Purpose To (a) evaluate whether plaque tissue characteristics determined with conventional computed tomographic (CT) angiography could be quantitated at higher levels of accuracy by using image processing algorithms that take characteristics of the image formation process coupled with biologic insights on tissue distributions into account by comparing in vivo results and ex vivo histologic findings and (b) assess reader variability. Materials and Methods Thirty-one consecutive patients aged 43-85 years (average age, 64 years) known to have or suspected of having atherosclerosis who underwent CT angiography and were referred for endarterectomy were enrolled. Surgical specimens were evaluated with histopathologic examination to serve as standard of reference. Two readers used lumen boundary to determine scanner blur and then optimized component densities and subvoxel boundaries to best fit the observed image by using semiautomatic software. The accuracy of the resulting in vivo quantitation of calcification, lipid-rich necrotic core (LRNC), and matrix was assessed with statistical estimates of bias and linearity relative to ex vivo histologic findings. Reader variability was assessed with statistical estimates of repeatability and reproducibility. Results A total of 239 cross sections obtained with CT angiography and histologic examination were matched. Performance on held-out data showed low levels of bias and high Pearson correlation coefficients for calcification (-0.096 mm2 and 0.973, respectively), LRNC (1.26 mm2 and 0.856), and matrix (-2.44 mm2 and 0.885). Intrareader variability was low (repeatability coefficient ranged from 1.50 mm2 to 1.83 mm2 among tissue characteristics), as was interreader variability (reproducibility coefficient ranged from 2.09 mm2 to 4.43 mm2). Conclusion There was high correlation and low bias between the in vivo software image analysis and ex vivo histopathologic quantitative measures of atherosclerotic plaque tissue characteristics, as well as low reader variability. Software algorithms can mitigate the blurring and partial volume effects of routine CT angiography acquisitions to produce accurate quantification to enhance current clinical practice. Clinical trial registration no. NCT02143102 © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on September 15, 2017.

Preeclampsia occurs in 3–5% of pregnancies, remaining the major source of maternal and fetal mortality and morbidity. Imbalances of cytokines, growth factors and soluble receptors in these pathologic pregnancies predispose the vasculature to accelerated atherosclerotic disease, and preeclamptic women and their offspring have a higher life-long risk of cardiovascular disease. Women with cardiovascular disease suffer from under-diagnosis and are more likely to die when acute coronary syndrome or stroke symptoms occur. Validated quantitative imaging biomarkers are needed to assess atherosclerotic plaque stability for prognostic and longitudinal use. Computer-aided prognosis (CAP) applies quantitative image analysis and multi-modal data fusion to provide new tools to physicians. The vascuCAP™ analysis software is proposed as a longitudinal assessment tool for women with a history of preeclampsia. A preclinical rabbit model with various stages of atherosclerotic plaques and luminal thrombosis of vulnerable plaques, closely simulating human disease, was used to assess the feasibility of the experimental vascuCAP™ software to analyze standard magnetic resonance (MR) images and quantitatively measure several crucial plaque parameters: lipid core, fibrosis, neovascularization, intra-plaque hemorrhage, vascular leak, calcification, and arterial wall remodeling (both inward and outward). The vascuCAP™ results were compared to the histological lesions as ground truth. Feasibility of vascuCAP™ analysis of arterial plaques including structural measurement and functional feature extraction for discriminating between tissue types consistent with stable and unstable atherosclerotic plaques was demonstrated. A pivotal clinical trial is in progress in carotid and femoral endarterectomy patients, where the vascuCAP™ results will be compared to histological ground truth. Subsequent studies will validate vascuCAP™ in the coronary circulation. Through use of MRI and vascuCAP™, longitudinal surveillance of women with a history of preeclampsia could be possible without exposure to ionizing radiation. Assessment of plaque characteristics during therapeutic medical interventions with anti-atherosclerotic agents could provide personalized medicine. J.C. Keith: Consultant; Commercial Interest: Elucid Bioimaging, Inc. A.J. Buckler: Commercial Interest: President & CEO, Elucid Bioimaging, Inc, Shareholder, Commercial Interest: Elucid Bioimaging, Inc. J.A. Hamilton: Shareholder, Commercial Interest: Elucid Bioimaging, Inc.

Background: From 2001-2011, >80% of potentially survivable United States battlefield deaths were due to severe hemorrhage. We subjected male rats to acute severe blood loss, administered a single dose of 17 alpha-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and measured survival and also mean arterial pressures (MAP).Methods: After controlled removal of 60% circulating blood volume (10-11 mL) over approximately 45 min, rats received EE-3-SO4 at 0 (vehicle controls), 0.1, 0.3, 1.0, or 3.0 mg/kg in 40 mu L/100 g BW saline intravenously. MAP was recorded for 40 min after drug administration and survival was recorded for 6 h.Results: The dose response curve was bell shaped with optimum survival at 1 mg/kg EE-3SO(4). Median survival times of rats receiving 1 mg/kg (360 min) were approximately 6 times that of the control group (57 min): P = 0.0001. The number of animals alive at 6 h was 16 of 20 (80%) in the 1 mg/kg group versus 0 of 20 (0%) in the control group. Early increases in MAP correlated with longer survival times.Conclusions: Administration of a single dose of 1 mg/kg EE-3-SO4 in 0.4 mL/kg of saline after controlled severe hemorrhage increased survival in rats by 6-fold. Partial recovery of blood pressure values correlated with longer survival time. These results, coupled with similar findings in a companion study in minipigs, support the further product development of EE-3-SO4 for: (1) severe hemorrhage when standard resuscitative fluids are not available, and (2) situations in which prolonged transportation periods are required for definitive treatment of the injured. (C) 2015 Elsevier Inc. All rights reserved.

