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631.
Bot I van Berkel TJ Biessen EA 《Current opinion in investigational drugs (London, England : 2000)》2007,8(9):729-735
Atherosclerosis is initially a chronic inflammatory disease as it involves inflammatory cells such as macrophages, T-lymphocytes and mast cells. At later stages, when plaques manifest clinically, thrombosis, coagulation and fibrinolysis contribute to the escalation of the disease, which culminates in acute cardiovascular syndromes. Serine proteases are instrumental in all of these processes, rendering their inhibition of clinical interest for the prevention of atherosclerotic plaque progression. Viral serine protease inhibitors, specifically engineered by pathogens to evade the host's defense system, not only display profound anti-inflammatory activity but also inhibit a range of serine proteases implicated in cardiovascular disease. In this review, the potential of viral serine protease inhibitors in anti-atherosclerotic therapy is discussed. 相似文献
632.
Increasing the level and duration of transgene expression and restricting expression to vascular cells are important goals for clinically useful gene therapy vectors. We evaluated several promoters, enhancers and introns in endothelial, smooth muscle and liver cells in tissue culture and in vivo, comparing local delivery to the carotid artery with intravenous delivery to the liver. A 1800-bp fragment of the oxidized LDL receptor (LOX-1) promoter showed highest in vivo activity in the carotid artery, achieving 39% the activity of the reference cytomegalovirus promoter, with 188-fold greater specificity for carotid artery over liver. An enhancer from the Tie2 gene in combination with the intracellular adhesion molecule-2 promoter improved endothelial specificity of plasmid vectors, increased the expression from adenoviral vectors in cultured endothelial cells and doubled the specificity for carotid artery over liver in vivo. Adding a short intron to expression cassettes increased expression in both endothelial and smooth muscle cells in vitro; however, the eNOS enhancer failed to consistently increase the expression or endothelial specificity of the vector. In conclusion, elements from the LOX-1 promoter and Tie2 enhancer together with an intron can be used to improve vectors for vascular gene transfer. 相似文献
633.
Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis
JO Friedrich R Wald SM Bagshaw KE Burns NK Adhikari 《Critical care (London, England)》2012,16(4):R146-16
ABSTRACT: INTRODUCTION: The objective of this systematic review and meta-analysis was to determine the effect of renal replacement therapy (RRT), delivered as hemofiltration vs. hemodialysis, on clinical outcomes in patients with acute kidney injury (AKI). METHODS: MEDLINE, EMBASE, and CENTRAL databases and conference abstracts were searched to June 2012 for parallel-group or crossover randomized and quasi-randomized controlled trials (RCTs) evaluating hemofiltration vs. hemodialysis in patients with AKI. Two authors independently selected studies and abstracted data on study quality and outcomes. Additional information was obtained from trial authors. We pooled data using random-effects models. RESULTS: Of 6657 citations, 19 RCTs (10 parallel-group and 9 crossover) met inclusion criteria. Sixteen trials used continuous RRT. Study quality was variable. The primary analysis included 3 parallel-group trials comparing similar doses of hemofiltration and hemodialysis; sensitivity analyses included trials comparing combined hemofiltration-hemodialysis or dissimilar doses. We found no effect of hemofiltration on mortality (risk ratio [RR] 0.96, 95% confidence interval [CI] 0.73-1.25, p=0.76; 3 trials, n=121 [primary analysis]; RR 1.10, 95%CI 0.88-1.38, p=0.38; 8 trials, n=540 [sensitivity analysis]) or other clinical outcomes (RRT dependence in survivors, vasopressor use, organ dysfunction) compared to hemodialysis. Hemofiltration appeared to shorten time to filter failure (mean difference [MD] -7 hours, 95%CI[-19,+5], p=0.24; 2 trials, n=50 [primary analysis]; MD -5 hours, 95%CI[-10, -1], p=0.01; 3 trials, n=113 [including combined hemofiltration-hemodialysis trials comparing similar doses]; MD -6 hours, 95% CI[-10, -1], p=0.02; 5 trials, n=383 [sensitivity analysis]). Data primarily from crossover RCTs suggested that hemofiltration increased clearance of medium to larger molecules, including inflammatory cytokines, compared to hemodialysis, although almost no studies measured changes in serum concentrations. Meta-analyses were based on very limited data. CONCLUSIONS: Data from small RCTs do not suggest beneficial clinical outcomes from hemofiltration, but confidence intervals were wide. Hemofiltration may increase clearance of medium to larger molecules. Larger trials are required to evaluate effects on clinical outcomes. 相似文献
634.
