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191.
Shemesh S Kamari Y Shaish A Olteanu S Kandel-Kfir M Almog T Grosskopf I Apte RN Harats D 《Atherosclerosis》2012,220(2):329-336
ObjectiveRecent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis.Methods and resultsL19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE?/? mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls (p < 0.01), whereas the macrophage marker Mac3 was significantly reduced (p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control (p < 0.03).ConclusionL19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE?/? mice resulting in significant plaque size reduction mediated by local Tregs. 相似文献
192.
193.
Corsetti JP Gansevoort RT Bakker SJ Navis G Sparks CE Dullaart RP 《Metabolism: clinical and experimental》2012,61(7):996-1002
Although there is great interest in the notion that dysfunctional transformation of high-density lipoprotein (HDL) facilitates development of atherosclerosis and cardiovascular disease (CVD), few studies in human populations directly address this issue. As apolipoprotein E (apoE) is a constituent of HDL thought to be important for HDL antiatherogenic function, we sought to assess the role of apoE in CVD risk in subjects likely to display dysfunctional transformation of HDL. Association of apoE levels with incident CVD risk was investigated using Cox multivariable proportional hazards modeling. Analyses were performed in subgroups of women and men likely to display dysfunctional transformation of HDL deriving from previous subgroup identification based upon defining characteristics of concurrently high levels of HDL cholesterol and systemic inflammation as reflected by high C-reactive protein levels. Results revealed apoE levels (dichotomized as highest quartile vs combined 3 lowest quartiles) as predicting subgroup risk in women (hazard ratio, 4.52; 95% confidence interval, 1.07-19.12; P = .040) but not in men. Further sex differences were manifested in terms of the relationship of apoE levels with age. Analysis revealed positive correlation of apoE levels with age in women (r = 0.47, P < .0001) but not in men (r = 0.04, P = .43). Apolipoprotein E levels predict incident CVD risk in women with high levels of HDL cholesterol and C-reactive protein but not in men. Future studies should be oriented toward investigations of apoE as related to multiplicity of HDL functionality and toward assessment of potential roles for apoE in dysfunctional transformation of HDL. 相似文献
194.
John Pietzsch Henning Gruell Stylianos Bournazos Bridget M. Donovan Florian Klein Ron Diskin Michael S. Seaman Pamela J. Bjorkman Jeffrey V. Ravetch Alexander Ploss Michel C. Nussenzweig 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(39):15859-15864
Passive transfer of neutralizing antibodies against HIV-1 can prevent infection in macaques and seems to delay HIV-1 rebound in humans. Anti-HIV antibodies are therefore of great interest for vaccine design. However, the basis for their in vivo activity has been difficult to evaluate systematically because of a paucity of small animal models for HIV infection. Here we report a genetically humanized mouse model that incorporates a luciferase reporter for rapid quantitation of HIV entry. An antibody’s ability to block viral entry in this in vivo model is a function of its bioavailability, direct neutralizing activity, and effector functions.HIV-1 (HIV), the causative agent of AIDS, represents a formidable global challenge, with the development of an effective vaccine being of paramount importance (1–4). Rapid progress in this area has been hindered in part by lack of a widely available small animal model for HIV entry. Currently available animal models include nonhuman primates and immunodeficient humanized mice, neither of which is readily available or amenable to genetic modifications (5, 6).Some viral pathogens exhibit a narrow host range, one of those being HIV. HIV’s entry into target cells is mediated by binding of its trimeric envelope spike (gp160) to human CD4 (hCD4) (7) and subsequently to a coreceptor such as human CXCR4 (8) or human CCR5 (hCCR5) (9–11). hCCR5 is of particular interest because it seems to be the primary coreceptor used for transmission (12, 13), as evidenced by the finding that homozygous deletion in the CCR5 allele confers resistance against HIV-1 acquisition (14, 15) and can also lead to long-term control of HIV after stem cell transplantation (16). Finally, HeLa cells and other HIV-resistant cells, including mouse cells, support viral entry when they are engineered to express hCD4/hCCR5/hCXCR4 (17–19).Here, we describe a hCCR5- and hCD4-expressing luciferase reporter mouse that can be used to measure HIV pseudovirus entry and antibody-mediated protection against initial infection in vivo. 相似文献
195.
C Beyrer SD Baral F van Griensven SM Goodreau S Chariyalertsak AL Wirtz R Brookmeyer 《Lancet》2012,380(9839):367-377
Epidemics of HIV in men who have sex with men (MSM) continue to expand in most countries. We sought to understand the epidemiological drivers of the global epidemic in MSM and why it continues unabated. We did a comprehensive review of available data for HIV prevalence, incidence, risk factors, and the molecular epidemiology of HIV in MSM from 2007 to 2011, and modelled the dynamics of HIV transmission with an agent-based simulation. Our findings show that the high probability of transmission per act through receptive anal intercourse has a central role in explaining the disproportionate disease burden in MSM. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiological data show substantial clustering of HIV infections in MSM networks, and higher rates of dual-variant and multiple-variant HIV infection in MSM than in heterosexual people in the same populations. Prevention strategies that lower biological transmission and acquisition risks, such as approaches based on antiretrovirals, offer promise for controlling the expanding epidemic in MSM, but their potential effectiveness is limited by structural factors that contribute to low health-seeking behaviours in populations of MSM in many parts of the world. 相似文献
196.
