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Background: Liver regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice., Methodology and Principal Findings: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV., Conclusion: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients' outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation.

Objective: Distal embolization (DE) during percutaneous lower extremity revascularization (LER) may cause severe clinical sequelae. To better define DE, we investigated which lesion types and treatment modalities increase the risk for embolization., Methods: A prospective registry of LER from 2004 to 2009 was reviewed. All cases with runoff evaluated before and after intervention were included. Angiograms and operative reports were reviewed for evidence of DE. Interventions included percutaneous transluminal angioplasty (PTA), with or without stent placement, and atherectomy with four different devices. Chi-square analysis and Fisher's exact test were used to assess significance. Patency rates were calculated using Kaplan-Meier analysis and compared using log-rank analysis., Results: There were 2137 lesions treated in 1029 patients. The embolization rate was 1.6% (34 events). Jetstream (Pathway, Kirkland, Wash) and DiamondBack 360 (Cardiovascular Systems Inc, St Paul Minn) devices had a combined embolization rate of 22% (8 of 36), 4 of 18 (22%) in each group, which was significantly higher than with PTA alone (5 of 570, 0.9%), PTA and stent (5 of 740, 0.7%), SilverHawk (ev3, Plymouth, Minn) atherectomy (14 of 736, 1.9%), and laser atherectomy (2 of 55, 3.6%; P < .001). There was a significantly higher rate of embolization for in-stent restenosis (6 of 188, 3.2%) and chronic total occlusions (15 of 615, 2.4%) compared with stenotic lesions (13 of 1334, 0.9%; P = .01). The embolization rate was significantly higher in Transatlantic Inter-Society Consensus (TASC) II C and D lesions compared with TASC A and B lesions (P = .018). DE rates were not affected by preoperative runoff status (P = .152). Patency was restored at the completion of the procedure in 32 of 34 cases of DE. The 24-month primary patency, assisted primary patency, and secondary patency in the DE group was 54.0% ± 11.9%, 70.0% ± 10.3%, and 73.2% ± 10.3%, respectively, and was 44.4% ± 1.7%, 61.5% ± 1.7%, and 68.2% ± 1.6%, respectively, when embolization did not occur (P > .05). Limb salvage was 72.6% ± 3.1% in lesions in which no DE occurred vs 83.3% ± 15.2% in lesions in which DE occurred (P = .699)., Conclusions: DE is a rare event that occurs more often with the Jetstream and DiamondBack 360 devices. In-stent and complex native lesions are at higher risk for DE. DE is typically reversible with endovascular techniques and has no effect on patency rates and limb salvage., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

A 31-year-old man underwent a Whipple procedure for a pancreatic neuroendocrine tumor, which consists of a pancreaticoduodenectomy and reconstruction to restore intestinal continuity. Six weeks after the operation, he presented with severe mid-epigastric pain radiating to his back. Imaging studies revealed a large pseudoaneurysm arising from the superior mesenteric artery. Selective superior mesenteric angiography confirmed the presence of the pseudoaneurysm. A 6 mm × 2.5 cm stent graft (Viabhan; W.L. Gore, Flagstaff, Ariz) was deployed across the pseudoaneurysm origin with preservation of the mesenteric branches. The patient had immediate resolution of symptoms and follow-up imaging showed patency of the stent graft and exclusion of the pseudoaneurysm., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete., Methodology/principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis., Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes.

Spinal cord ischemia is a rare complication after abdominal aortic surgery and has been attributed to surgical devascularization of the spinal cord, atheroembolization of the cord circulation, or hypoperfusion of cord structures secondary to hypotension or cord edema. We present a diabetic, hypertensive 75-year-old male with endstage renal disease who presented with a 5.5 cm asymptomatic infrarenal abdominal aortic aneurysm, and concomitant 3.5 cm right common iliac artery aneurysm. After undergoing successful endovascular repair with an aorto-uni-iliac device, unilateral hypogastric artery embolization, and femoral-femoral bypass, he was discharged to a rehabilitation facility neurologically intact with a stage 2 decubitus ulcer. He returned on postoperative day 21 with a large stage 4 septic decubitus ulcer, fever, leukocytosis, hypotension, and paraplegia. We hypothesize that the compromised blood flow from the initial reconstruction, combined with the delayed hypotension imposed by sepsis, resulted in spinal cord infarction. He was eventually discharged to a nursing facility with no improvement in his neurologic status. We report the first case of significantly delayed permanent paraplegia after endovascular abdominal aortic aneurysmorrhaphy.