BACKGROUND: Of the potentially survivable US battlefield deaths from 2001 to 2011, 80% to 91% were caused by severe hemorrhage. We subjected minipigs to acute severe blood loss, administered a single dose of 17 alpha-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and determined survival as well as cardiovascular, biochemical, and physiologic response parameters.METHODS: Following controlled removal of 60% circulating blood volume over 1 hour, minipigs received EE-3-SO4 at 0, 1, 3, or 5-mg/mL saline per kilogram of body weight in Experiment 1 (n = 25) and 0-, 0.1-, 0.3-, or 1-mg/mL saline per kilogram in Experiment 2 (n = 23). Survival times and response parameters were recorded for the next 6 hours.RESULTS: Median survival times of the minipigs receiving 1 mg/kg (257 minutes and 360 minutes) were 1.8 times and 5 times those of the control group (140 minutes and 65 minutes) in Experiments 1 and 2, respectively. For both experiments combined, the log-rank p value was 0.0002, and the number of animals alive at 6 hours was 6 (50%) of 12 in the 1-mg/kg groups versus 0 (0%) of 12 in the control groups. Early increases in glucose, lactate, potassium, and phosphate as well as decreases in bicarbonate and mean arterial pressure correlated with shorter survival times.CONCLUSION: Administration of a single dose of 1-mg/kg EE-3-SO4 in 1-mL/kg of saline following severe hemorrhage increased survival in 60% acutely bled minipigs by 3.5-fold. Slightly elevated blood pressure values, more physiologic values of oxidative phosphorylation parameters, and lower elevations of possible tissue necrosis parameters correlated with longer survival time. These results support the further product development of EE-3-SO4 for the indication of severe hemorrhage when standard resuscitative fluids are not available. (J Trauma Acute Care Surg. 2014; 76: 1409-1416. Copyright (C) 2014 by Lippincott Williams & Wilkins)

Effective biomarkers are needed for assessing atherosclerotic plaque vulnerability for prognostic and longitudinal use. We report on a preliminary proof of concept using contrast MRI and textural kinetic analysis. Multivariate quantitative descriptors are developed using controlled outcome studies on a specialized model to identify candidate imaging markers that in composite are able to accurately distinguish vulnerable and stable plaque in both cross‐sectional and longitudinal applications. We hypothesize that characteristic patterns of lipid intermixed with extracellular matrix fibers, necrotic tissue, inflammatory cells and intra‐plaque hemorrhage are detectable via the use of steerable, multi‐scale Gabor filters, localized pixel statistics, and second order co‐occurrence textural features. These derived attributes are capable of discriminating functional microvascular networks without requiring resolution beyond that of standard DCE MRI. Neovascularization, presence of extracellular matrix and increased tissue permeability leading to increased distribution volume is evaluated by fitting cubic polynomials to the contrast media uptake signal to provide more effective separation between vulnerable and stable plaque than possible by merely relying on thresholding of time activity curves. Preliminary results demonstrate good discrimination between interventional study arms.

BACKGROUND:The effect of interleukin-11 (IL-11) on transforming growth factor-ß (TGF-ß) is controversial and has not been examined in renal diseases. In this study, we (i) characterised the up-regulation of TGF-ß1, phospho-p38 MAPK (p-p38 MAPK) and extracellular matrix during pathogenesis of glomerulonephritis and (ii) examined the effect of rhIL-11 on these processes in vivo.METHODS:Following induction of nephrotoxic nephritis, expression of TGF-ß1, alpha-smooth muscle actin (alpha-SMA), fibronectin and p-p38 MAPK was detected in the kidney. Rats were treated either with vehicle or rhIL-11 at a high or low dose and culled on day 6.RESULTS:A high dose of rhIL-11 resulted in a significant reduction in the glomerular expression of TGF-ß1 (0.4 ± 0.1 vs. 2.04 ± 0.4 semiquantitative score, p<0.005), alpha-SMA (0.6 ± 0.2 vs. 1.5 ± 0.3, p<0.01) and fibronectin (0.6 ± 0.1 vs. 1.5 ± 0.1, p<0.02). The periglomerular expression of alpha-SMA and fibronectin was significantly reduced in rats treated with the high dose of rhIL-11 (9.6% ± 2% vs. 92% ± 2.5% of glomeruli, p<0.01; and 26% ± 4.9% vs. 94% ± 1.9% of glomeruli, p<0.005, respectively). There was a slight but insignificant reduction of p-p38 MAPK in IL-11 treated rats. Treatment with low-dose rhIL-11 did not reduce expression of these molecules.CONCLUSION:IL-11 suppresses glomerular expression of TGF-ß1 and extracellular matrix deposition in experimental glomerulonephritis.

The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti-RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation.

Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.

BACKGROUND:Nonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis.METHODS:In these experiments, ERbeta agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY-202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples.RESULTS:ERbeta agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth.CONCLUSIONS:ERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.