Citations

ObjectivesTo investigate the prognostic implications of the presence of severe lesion calcification in patients undergoing coronary artery bypass graft (CABG) operation.BackgroundThere is robust evidence that lesion calcification is a predictor of worse prognosis in patients undergoing percutaneous coronary intervention; however, there is limited data about the prognostic implication of lesion calcium in patients treated with CABG.MethodsWe retrospectively analyzed data from 1,545 patients who underwent CABG and were recruited in the SYNTAX study and CABG registry. Two experts reviewed the angiographic data and classified patients in two groups: those with severely calcified coronary arteries and those without severe lesion calcification. Clinical outcomes at 5‐year follow‐up were collected and compared in the two groups.ResultsOne out of three patients exhibited severe lesion calcification (n = 588). Patients with calcified coronaries had an increased mortality at 5‐year follow‐up (17.1% vs. 9.9%, P < 0.001) and a higher event rate of death‐myocardial infarction (MI) compared with those without (19.4% vs. 13.2%, P = 0.003), but there was no statistical significant difference between the two groups for major adverse cardiovascular events (MACE, 26.8% vs. 21.8%, P = 0.057). In multivariate Cox regression analysis severe lesion calcification was an independent predictor of an increased all‐cause mortality (hazard ratio: 1.39, 95% confidence interval: 1.02–1.89; P = 0.037) but it was not an independent predictor of the combined end‐points death‐MI or MACE.ConclusionsSevere lesion calcification is associated with an increased mortality in patients undergoing CABG, but it is not an independent predictor of death‐MI or MACE. This paradox can be attributed to the fact that CABG allows perfusion of the healthy coronaries bypassing the diseased arteries and thus it minimizes the risk of coronary events due to progressive atherosclerosis. © 2014 Wiley Periodicals, Inc.

Abstract Aquaporin‐4 ( AQP 4) is a water channel protein that is most highly, but not exclusively, expressed in the central nervous system. In 2005 AQP 4 was shown to be the antigenic target of neuromyelitis optica‐immunoglobulin G ( NMO ‐IgG, or AQP 4‐IgG), an antibody found specifically in patients with NMO and in formes frustes of NMO , such as longitudinally extensive transverse myelitis (LETM) or optic neuritis (ON). This discovery facilitated the clinical, pathological, and radiological distinction of NMO and the spectrum of NMO ‐related disorders from classical multiple sclerosis. In addition to its use as a diagnostic tool, AQP 4‐IgG predicts a high risk of relapse in patients with a clinically isolated syndrome of either LETM or ON. As disability in NMO is attack‐related, early diagnosis and treatment are predicted to have a major effect on long‐term disability. Thus, the importance of sensitive and specific assays to detect AQP 4‐IgG cannot be overstated. Both academic institutions and commercial companies have developed assays to identify AQP 4‐IgG in patients' sera or cerebrospinal fluid. Both AQP 4 isoforms from different species have been used as the antigenic target in the form of frozen tissue sections in indirect immunofluorescence assays, partially purified protein for fluorescence immunoprecipitation assay, radioimmunoprecipitation assay or enzyme‐linked immunosorbent assay, or transfected into cells for cell based assays or flow cytometry. We carried out a systematic review of the literature reporting different methodologies used to identify AQP 4‐IgG, examine whether longitudinal AQP 4‐IgG titers predict relapses in seropositive patients, and attempt to establish a reasonable timeframe for retesting negative serum samples.

Abstract Infection of epithelial cells by Cryptosporidium parvum triggers a variety of host-cell innate and adaptive immune responses including release of cytokines/chemokines and up-regulation of antimicrobial peptides. The mechanisms that trigger these host-cell responses are unclear. Thus, we evaluated the role of TLRs in host-cell responses during C. parvum infection of cultured human biliary epithelia (i.e., cholangiocytes). We found that normal human cholangiocytes express all known TLRs. C. parvum infection of cultured cholangiocytes induces the selective recruitment of TLR2 and TLR4 to the infection sites. Activation of several downstream effectors of TLRs including IL-1R-associated kinase, p-38, and NF-κB was detected in infected cells. Transfection of cholangiocytes with dominant-negative mutants of TLR2 and TLR4, as well as the adaptor molecule myeloid differentiation protein 88 (MyD88), inhibited C. parvum-induced activation of IL-1R-associated kinase, p-38, and NF-κB. Short-interfering RNA to TLR2, TLR4, and MyD88 also blocked C. parvum-induced NF-κB activation. Moreover, C. parvum selectively up-regulated human β-defensin-2 in directly infected cells, and inhibition of TLR2 and TLR4 signals or NF-κB activation were each associated with a reduction of C. parvum-induced human β-defensin-2 expression. A significantly higher number of parasites were detected in cells transfected with a MyD88 dominant-negative mutant than in the control cells at 48–96 h after initial exposure to parasites, suggesting MyD88-deficient cells were more susceptible to infection. These findings demonstrate that cholangiocytes express a variety of TLRs, and suggest that TLR2 and TLR4 mediate cholangiocyte defense responses to C. parvum via activation of NF-κB.