Ron Wald Jan O Friedrich Sean M Bagshaw Karen EA Burns Amit X Garg Michelle A Hladunewich Andrew A House Stephen Lapinsky David Klein Neesh I Pannu Karen Pope Robert M Richardson Kevin Thorpe Neill KJ Adhikari 《Critical care (London, England)》2012,16(5):R205
Introduction
Among critically ill patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT), the effect of convective (via continuous venovenous hemofiltration [CVVH]) versus diffusive (via continuous venovenous hemodialysis [CVVHD]) solute clearance on clinical outcomes is unclear. Our objective was to evaluate the feasibility of comparing these two modes in a randomized trial.Methods
This was a multicenter open-label parallel-group pilot randomized trial of CVVH versus CVVHD. Using concealed allocation, we randomized critically ill adults with AKI and hemodynamic instability to CVVH or CVVHD, with a prescribed small solute clearance of 35 mL/kg/hour in both arms. The primary outcome was trial feasibility, defined by randomization of >25% of eligible patients, delivery of >75% of the prescribed CRRT dose, and follow-up of >95% of patients to 60 days. A secondary analysis using a mixed-effects model examined the impact of therapy on illness severity, defined by sequential organ failure assessment (SOFA) score, over the first week.Results
We randomized 78 patients (mean age 61.5 years; 39% women; 23% with chronic kidney disease; 82% with sepsis). Baseline SOFA scores (mean 15.9, SD 3.2) were similar between groups. We recruited 55% of eligible patients, delivered >80% of the prescribed dose in each arm, and achieved 100% follow-up. SOFA tended to decline more over the first week in CVVH recipients (-0.8, 95% CI -2.1, +0.5) driven by a reduction in vasopressor requirements. Mortality (54% CVVH; 55% CVVHD) and dialysis dependence in survivors (24% CVVH; 19% CVVHD) at 60 days were similar.Conclusions
Our results suggest that a large trial comparing CVVH to CVVHD would be feasible. There is a trend toward improved vasopressor requirements among CVVH-treated patients over the first week of treatment.Trial Registration
ClinicalTrials.gov: NCT00675818相似文献635.
John M Finney A Sarah Walker Tim EA Peto David H Wyllie 《BMC medical informatics and decision making》2011,11(1):7
Background
Integration of information on individuals (record linkage) is a key problem in healthcare delivery, epidemiology, and "business intelligence" applications. It is now common to be required to link very large numbers of records, often containing various combinations of theoretically unique identifiers, such as NHS numbers, which are both incomplete and error-prone. 相似文献636.
von der Thüsen JH Borensztajn KS Moimas S van Heiningen S Teeling P van Berkel TJ Biessen EA 《The American journal of pathology》2011,178(2):924-934
Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. 相似文献
637.
Jackson CL Bennett MR Biessen EA Johnson JL Krams R 《Arteriosclerosis, thrombosis, and vascular biology》2007,27(4):714-720
There is an urgent need for representative animal models where prospective examination of the events leading up to plaque rupture and the rupture process itself can be performed. Recently, reports have begun to emerge that apolipoprotein E and low density lipoprotein receptor knockout mice may spontaneously develop unstable atherosclerosis, with plaques in certain parts of the arterial tree showing features suggestive of plaque rupture. Here we discuss the problems inherent in applying definitions of plaque rupture as seen in human arteries to mice; the anatomic locations in mice where unstable plaques do and do not occur; methods of inducing plaque instability in mice; and how to assess plaque stability in mice. These considerations lead us to a number of general recommendations. 相似文献
638.
Intestinal microcirculation and gut permeability in acute pancreatitis: Early changes and therapeutic implications 总被引:11,自引:1,他引:11
Dr. Hubert G. Hotz M.D. Thomas Foitzik M.D. Janine Rohweder M.D. Joerg D. Schulzke M.D. Micbael Fromm M.D. Norbert S. F. Runkel M.D. Heinz J. Bubr M.D. EA.C.S. 《Journal of gastrointestinal surgery》1998,2(6):518-525
Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal
permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may
involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary
blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced
by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours
after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary
perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis,
pancreatic capillary perfusion remained unchanged (2.13 ± 0.06 vs. 1.98 ± 0.04 nl-min−l.cap −1 [control]; P = NS), whereas mucosal (1.59 _± 0.03 vs. 2.28 ± 0.03 nl.min−l.cap −1 [control]; P <0.01) and subserosal (2.47 ± 0.04 vs. 3.74 ± 0.05 nl-min−l.cap -1 [control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked
reduction in both pancreatic (1.06 = 0.03 vs. 1.98 ± 0.04 nl’min-1.cap -1 [control]; P <0.01) and colonic (mucosal: 0.59 = 0.01 vs. 2.28 ± 0.03 nl.min−l.cap -1 [control], P < 0.01; subserosal: 1.96 ± 0.05 vs. 3.74 ± 0.05 nl.min−l.cap -1 [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control:
147 ±19 nmol.hr−l.cm {−2}2; mild pancreatitis: 158±23 nmol-hr−l.cm-2; severe pancreatitis: 181 ±33 nmol.hr−l.cm-2; P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood
flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis
or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory
injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window
of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result
in improved intestinal microcirculation.
Presented at the Thirty-Seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May
19–22, 1996.
Supported in part by Deutsche Forschungsgemeinschaft (DFG Fo 197/3). 相似文献