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Objectives: The aim of this study was to compare trends and outcomes of 3 approaches to carotid revascularization in the coronary artery bypass graft (CABG) population when performed during the same hospitalization., Background: The optimal approach to managing coexisting severe carotid and coronary disease remains controversial. Carotid endarterectomy (CEA) or carotid artery stenting (CAS) are used to decrease the risk of stroke in patients with carotid disease undergoing CABG surgery., Methods: The authors conducted a serial, cross-sectional study with time trends of 3 revascularization groups during the same hospital admission: 1) combined CEA+CABG; 2) staged CEA+CABG; and 3) staged CAS+CABG from the Nationwide Inpatient Sample database 2004 to 2012. The primary composite endpoints were in-hospital all-cause death, stroke, and death/stroke., Results: During the 9-year period, 22,501 concurrent carotid revascularizations and CABG surgeries during the same hospitalization were performed. Of these, 15,402 (68.4%) underwent combined CEA+CABG, 6,297 (28.0%) underwent staged CEA+CABG, and 802 (3.6%) underwent staged CAS+CABG. The overall rate of CEA+CABG decreased by 16.1% (p trend  = 0.03) from 2004 to 2012, whereas the rate of CAS+CABG did not significantly change during these years (p trend  = 0.10). The adjusted risk of death was greater, whereas risk of stroke was lower with both combined CEA+CABG (death odds ratio [OR]: 2.08, 95% confidence interval [CI]: 1.08 to 3.97; p = 0.03; stroke OR: 0.65, 95% CI: 0.42 to 1.01; p = 0.06) and staged CEA+CABG (death OR: 2.40, 95% CI: 1.43 to 4.05; p = 0.001; stroke OR: 0.50, 95% CI: 0.31 to 0.80; p = 0.004) approaches compared with CAS+CABG. The adjusted risk of death or stroke was similar in the 3 groups., Conclusions: In patients with concomitant carotid and coronary disease undergoing combined revascularization, combined CEA+CABG is utilized most frequently, followed by staged CEA+CABG and staged CAS+CABG strategies. The staged CAS+CABG strategy was associated with lower risk of mortality, but higher risk of stroke. Future studies are needed to examine the risks/benefits of different carotid revascularization strategies for high-risk patients requiring concurrent CABG., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare the stroke/death rates between proximal embolic protection devices (P-EPDs) and distal filter embolic protection devices (F-EPDs) in elective carotid artery stenting (CAS)., Background: P-EPDs have theoretical advantages that may make them superior to F-EPDs for stroke prevention during CAS., Methods: We examined 10,246 consecutive elective CAS procedures performed with embolic protection in the NCDR CARE registry between January 2009 and March 2013. We analyzed crude and propensity-matched rates of in-hospital combined death/stroke in patients treated with P-EPDs versus F-EPDs. Secondary analyses included 30-day adverse event rates and stroke rates by the involved cerebrovascular territory., Results: P-EPDs were used in 590 of 10,246 cases (5.8%). Patients treated with P-EPDs had higher rates of symptomatic lesion status (46.8% vs. 39.7%, p<0.001), atrial fibrillation/flutter (16.1% vs. 13.0%, p=0.03), and history of a neurological event (51.2% vs. 46.6%, p=0.03). In unadjusted and propensity-matched analyses, differences in in-hospital stroke/death between P-EPD and F-EPD cohorts were nonsignificant (1.5% vs. 2.4%, p=0.16 and 1.6% vs. 2.0%, p=0.56, respectively). For patients with available data (n=7,693, 75.1%), 30-day adverse events rates were similar for P-EPDs and F-EPDs before (2.5% vs. 4.2%, p=0.07) and after (2.7% vs. 4.0%, p=0.22) propensity matching., Conclusions: Use of a P-EPD during CAS was associated with low rates of in-hospital stroke/death similar to those with an F-EPD in the first comparative effectiveness study of the devices. An adequately powered randomized trial comparing clinical outcomes between these devices is unlikely to be feasible., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Urinary exosome-like vesicles (ELVs) are a heterogenous mixture (diameter 40-200 nm) containing vesicles shed from all segments of the nephron including glomerular podocytes. Contamination with Tamm-Horsfall protein (THP) oligomers has hampered their isolation and proteomic analysis. Here we improved ELV isolation protocols employing density centrifugation to remove THP and albumin, and isolated a glomerular membranous vesicle (GMV)-enriched subfraction from 7 individuals identifying 1830 proteins and in 3 patients with glomerular disease identifying 5657 unique proteins. The GMV fraction was composed of podocin/podocalyxin-positive irregularly shaped membranous vesicles and podocin/podocalyxin-negative classical exosomes. Ingenuity pathway analysis identified integrin, actin cytoskeleton, and Rho GDI signaling in the top three canonical represented signaling pathways and 19 other proteins associated with inherited glomerular diseases. The GMVs are of podocyte origin and the density gradient technique allowed isolation in a reproducible manner. We show many nephrotic syndrome proteins, proteases, and complement proteins involved in glomerular disease are in GMVs and some were only shed in the disease state (nephrin, TRPC6, INF2 and phospholipase A2 receptor). We calculated sample sizes required to identify new glomerular disease biomarkers, expand the ELV proteome, and provide a reference proteome in a database that may prove useful in the search for biomarkers of glomerular disease.