Abstract The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.

Abstract Biliary epithelial cells (cholangiocytes) respond to proinflammatory cytokines such as IFN-γ and actively participate in the regulation of biliary inflammatory response in the liver. B7-H1 (also known as CD274 or PD-L1) is a member of the B7 costimulatory molecules and plays a critical immunoregulatory role in cell-mediated immune responses. In this study, we show that resting human cholangiocytes in culture express B7-H1 mRNA, but not B7-H1 protein. IFN-γ induces B7-H1 protein expression and alters the microRNA (miRNA) expression profile in cholangiocytes. Of those IFN-γ-down-regulated miRNAs, we identified microRNA-513 (miR-513) with complementarity to the 3′-untranslated region of B7-H1 mRNA. Targeting of the B7-H1 3′-untranslated region by miR-513 results in translational repression. Transfection of cholangiocytes with an antisense oligonucleotide to miR-513 induces B7-H1 protein expression. Additionally, transfection of miR-513 precursor decreases IFN-γ-induced B7-H1 protein expression and consequently influences B7-H1-associated apoptotic cell death in cocultured Jurkat cells. Thus, miR-513 regulates B7-H1 translation and is involved in IFN-γ-induced B7-H1 expression in human cholangiocytes, suggesting a role for miRNA-mediated gene silencing in the regulation of cholangiocyte response to IFN-γ.

Abstract Clinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2−/− and eotaxin-1/2−/− mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80+CD11b+ macrophages in DSS-induced epithelial injury and to CD68+ intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.

Background— Current guidelines recommend coronary artery bypass graft surgery (CABG) when treating significant de novo left main coronary artery (LM) stenosis; however, percutaneous coronary intervention (PCI) has a class IIa indication for unprotected LM disease in selected patients. This analysis compares 5-year clinical outcomes in PCI- and CABG-treated LM patients in the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial, the largest trial in this group to date. Methods and Results— The SYNTAX trial randomly assigned 1800 patients with LM or 3-vessel disease to receive either PCI (with TAXUS Express paclitaxel-eluting stents) or CABG. The unprotected LM cohort (N=705) was predefined and powered. Major adverse cardiac and cerebrovascular event rates at 5 years was 36.9% in PCI patients and 31.0% in CABG patients (hazard ratio, 1.23 [95% confidence interval, 0.95–1.59]; P =0.12). Mortality rate was 12.8% and 14.6% in PCI and CABG patients, respectively (hazard ratio, 0.88 [95% confidence interval, 0.58–1.32]; P =0.53). Stroke was significantly increased in the CABG group (PCI 1.5% versus CABG 4.3%; hazard ratio, 0.33 [95% confidence interval, 0.12–0.92]; P =0.03) and repeat revascularization in the PCI arm (26.7% versus 15.5%; hazard ratio, 1.82 [95% confidence interval, 1.28–2.57]; P <0.01). Major adverse cardiac and cerebrovascular events were similar between arms in patients with low/intermediate SYNTAX scores but significantly increased in PCI patients with high scores (≥33). Conclusions— At 5 years, no difference in overall major adverse cardiac and cerebrovascular events was found between treatment groups. PCI-treated patients had a lower stroke but a higher revascularization rate versus CABG. These results suggest that both treatments are valid options for LM patients. The extent of disease should accounted for when choosing between surgery and PCI, because patients with high SYNTAX scores seem to benefit more from surgery compared with those in the lower tertiles. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00114972.