approximation is good to only $\sim 10-15$. We also analyze the $O(ma)$ discretization errors in heavy quark masses.Comment: 52 pages. Tex. Modified "axis" source for figures also included. Needs macro packages lanlmac and epsf. Uses hyperbasics if available. Significant number of typographical errors correcte

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