Objectives: This study sought to characterize usage and outcomes of carotid stenting platforms., Background: A variety of stents and embolic protection devices (EPDs) are used for carotid artery stenting. Little is known about current usage patterns and differences in outcomes with these devices., Methods: We analyzed 12,135 consecutive carotid stent procedures in the NCDR (National Cardiovascular Data Registry) CARE (Carotid Artery Revascularization and Endarterectomy) registry performed between January 1, 2007 and March 31, 2012. We compared baseline characteristics and crude and multivariable-adjusted rates of in-hospital combined death/stroke among patients treated with Acculink/Accunet (Abbott Laboratories, Abbott Park, Illinois), Xact/Emboshield (Abbott), and Precise/Angioguard (Cordis Corporation, Bridgewater, New Jersey) stent/EPD combinations., Results: In 78.2% of cases, stents were used in conjunction with their specific, corresponding U.S. Food and Drug Administration-approved EPD. The Acculink/Accunet (n = 2,617, 21.6%), Xact/Emboshield (n = 3,507, 28.9%), and Precise/Angioguard (n = 2,696, 22.2%) stent/EPD combinations were used in 72.7% of all cases. The Protégé/SpiderFx (ev3 Endovascular Inc., Plymouth, Minnesota) (n = 453, 3.7%) and Wallstent/Filterwire (Boston Scientific, Natick, Massachusetts) (n = 213, 1.8%) devices were used in a minority of cases. In unadjusted analyses, the Precise/Angioguard system was associated with higher rates of the primary outcome than were the Acculink/Accunet (2.5% vs. 1.8%; p = 0.058) and Xact/Emboshield (2.5% vs. 1.9%; p = 0.14) systems that were not statistically different. In adjusted analyses, differences between Precise/Angioguard and Accunet/Acculink (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 0.89 to 2.47; p = 0.065), Precise/Angioguard and Xact/Emboshield (OR: 1.16, 95% CI: 0.77 to 1.76; p = 0.38), and Xact/Emboshield and Accunet/Acculink (OR: 1.28, 95% CI: 0.82 to 1.97; p = 0.18) remained nonsignificant., Conclusions: In modern U.S. practice, the Acculink/Accunet, Xact/Emboshield, and Precise/Angioguard carotid stenting systems are used in most cases and are associated with similarly low rates of adverse events., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The A-E+ transgenic mouse is highly susceptible to human thyroglobulin (hTg)-induced thyroiditis, but strongly tolerant to a challenge by mouse thyroglobulin (mTg), in stark contrast to traditionally susceptible strains, wherein mTg induces stronger thyroiditis. To identify mouse thyroid epitopes recognized by destructive, hTg-primed T cells, we selected the three hTg epitopes known to be presented by H2E(b), as the basis for synthesizing potential mTg epitopes. One 15-mer peptide, mTg409, did prime T cells, elicit Ab, and induce thyroiditis. Moreover, cells primed with corresponding, pathogenic hTg410 cross-reacted with mTg409, and vice versa. mTg409 contained 4/4 anchor residues, similar to the corresponding hTg peptide. Based on this finding, a second mTg epitope, mTg179, was subsequently identified. These mTg autoepitopes, identified by using thyroiditogenic hTg epitopes, help to explain the severe thyroiditis seen in this novel A-E+ transgenic model.