Objective: Intimal hyperplasia is a common cause of vein graft failure in cardiovascular surgery. The molecular basis for intimal hyperplasia remains poorly defined. We have previously identified, by gene chip analysis of vein grafts, increased messenger (mRNA) for the adhesion molecule cadherin 11/osteoblast-cadherin (CDH11). The function of CDH11 in vascular cells is unknown. The aim of the present study is to confirm CDH11 expression in vein grafts and characterize its role in vascular remodeling., Methods: Cephalic vein interposition grafts were implanted in a canine model and harvested at predetermined time points. CDH11 protein expression was determined by immunohistochemistry. Early passage human coronary artery smooth muscle cells (SMCs) were used for in vitro studies. Real-time polymerase chain reaction was used to assess cellular CDH11 mRNA levels. CDH11 signaling was inhibited by either transfection with silencing RNA targeting CDH11 or with a blocking antibody to CDH11. Cellular migration was evaluated and cellular proliferation was assessed., Results: Expression of CDH11 was increased in medial SMCs of vein grafts recovered at 7, 14, and 30 days after surgery compared with control veins from the same animals. In vitro CDH11 mRNA was up-regulated 1.8 +/- 0.2-fold (P = .003) in SMCs after treatment with tumor necrosis factor-alpha. Cellular migration was attenuated by inhibition of CDH11 both with a blocking antibody (0.67 +/- 0.09; P = .063) and gene knockdown mediated by small interfering RNA (0.67 +/- 0.14; P = .036). SMC proliferation decreased by 3.1-fold (P = .006) in the presence of CDH11-blocking antibody. Knockdown of CDH11 mediated by small interfering RNA resulted in a 1.3-fold (P = .018) decrease in proliferation., Conclusions: CDH11 is up-regulated in SMC in vivo and in vitro as part of the response to injury. Inhibition of CDH11 decreases SMC migration and proliferation, two pathogenic effectors of intimal hyperplasia.

Objective: Patients undergoing infrainguinal arterial reconstruction frequently have increased cardiac risk factors. Diabetic patients are often asymptomatic despite advanced cardiac disease. This study investigates whether preoperative cardiac testing improves the outcome in diabetic patients at risk for cardiac disease., Methods: We retrospectively reviewed all patients undergoing lower-extremity arterial reconstructions in a 32-month period from July 1999 to February 2002. Of the 433 patients identified undergoing 539 procedures, 295 had diabetes mellitus and considered in this study. The patients were stratified into two groups according to the present American College of Cardiology, American Heart Association (ACC/AHA) algorithm. We identified 140 patients with two or more of ACC (Eagle) criteria who met the inclusion criteria for a preoperative cardiac evaluation. These patients were separated into two groups: those undergoing a cardiac work-up (WU) according to the ACC/AHA algorithm and those not undergoing the recommended work-up (NWU). Outcomes included perioperative mortality, postoperative myocardial infarction, congestive heart failure, arrhythmia, and length of hospitalization. Significance of association was assessed by the Fisher exact test. Length of hospitalization was compared using the Kruskal-Wallis rank sum test. Survival data was analyzed with the Kaplan-Meier method., Results: One hundred forty patients met the criteria for moderate risk. There were 61 patients in the NWU group and 79 in the WU group. Ten patients in the WU group underwent preoperative coronary revascularization (6 had percutaneous transluminal coronary angioplasty, 4 underwent coronary artery bypass grafting). There was no difference between perioperative mortality (WU, 1%; NWU, 2%; P = 1.00) or in postoperative cardiac morbidity, including myocardial infarction, congestive heart failure, and arrhythmia requiring treatment (WU, 5%; NWU, 6%; P = .71). There were no perioperative deaths and one episode of congestive heart failure in the group that had preoperative coronary revascularization. Median length of hospitalization was 10 days in the WU group and 8 days in the NWU group ( P = .11). Patient survival at 12 months for the NWU, WU, and revascularized groups was 85.3%, 78.5%, and 80.0%, respectively; 36-month survival was 73.6%, 62.9%, and 80.0%, respectively. The three survival curves did not differ significantly ( P = .209)., Conclusions: Preoperative cardiac evaluation, as defined by the ACC/AHA algorithm, does not predict or improve postoperative morbidity, mortality, or 36-month survival in asymptomatic, diabetic patients undergoing elective lower-extremity arterial reconstruction. These data do not support the current ACC/AHA recommendations as a standard of care for diabetic patients with an intermediate clinical predictor who undergo peripheral arterial reconstruction, a high-risk surgical procedure.