MRI Contrast-enhancement with superparamagnetic iron oxide nanoparticles amplify macrophage foam cell apoptosis in human and murine atherosclerosis

(Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidemic models of atherosclerosis.RAW264.7 foam cells, exposed in vitro to Ferumoxide (dextran-coated SPIO), Ferumoxtran (dextran-coated USPIO), or Ferumoxytol (carboxymethyl dextran-coated USPIO) (all 1 mg Fe/ml) showed increased apoptosis and ROS accumulation for Ferumoxide and Ferumoxtran, whereas Ferumoxytol was tolerated well. Pro-apoptotic (TUNEL+) and pro-oxidant activity of Ferumoxide (0.3 mg Fe/kg) and Ferumoxtran (1 mg Fe/kg) were confirmed in plaque, spleen, and liver of hyperlipidemic ApoE-/- (n = 9/group) and LDLR-/- (n = 9-16/group) mice that had received single IV injections compared to saline-treated controls. Again, Ferumoxytol treatment (1 mg Fe/kg) failed to induce apoptosis or oxidative stress in these tissues. Concomitant antioxidant treatment (EUK-8/EUK-134) largely prevented these effects in vitro (-68%, P Ferumoxide and Ferumoxtran, but not Ferumoxytol, induced apoptosis of lipid-laden macrophages in human and murine atherosclerosis, potentially impacting disease progression in patients with advanced atherosclerosis.Biopharmaceutic

Emerging role of USPIOs for MR imaging of atherosclerosis

Atherosclerosis is an inflammatory disease of the arteries, which causes more than 19 million deaths worldwide every year. Most complications of atherosclerosis are caused by rupture of a vulnerable plaque. Currently, there are no imaging techniques available in clinical practice that can accurately identify a vulnerable plaque. There is an emerging role for Ultrasmall Super-paramagnetic Iron Oxide Particles (USPIOs) in MR imaging of atherosclerosis. This review will first give an update on the biology of atherosclerosis. Next, we will focus on the physicochemical properties of USPIOs and describe animal and human studies that showed USPIO uptake mainly in macrophages of atherosclerotic plaque, which could be detected as areas of focal signal loss in MR images. Novel superparamagnetic particles are currently being developed which enable visualization of other cell types and functions than macrophage uptake that are relevant for atherosclerosis. We conclude that USPIOs are a highly promising imaging tool for atherosclerosis and larger prospective studies are warranted to prove the value in daily clinical practice

Robust, defensible, and fair: The AMEE guide to selection into medical school: AMEE Guide No. 153

Selection is the first assessment of medical education and training. Medical schools must select from a pool of academically successful applicants and ensure that the way in which they choose future clinicians is robust, defensible, fair to all who apply and cost-effective. However, there is no comprehensive and evidence-informed guide to help those tasked with setting up or rejuvenating their local selection process. To address this gap, our guide draws on the latest research, international case studies and consideration of common dilemmas to provide practical guidance for designing, implementing and evaluating an effective medical school selection system. We draw on a model from the field of instructional design to frame the many different activities involved in doing so: the ADDIE model. ADDIE provides a systematic framework of Analysis (of the outcomes to be achieved by the selection process, and the barriers and facilitators to achieving these), Design (what tools and content are needed so the goals of selection are achieved), Development (what materials and resources are needed and available), Implementation (plan [including piloting], do study and adjust) and Evaluation (quality assurance is embedded throughout but the last step involves extensive evaluation of the entire process and its outcomes)

