Sepsis-Induced Glomerular Endothelial Dysfunction Mediates Reductions in GFR and Increases in Protein Filtration

poster abstractBackground: Sepsis is now the leading cause of acute kidney injury (AKI) known to decrease Glomerular filtration rate (GFR) and increase proteinuria. There also exists a discrepancy between renal perfusion and GFR. Methods: To evaluate the potential role of the glomerulus in the overall pathogenesis of these abnormalities, we studied surface glomeruli in 8-10 week old Munich Wistar Frmter rats using intravital 2-photon microscopy in a cecal ligation and puncture (CLP) model of sepsis to ask targeted questions and compare the metric of measured GFR to serum creatinine changes at 24 hours post CLP. Results: Male rats undergoing CLP showed an increase in serum creatinine from 0.23 +/- 0.06 mg/dl to 0.80 +/-0.17 (P0.01) and a decrease in real time GFR from 0.69 +/- 0.06 ml/min/100gm body wt to 0.34 +/-0.15 (P0.01). Hemodynamic monitoring revealed normal and hyperdynamic cardiac status within the CLP group. Quantitative analysis of 15 glomeruli in three CLP septic rats revealed a reduction in red blood cell flow rates within capillary loops from 1,771 +/- 467 to 576 +/- 327 um/sec (P0.01); an increase in WBC adherence to glomerular capillary endothelial cells from 0.42 +/-0.33 to 7.25 +/- 5.82 WBC's/standardized glomerular volume (P0.05) in CLP rats; and an increase in the glomerular sieving coefficient (GSC) of a 150kD dextran from 0.007 +/- 0.003 to 0.097 +/- 0.046 (P0.05). Rouleaux formations were seen only in septic rats. Conclusions: These data indicate glomerular endothelial-WBC interactions during sepsis, in part, explain the reduction in GFR and increased filtration of large molecular weight proteins. The results from real time GFR accurately detected the drop in renal function for this model of sepsis

Collective Flow from the Intranuclear Cascade Model

The phenomenon of collective flow in relativistic heavy ion collisions is studied using the hadronic cascade model ARC. Direct comparison is made to data gathered at the Bevalac, for Au+Au at $p=1-2$ GeV/c. In contrast to the standard lore about the cascade model, collective flow is well described quantitatively without the need for explicit mean field terms to simulate the nuclear equation of state. Pion collective flow is in the opposite direction to nucleon flow as is that of anti-nucleons and other produced particles. Pion and nucleon flow are predicted at AGS energies also, where, in light of the higher baryon densities achieved, we speculate that equation of state effects may be observable.Comment: 9 pages, 2 figures include

Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI

Protective vascular coagulation in response to bacterial infection of the kidney is regulated by bacterial lipid A and host CD147

Bacterial infection of the kidney leads to a rapid cascade of host protective responses, many of which are still poorly understood. We have previously shown that following kidney infection with uropathogenicEscherichia coli (UPEC), vascular coagulation is quickly initiated in local perivascular capillaries that protects the host from progressing from a local infection to systemic sepsis. The signaling mechanisms behind this response have not however been described. In this study, we use a number ofin vitro andin vivo techniques, including intravital microscopy, to identify two previously unrecognized components influencing this protective coagulation response. The acylation state of the Lipid A of UPEC lipopolysaccharide (LPS) is shown to alter the kinetics of local coagulation onsetin vivo. We also identify epithelial CD147 as a potential host factor influencing infection-mediated coagulation. CD147 is expressed by renal proximal epithelial cells infected with UPEC, contingent to bacterial expression of the α-hemolysin toxin. The epithelial CD147 subsequently can activate tissue factor on endothelial cells, a primary step in the coagulation cascade. This study emphasizes the rapid, multifaceted response of the kidney tissue to bacterial infection and the interplay between host and pathogen during the early hours of renal infection

Fragment properties of fragmenting heavy nuclei produced in central and semi-peripheral collisions

Fragment properties of hot fragmenting sources of similar sizes produced in central and semi-peripheral collisions are compared in the excitation energy range 5-10 AMeV. For semi-peripheral collisions a method for selecting compact quasi-projectiles sources in velocity space similar to those of fused systems (central collisions) is proposed. The two major results are related to collective energy. The weak radial collective energy observed for quasi-projectile sources is shown to originate from thermal pressure only. The larger fragment multiplicity observed for fused systems and their more symmetric fragmentation are related to the extra radial collective energy due to expansion following a compression phase during central collisions. A first attempt to locate where the different sources break in the phase diagram is proposed.Comment: 23 pages submitted to NP

A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease

Peer reviewedPublisher PD

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BackgroundPatients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.MethodsAn IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.ResultsMedian survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0).ConclusionsBrain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com

Differential flow in heavy-ion collisions at balance energies

A strong differential transverse collective flow is predicted for the first time to occur in heavy-ion collisions at balance energies. We also give a novel explanation for the disappearance of the total transverse collective flow at the balance energies. It is further shown that the differential flow especially at high transverse momenta is a useful microscope capable of resolving the balance energy's dual sensitivity to both the nuclear equation of state and in-medium nucleon-nucleon cross sections in the reaction dynamics.Comment: Phys. Rev. Lett. (1999) in pres

Delta degrees of freedom in antisymmetrized molecular dynamics and (p,p') reactions in the delta region

Delta degrees of freedom are introduced into antisymmetrized molecular dynamics (AMD). This is done by increasing the number of basic states in the AMD wave function, introducing a Skyrme-type delta-nucleon potential, and including $NN\leftrightarrow N\Delta$ reactions in the collision description. As a test of the delta dynamics, the extended AMD is applied to (p,p$'$) recations at $E_{\rm lab}=800$ MeV for a $^{12}$C target. It is found that the ratio and the absolute values for delta peak and quasielastic peak (QEP) in the $^{12}$C(p,p$'$) reaction are reproduced for angles \Theta_{\rm lab} \agt 40^\circ, pointing to a correct treatment of the delta dynamics in the extended AMD. For forward angles the QEP is overestimated. The results of the AMD calculations are compared to one-step Monte Carlo (OSMC) calculations and a detailed analysis of multi-step and delta potential effects is given. As important side results we present a way to apply a Gallilei invariant theory for (N,N$'$) reactions up to $E_{\rm lab} \approx 800$ MeV which ensures approximate Lorentz invariance and we discuss how to fix the width parameter $\nu$ of the single particle momentum distribution for outgoing nucleons in the AMD calculation.Comment: 28 pages, revtex, 12 figures included, figures are also available upon request as postscript files from the authors (e-mail: [email protected]), submitted to Phys. Rev.

Measurements of sideward flow around the balance energy

Sideward flow values have been determined with the INDRA multidetector for Ar+Ni, Ni+Ni and Xe+Sn systems studied at GANIL in the 30 to 100 A.MeV incident energy range. The balance energies found for Ar+Ni and Ni+Ni systems are in agreement with previous experimental results and theoretical calculations. Negative sideward flow values have been measured. The possible origins of such negative values are discussed. They could result from a more important contribution of evaporated particles with respect to the contribution of promptly emitted particles at mid-rapidity. But effects induced by the methods used to reconstruct the reaction plane cannot be totally excluded. Complete tests of these methods are presented and the origins of the ``auto-correlation'' effect have been traced back. For heavy fragments, the observed negative flow values seem to be mainly due to the reaction plane reconstruction methods. For light charged particles, these negative values could result from the dynamics of the collisions and from the reaction plane reconstruction methods as well. These effects have to be taken into account when comparisons with theoretical calculations are done.Comment: 27 pages, 15 figure