Kardys I Oemrawsingh RM Kay IP Jones GT McCormick SP Daemen J Van Geuns RJ Boersma E Van Domburg RT Serruys PW 《Clinical cardiology》2012,35(8):482-489
Background:
This prospective study investigated the association between preprocedural biomarker levels and incident major adverse cardiac events (MACE) in complex patients undergoing percutaneous coronary intervention (PCI) with sirolimus‐eluting stenting.Hypothesis:
Lipoprotein(a) (Lp[a]), interleukin‐10 (IL‐10), and high‐sensitivity C‐reactive protein (CRP) have long‐term prognostic value in patients undergoing PCI.Methods:
Between April 2002 and February 2003, 161 patients were included in the study. Blood was drawn before the procedure, and biomarkers were measured. Patients were followed‐up for MACE (death, nonfatal myocardial infarction, and repeat revascularization). Cox proportional hazard models were used to determine risk of MACE for tertiles of biomarkers. Both 1‐year and long‐term follow‐up (median, 6 years; maximum, 8 years) were evaluated.Results:
Mean age was 59 years, and 68% were men. During long‐term follow‐up, 72 MACE occurred (overall crude cumulative incidence: 45% [95% confidence interval (CI): 37%‐52%]). Lp(a) was associated with a higher 1‐year risk of MACE, with an adjusted hazard ratio (HR) of 3.1 (95% CI: 1.1‐8.6) for the highest vs the lowest tertile. This association weakened and lost significance with long‐term follow‐up. IL‐10 showed a tendency toward an association with MACE. The 1‐year HR was 2.1 (95% CI: 0.92‐5.0). Long‐term follow‐up rendered a similar result. The association of CRP with MACE did not reach statistical significance at 1‐year follow‐up. However, CRP was associated with long‐term risk of MACE, with an HR of 1.9 (95% CI: 1.0‐3.5).Conclusions:
In this prospective study, preprocedural Lp(a) level was associated with short‐term prognosis after PCI. The preprocedural CRP level was associated with long‐term prognosis after PCI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21988 The authors have no funding, financial relationships, or conflicts of interest to disclose. 相似文献197.
Bulvik BE Berenshtein E Konijn AM Grinberg L Vinokur V Eliashar R Chevion MM 《Age (Dordrecht, Netherlands)》2012,34(3):693-704
Organ-specific changes of iron- and redox-related proteins occur with age in the rat. Ferritin, the major iron storage and
detoxifying protein, as well as the proteins of the methionine-centered redox cycle (MCRC) were examined in old and young
animals, and showed organ-dependent changes. In spleens and livers of aged rats, ferritin (protein) levels were greater than
in young ones, and their iron saturation increased, rendering higher ferritin-bound iron (FtBI). Iron saturation of the ferritin
molecule in the tongues and sternohyoids of old rats was lower but ferritin level was higher than in young rats, resulting
in increased FtBI with age. Ferritin level in the esophagus of older rats was lower than in young rats but its molecular iron
content higher thus the total FtBI remained the same. In the larynx, both ferritin and its iron content were the same in young
and old animals. MCRC proteins were measured in livers and spleens only. With aging, methionine sulfoxide reductase A and
B (MsrA and MsrB) levels in livers and spleens decreased. Thioredoxin1 (Trx) and Trx-reductase1 were elevated in old spleens,
but reduced in livers. Aged spleens showed reduced Msr isozyme activity; but in the liver, its activity increased. mRNA changes
with age were monitored and found to be organ specific. These organ-specific changes could reflect the different challenges
and the selective pathways of each organ and its resultant capacity to cope with aging. 相似文献
198.
Wasfy MM Brady TJ Abbara S Nasir K Ghoshhajra BB Truong QA Hoffmann U Di Carli MF Blankstein R 《The American journal of cardiology》2012,109(7):998-1004
We sought to evaluate the ability of the Diamond and Forrester method (DFM) and the Duke Clinical Score (DCS) to predict obstructive coronary artery disease (CAD) on coronary computed tomographic angiography (CCTA) and the effect of these different risk scores on the appropriateness level using the 2010 Appropriate Use Criteria. Consecutive symptomatic patients who underwent CCTA for evaluation of CAD (n = 114) were classified as having a low, intermediate, or high pretest probability using the DFM and DCS. Using the Appropriate Use Criteria, the indications for CCTA were classified according to the pretest probability and previous testing. The CCTA results were classified as revealing obstructive (≥70% stenosis), nonobstructive (<70%), or no CAD. When the patients' risk was classified using the DFM, 18% were low, 65% intermediate, and 17% high risk. When using the DCS, 53% of patients had a reclassification of their risk, most of whom changed from intermediate to either low or high risk (50% low, 19% intermediate, 35% high risk). The net reclassification improvement for the prediction of obstructive CAD was 51% (p = 0.01). Of the 37 patients who were reclassified as low risk, 36 (97%) lacked obstructive CAD. Appropriateness for CCTA was reclassified for 13% of patients when using the DCS instead of the DFM, and the number of appropriate examinations was significantly fewer (68% vs 55%, p <0.001). In conclusion, reclassification of risk using the DCS instead of the DFM resulted in improved prediction of obstructive CAD on CCTA, especially in low-risk patients. More patients were categorized as having a high pretest probability of CAD, resulting in reclassification of their examination indications as uncertain or inappropriate. These results identify the need for improved pretest risk scores for noninvasive tests such as CCTA and suggest that the method of risk assessment could have important implications for patient selection and quality assurance programs. 相似文献
199.