High-sensitive Troponin T assay for the diagnosis of acute myocardial infarction: an economic evaluation

markdownabstract__Abstract__ Background: Delayed diagnosis and treatment of Acute Myocardial Infarction (AMI) has a major adverse impact on prognosis in terms of both morbidity and mortality. Since conventional cardiac Troponin assays have a low sensitivity for diagnosing AMI in the first hours after myocardial necrosis, high-sensitive assays have been developed. The aim of this study was to assess the cost effectiveness of a high-sensitive Troponin T assay (hsTnT), alone or combined with the heart-type fatty acid-binding protein (H-FABP) assay in comparison with the conventional cardiac Troponin (cTnT) assay for the diagnosis of AMI in patients presenting to the hospital with chest pain.Methods: We performed a cost-utility analysis (quality adjusted life years-QALYs) and a cost effectiveness analysis (life years gained-LYGs) based on a decision analytic model, using a health care perspective in the Dutch context and a life time time-horizon. The robustness of model predictions was explored using one-way and probabilistic sensitivity analyses.Results: For a life time incremental cost of 30.70 Euros, use of hsTnT over conventional cTnT results in gain of 0.006 Life Years and 0.004 QALY. It should be noted here that hsTnT is a diagnostic intervention which costs only 4.39 Euros/test more than the cTnT test. The ICER generated with the use of hsTnT based diagnostic strategy comparing with the use of a cTnT-based strategy, is 4945 Euros per LYG and 7370 Euros per QALY. The hsTnT strategy has the highest probability of being cost effective at thresholds between 8000 and 20000 Euros per QALY. The combination of hsTnT and h-FABP strategy's probability of being cost effective remains lower than hsTnT at all willingness to pay thresholds.Conclusion: Our analysis suggests that hsTnT assay is a very cost effective diagnostic tool relative to conventional TnT assay. Combination of hsTnT and H-FABP does not offer any additional economic and health benefit over hsTnT test alone

Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging

AB Background-: One of the features of high-risk atherosclerotic plaques is a preponderance of macrophages. Experimental studies with hyperlipidemic rabbits have shown that ultrasmall superparamagnetic particles of iron oxide (USPIOs) accumulate in plaques with a high macrophage content and that this induces magnetic resonance (MR) signal changes. The purpose of our study was to investigate whether USPIO-enhanced MRI can also be used for in vivo detection of macrophages in human plaques. Methods and Results-: MRI was performed on 11 symptomatic patients scheduled for carotid endarterectomy before and 24 (n=11) and 72 (n=5) hours after administration of USPIOs (Sinerem) at a dose of 2.6 mg Fe/kg. Histological and electron microscopical analyses of the plaques showed USPIOs primarily in macrophages within the plaques in 10 of 11 patients. Histological analysis showed USPIOs in 27 of 36 (75%) of the ruptured and rupture-prone lesions and 1 of 14 (7%) of the stable lesions. Of the patients with USPIO uptake, signal changes in the post-USPIO MRI were observed by 2 observers in the vessel wall in 67 of 123 (54%) and 19 of 55 (35%) quadrants of the T2*-weighted MR images acquired after 24 and 72 hours, respectively. For those quadrants with changes, there was a significant signal decrease of 24% (95% CI, 33% to 15%) in regions of interest in the images acquired after 24 hours, whereas no significant signal change was found after 72 hours. Conclusions-: Accumulation of USPIOs in macrophages in predominantly ruptured and rupture-prone human atherosclerotic lesions caused signal decreases in the in vivo MR images. (C) 2003 American Heart Association, Inc

Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging

AB Background-: One of the features of high-risk atherosclerotic plaques is a preponderance of macrophages. Experimental studies with hyperlipidemic rabbits have shown that ultrasmall superparamagnetic particles of iron oxide (USPIOs) accumulate in plaques with a high macrophage content and that this induces magnetic resonance (MR) signal changes. The purpose of our study was to investigate whether USPIO-enhanced MRI can also be used for in vivo detection of macrophages in human plaques. Methods and Results-: MRI was performed on 11 symptomatic patients scheduled for carotid endarterectomy before and 24 (n=11) and 72 (n=5) hours after administration of USPIOs (Sinerem) at a dose of 2.6 mg Fe/kg. Histological and electron microscopical analyses of the plaques showed USPIOs primarily in macrophages within the plaques in 10 of 11 patients. Histological analysis showed USPIOs in 27 of 36 (75%) of the ruptured and rupture-prone lesions and 1 of 14 (7%) of the stable lesions. Of the patients with USPIO uptake, signal changes in the post-USPIO MRI were observed by 2 observers in the vessel wall in 67 of 123 (54%) and 19 of 55 (35%) quadrants of the T2*-weighted MR images acquired after 24 and 72 hours, respectively. For those quadrants with changes, there was a significant signal decrease of 24% (95% CI, 33% to 15%) in regions of interest in the images acquired after 24 hours, whereas no significant signal change was found after 72 hours. Conclusions-: Accumulation of USPIOs in macrophages in predominantly ruptured and rupture-prone human atherosclerotic lesions caused signal decreases in the in vivo MR images. (C) 2003 American Heart Association, Inc

Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: initial experience

PURPOSE: To prospectively determine, by using a stepwise logistic regression model, the optimal magnetic resonance (MR) weighting (ie, pulse sequence) combinations for plaque assessment and corresponding cutoff values of relative signal intensities (rSIs). MATERIALS AND METHODS: Institutional review board approval and patient consent were obtained. Eleven patients (seven men, four women; mean age ± standard deviation, 68 years ± 4) with symptomatic carotid disease and stenosis of more than 70% were investigated at MR imaging before carotid endarterectomy. The MR images were matched with histologic features of the endarterectomy specimens (reference standard). The rSIs (compared with that of muscle tissue) from regions of interest were assessed qualitatively and semiquantitatively. For all major components (calcification, lipid core, intraplaque hemorrhage, and fibrous tissue), optimal cutoff points for the rSIs were determined for five MR weightings by means of receiver operating characteristic curves. The best predicting combinations of these five dichotomized MR weightings were selected by means of stepwise logistic regression analysis. The potential sensitivity and specificity of MR imaging for vulnerable plaque with hemorrhage and/or lipid core were determined. RESULTS: The same optimal MR weighting combinations for identifying the four plaque components were found with qualitative and semiquantitative analysis. Sensitivity and specificity for vulnerable plaque were 93% (95% confidence interval: 77%, 99%) and 96% (95% confidence interval: 86%, 100%), respectively, for the qualitative analysis and 76% (95% confidence interval: 56%, 90%) and 100% (95% confidence interval: 93%, 100%) for the semiquantitative analysis. CONCLUSION: This study demonstrates the potential of a systematic approach of atherosclerotic plaque assessment with multisequence MR imaging by using the information provided from five different MR weightings in a stepwise logistic regression model. © RSNA, 2005

In vivo detection of hemorrhage in human atherosclerotic plaques with magnetic resonance imaging

Purpose: To investigate the performance of high-resolution T1-weighted (T1w) turbo field echo (TFE) magnetic resonance imaging (MRI) for the identification of the high-risk component intraplaque hemorrhage, which is described in the literature as a troublesome component to detect. Materials and Methods: An MRI scan was performed preoperatively on 11 patients who underwent carotid endarterectomy because of symptomatic carotid disease with a stenosis larger than 70%. A commonly used double inversion recovery (DIR) T1w turbo spin echo (TSE) served as the T1w control for the T1w TFE pulse sequence. The MR images were matched slice by slice with histology, and the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the MR images were calculated. Additionally, two readers, who were blinded for the histological results, independently assessed the MR slices concerning the presence of intraplaque hemorrhage. Results: More than 80% of the histological proven intraplaque hemorrhage could be detected using the TFE sequence with a high interobserver agreement (Kappa = 0.73). The TFE sequence proved to be superior to the TSE sequence concerning SNR and CNR, but also in the qualitative detection of intraplaque hemorrhage. The false positive TFE results contained fibrous tissue and were all located outside the main plaque area. Conclusion: The present study shows that in vivo high-resolution Tlw TFE MRI can identify the high-risk component intraplaque hemorrhage with a high detection rate in patients with symptomatic carotid disease. Larger clinical trials are warranted to investigate whether this technique can identify patients at risk for an ischemic attack