Magnetic resonance imaging contrast-enhancement with superparamagnetic iron oxide nanoparticles amplifies macrophage foam cell apoptosis in human and murine atherosclerosis.

Aims: (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 normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic models of atherosclerosis.

Methods And Results: RAW264.

Outcomes-Based Selection Into Medical School: Predicting Excellence in Multiple Competencies During the Clinical Years.

Purpose: Medical school selection committees aim to identify the best possible students and, ultimately, the best future doctors from a large, well-qualified, generally homogeneous pool of applicants. Constructive alignment of medical school selection, curricula, and assessment with the ultimate outcomes (e.g.

Increasing value in research: cost evaluations in health professions education.

The authors use Foo et al.'s discussion of the value of economic evaluations to consider how such techniques might advance the practice of selection for medical school.

Opening the black box of selection.

Medical school selection is currently in the paradoxical situation in which selection tools may predict study outcomes, but which constructs are actually doing the predicting is unknown (the 'black box of selection'). Therefore, our research focused on those constructs, answering the question: do the internal structures of the tests in an outcome-based selection procedure reflect the content that was intended to be measured? Downing's validity framework was applied to organize evidence for construct validity, focusing on evidence related to content and internal structure. The applied selection procedure was a multi-tool, CanMEDS-based procedure comprised of a video-based situational judgement test (focused on (inter)personal competencies), and a written aptitude test (reflecting a broader array of CanMEDS competencies).

Does selection pay off? A cost-benefit comparison of medical school selection and lottery systems.

Context: Resources for medical education are becoming more constrained, whereas accountability in medical education is increasing. In this constrictive environment, medical schools need to consider and justify their selection procedures in terms of costs and benefits. To date, there have been no studies focusing on this aspect of selection.

Selection into medicine: the predictive validity of an outcome-based procedure.

Background: Medical schools must select students from a large pool of well-qualified applicants. A challenging issue set forward in the broader literature is that of which cognitive and (inter)personal qualities should be measured to predict diverse later performance. To address this gap, we designed a 'backward chaining' approach to selection, based on the competences of a 'good doctor'.

Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE-/- Mice.

Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice.

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

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.

Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes.

Cytokines play an important role in ischemic injury and repair. However, little is known about their prognostic value in cardiovascular disease. The aim of this study was to investigate the prognostic importance of chemokines CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC for the risk of future cardiovascular events in patients with acute coronary syndromes (ACS).

Cathepsin K gene disruption does not affect murine aneurysm formation.

Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated.

Noninvasive diagnosis of ruptured peripheral atherosclerotic lesions and myocardial infarction by antibody profiling.

Novel biomarkers, such as circulating (auto)antibody signatures, may improve early detection and treatment of ruptured atherosclerotic lesions and accompanying cardiovascular events, such as myocardial infarction. Using a phage-display library derived from cDNAs preferentially expressed in ruptured peripheral human atherosclerotic plaques, we performed serological antigen selection to isolate displayed cDNA products specifically interacting with antibodies in sera from patients with proven ruptured peripheral atherosclerotic lesions. Two cDNA products were subsequently evaluated on a validation series of patients with peripheral atherosclerotic lesions, healthy controls, and patients with coronary artery disease at different stages.

Comparison of lipid-rich necrotic core size in symptomatic and asymptomatic carotid atherosclerotic plaque: Initial results.

Purpose: To investigate the potential difference in the size of the lipid-rich necrotic core (LRNC) in carotid plaques of symptomatic patients versus asymptomatic patients. Pathological studies established that a large LRNC is an important feature of vulnerable atherosclerotic plaque. Previously, we have demonstrated a high correlation between semiquantitative analysis of the LRNC size in T1-weighted (w) turbo field echo (TFE) MR images and histology.

Comparison of single-sequence T1w TFE MRI with multisequence MRI for the quantification of lipid-rich necrotic core in atherosclerotic plaque.

Purpose: To prospectively determine the accuracy of semiquantitative analysis of the amount of lipid-rich necrotic core (LRNC) in atherosclerotic plaque using multi- as well as single-sequence T1-weighted (w) turbo field echo (TFE) MRI. Histology served as a reference standard.

Materials And Methods: Sixty-four symptomatic patients with carotid stenosis > or =70% were included and underwent endarterectomy after an MRI scan.

Cathepsin cysteine proteases in cardiovascular disease.

Extracellular matrix (ECM) remodeling is one of the underlying mechanisms in cardiovascular diseases. Cathepsin cysteine proteases have a central role in ECM remodeling and have been implicated in the development and progression of cardiovascular diseases. Cathepsins also show differential expression in various stages of atherosclerosis, and in vivo knockout studies revealed that deficiency of cathepsin K or S reduces atherosclerosis.

Dead or alive: gene expression profiles of advanced atherosclerotic plaques from autopsy and surgery.

Since inclusion of atherosclerotic tissues from different sources is often indispensable to study the full atherogenic spectrum, we investigated to what extent the expression profiles of advanced, stable atherosclerotic lesions obtained during autopsy and surgery are comparable. The gene expression profiles of human carotids with advanced atherosclerosis obtained at autopsy and at vascular surgery were studied by microarray analysis. Expression analysis was performed both at the single gene (Rosetta, Gene Ontology) and at the pathway level using Ingenuity and Gene Set Enrichment Analysis.

Osteoclastic bone degradation and the role of different cysteine proteinases and matrix metalloproteinases: differences between calvaria and long bone.

Unlabelled: Osteoclastic bone degradation involves the activity of cathepsin K. We found that in addition to this enzyme other, yet unknown, cysteine proteinases participate in digestion. The results support the notion that osteoclasts from different bone sites use different enzymes to degrade the collagenous bone matrix.

Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis.

The PTEN tumor suppressor gene is frequently inactivated in human tumors, including prostate cancer. Based on the Cre/loxP system, we generated a novel mouse prostate cancer model by targeted inactivation of the Pten gene. In this model, Cre recombinase was expressed under the control of the prostate-specific antigen (PSA) promoter.

Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody.

Background: Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified.

Methods And Results: Microarray analysis was performed on mRNA of aortic arches of ApoE-/- mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months.

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 loss of PTEN allows TCR alphabeta lineage thymocytes to bypass IL-7 and Pre-TCR-mediated signaling.

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates cell survival and proliferation mediated by phosphoinositol 3 kinases. We have explored the role of the phosphoinositol(3,4,5)P3-phosphatase PTEN in T cell development by analyzing mice with a T cell-specific deletion of PTEN. Pten(flox/flox)Lck-Cre mice developed thymic lymphomas, but before the onset of tumors, they showed normal thymic cellularity.

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.

Inflammation and restenosis: implications for therapy.

Restenosis is the process of luminal narrowing in an atherosclerotic artery after an intra-arterial intervention such as balloon angioplasty and stenting. It is believed that this process is mainly characterized by migration and proliferation of smooth muscle cells and extracellular matrix accumulation. However, there is now increasing evidence for a role of inflammation in the development of restenosis.

Atherosclerotic plaque rupture: local or systemic process?

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as "vulnerable plaque," and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture.

The dynamic extracellular matrix: intervention strategies during heart failure and atherosclerosis.

The extracellular matrix is no longer seen as the static embedding in which cells reside; it has been shown to be involved in cell proliferation, migration and cell-cell interactions. Turnover of the different extracellular matrix components is an active process with multiple levels of regulation. Collagen, a major extracellular matrix constituent of the myocardium and the arterial vascular wall, is synthesized by (myo)fibroblasts in the myocardium and smooth muscle cells in the medial arterial vascular wall.