Ben-Dor I Maluenda G Iyasu GD Laynez-Carnicero A Hauville C Torguson R Okubagzi P Xue Z Goldstein SA Lindsay J Satler LF Pichard AD Waksman R 《The American journal of cardiology》2012,109(7):1031-1037
Left ventricular systolic dysfunction in patients with severe aortic stenosis (AS) is associated with poor outcome. This analysis was designed primarily to describe the clinical course of a large series of consecutive patients with severe AS and low ejection fraction (EF) (<40%) who, because of high surgical risk, were referred for transcatheter aortic valve implantation consideration. A cohort of 270 patients with severe AS and low EF (<40%) who were referred to participate in a clinical trial of transcatheter aortic valve implantation was studied. Clinical, hemodynamic, and periprocedural complications and follow-up mortality data were collected and compared between patients with low mean transvalvular gradients (≤40 mm Hg, n = 170 [63%]) and high transvalvular gradients (>40 mm Hg, n = 100 [37%]). Patients with low gradients were younger (mean age 79.8 ± 9.1 vs 83.8 ± 7.7 years, p <0.001) and had higher incidences of coronary artery disease and renal failure. Mean aortic valve area was larger (0.73 ± 0.23 vs 0.53 ± 0.18 cm(2), p <0.001), while mean EF (26.4 ± 6.9% vs 30.5% ± 6.6%, p <0.001), cardiac output (3.7 ± 1.1 vs 4.1 ± 1.3 L/min, p = 0.04), and cardiac index (1.9 ± 0.5 vs 2.1 ± 0.6 L/min/m(2), p = 0.04) were lower in patients with lower gradients compared to those with higher gradients, respectively. Mortality was higher in patients with low gradients (53.8%) at a mean follow-up of 151 days compared to those with high gradients (41%) at a mean follow-up of 256 days (p = 0.01). In conclusion, patients with severe AS and low EF with low transvalvular gradients are at higher risk for worse outcomes compared to patients with high transvalvular gradients. Surgery or transcatheter aortic valve implantation treatment and high baseline transvalvular gradient are associated with EF improvement. 相似文献
200.
Waksman R Barbash IM Dvir D Torguson R Ben-Dor I Maluenda G Xue Z Satler LF Suddath WO Kent KM Pichard AD 《The American journal of cardiology》2012,109(9):1288-1294
Data from randomized clinical trials have shown the safety and efficacy of the XIENCE V in selected populations. However, limited data are available comparing the XIENCE V to the first-generation CYPHER sirolimus-eluting stent. This study aimed to assess the long-term safety and clinical efficacy of the XIENCE V everolimus-eluting stent compared to first-generation stents in an unselected patient population. This retrospective analysis included 6,069 patients treated with CYPHER, TAXUS, and XIENCE stents from 2003 to 2009 at our institution. The patients were followed up for ≥1 year after the index procedure. The baseline characteristics were generally comparable among the 3 groups, with the exception of a significantly greater prevalence of diabetes mellitus, systemic hypertension, and a history of angioplasty and coronary bypass surgery among the XIENCE patients. The XIENCE patients also had a twofold greater rate of type C lesions. One-year follow-up data were available for 82% of the patients. The 1-year major adverse cardiovascular events rate was 9.3% for the XIENCE stent versus 9.8% for the CYPHER stent and 11.5% for the TAXUS stent (p = 0.11). Mortality was lower in the XIENCE group than in the CYPHER and TAXUS groups (3.6% vs 4.9% vs 7.2%, respectively, p <0.001), and target lesion revascularization was similar (5.9% vs 5.2% vs 5.6%, respectively; p = 0.34). Stent thrombosis was lower in the XIENCE patients (0.2% vs 1.2% vs 0.7%, p = 0.007). In conclusion, in a contemporary United States clinical practice with an unselected patient population, use of the XIENCE V stent was associated with an improved safety profile and reduction of all-cause mortality and stent thrombosis compared to first-generation drug-eluting stents. The XIENCE V failed to demonstrate superiority for overall major adverse cardiovascular events, Q-wave myocardial infarction, and revascularization rates. 相似文献