Mantle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma (NHL) that behaves aggressively and remains incurable. In order to understand the pathogenesis of MCL and design new therapies, it is important to accurately analyze molecular changes in pathways dysregulated in MCL. We used antibody microarrays to compare patterns of protein expression between CD19(+) purified B lymphocytes from normal tonsil and 7 cases of histologically confirmed MCL. Protein overexpression was defined as a higher than 1.3-fold or 2-fold increase in at least 67% of tumor samples compared with normal B-cell control. Of the polypeptides, 77 were overexpressed using the higher than 1.3-fold cutoff, and 13 were overexpressed using the 2-fold cutoff. These included cell cycle regulators (regulator of chromosome condensation 1 [RCC1], murine double minute 2 [MDM2]), a kinase (citron Rho-interacting kinase [CRIK]), chaperone proteins (heat shock 90-kDa protein [Hsp90], Hsp10), and phosphatase regulators (A-kinase anchor protein 1 [AKAP149], protein phosphatase 5 [PP5], and inhibitor 2). The elevated expression of some of these polypeptides was confirmed by immunoblotting and immunohistochemistry, whereas elevated expression of others could not be confirmed, illustrating the importance of confirmatory studies. This study describes a novel technique that identifies proteins dysregulated in MCL.

To identify pathogenic epitopes on human thyroglobulin (hTg), a homodimer of 660kDa, we have applied a computer-based algorithm to predict potential HLA-DR3-binding peptides and have tested them in DR3-transgenic mice. Of the 39 peptides selected, four stimulated a proliferative response from hTg-primed cells of DR3+ mice, but not DQ8+ mice. Of the four peptides, one, hTg2079, was consistently pathogenic. Thyroiditis was not only produced by adoptive transfer of hTg-primed, hTg2079-activated cells but also by direct immunization with the peptide. These results demonstrate the utility of using this computer-based algorithm with synthetic peptides to help identify pathogenic T cell epitopes on hTg.

Synovial fluid (SF) is a dynamic reservoir for proteins originating from serum, synovial tissue, and cartilage. The composition of the SF proteome may reflect the pathophysiological conditions affecting the circulatory system and cartilage. Our long-term goal is to identify reliable protein markers for osteoarthritis (OA) in SF. We first evaluated the pattern of SF proteins on two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) as a function of protein loading, pH range for isoelectric focusing, and concentration of acrylamide in SDS-PAGE. Removal of albumin and Gamma-globulins from the samples did not improve the detection of protein spots on 2D-PAGE. The repeatability of protein spot intensity was tested by triplicate 2D-PAGE of a given sample; these experiments showed low intrasample variability (correlation coefficients 0.89-0.95). Differences between multiple samples were tested by comparing the 2D-PAGE of four samples. These experiments showed slightly greater variation between samples (correlation coefficients 0.85-0.93) and a number of differentially expressed proteins. The intensity of 18 protein spots differed more than fivefold, and the intensity of nine protein spots differed more than 100-fold. These results show that 2D-PAGE can be used under standard conditions to screen SF samples and identify a small subset of proteins in SF that are potential markers associated with OA.

Peptide nucleic acids (PNAs) are uncharged DNA analogs that hybridize to complementary sequences with high affinity and stability. We previously showed that PNAs, after intraperitoneal injection into rats, are effective antisense compounds in vivo. The present study was designed to test whether PNAs also have antigene effects in vivo. The renin-angiotensin system is critical in the control of blood pressure. We designed and synthesized sense (antigene) PNAs to angiotensinogen, which is the precursor protein that leads to angiotensin I and II. Spontaneously hypertensive rats received intraperitoneal injections of either 20 mg/kg sense-angiotensinogen-PNA, mismatch-angiotensinogen PNA, or saline. Only the sense-angiotensinogen PNA treatment resulted in a significant decrease in plasma angiotensin I, systolic blood pressure, and liver and brain angiotensinogen mRNA levels. Thus, these results demonstrate on the molecular, protein, and physiological levels that antigene PNAs are effective in vivo upon systemic administration.