Validation of the INCEPT: A Multisource Feedback Tool for Capturing Different Perspectives on Physicians' Professional Performance.

Introduction: Multisource feedback (MSF) instruments are used to and must feasibly provide reliable and valid data on physicians' performance from multiple perspectives. The "INviting Co-workers to Evaluate Physicians Tool" (INCEPT) is a multisource feedback instrument used to evaluate physicians' professional performance as perceived by peers, residents, and coworkers. In this study, we report on the validity, reliability, and feasibility of the INCEPT.

Sunitinib uptake inhibits platelet function in cancer patients.

Background: Sunitinib is an oral tyrosine kinase inhibitor used for cancer treatment. Patients treated with sunitinib are at higher bleeding risk. As tyrosine kinases are essential for platelet signalling, the effects of sunitinib on platelet function in vitro and in cancer patients on treatment were investigated.

Narrative information obtained during student selection predicts problematic study behavior.

Introduction: Up to now, student selection for medical schools is merely used to decide which applicants will be admitted. We investigated whether narrative information obtained during multiple mini-interviews (MMIs) can also be used to predict problematic study behavior.

Methods: A retrospective exploratory study was performed on students who were selected into a four-year research master's program Physician-Clinical Investigator in 2007 and 2008 (n = 60).

Easing the transition: the final year of medical education at Maastricht University.

This manuscript describes the final year of medical education at Maastricht University as it has been operating since 2006. At the time external drivers for the development of a new structure of the final year were: the desire to prepare medical students for lifelong learning, the CanMEDs that were increasingly acknowledged to state the final attainment level of medical education and an increasing recognition of the importance of learning by participating actively and by taking more responsibility. Internal drivers were students' evaluations and our wish to improve instructional design and quality control.

Role of newly formed platelets in thrombus formation in rat after clopidogrel treatment: comparison to the reversible binding P2Y₁₂ antagonist ticagrelor.

Platelet P2Y₁₂ receptors play an important role in arterial thrombosis by stimulating thrombus growth. Both irreversibly (clopidogrel) and reversibly binding (ticagrelor, AZD6140) P2Y₁₂ antagonists are clinically used for restricted periods, but possible differences in platelet function recovery after drug cessation have not been investigated. We treated WKY rats with a single, high dose of 200 mg/kg clopidogrel or 40 mg/kg ticagrelor.

Endothelial glycocalyx structure in the intact carotid artery: a two-photon laser scanning microscopy study.

Background: The endothelial glycocalyx (EG) is the carbohydrate-rich luminal lining of endothelial cells that mediates permeability and blood cell-vessel wall interactions. To establish an atheroprotective role of the EG, adequate imaging and quantification of its properties in intact, viable, atherogenesis-prone arteries is needed.

Methods: Carotid arteries of C57Bl6/J mice (n=22) were isolated including the bifurcation, mounted in a perfusion chamber, and perfused with fluorescent lectin wheat germ agglutinin-fluorescein isothiocyanate.

Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer.

Purpose: Tumor-released proangiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy.

The role of blood platelets in tumor angiogenesis.

Coagulation abnormalities occur frequently in cancer patients. It is becoming evident that blood platelets have an important function in this process. However, understanding of the underlying mechanisms is still very modest.

Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques.

Background: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques.

In vivo high-resolution structural imaging of large arteries in small rodents using two-photon laser scanning microscopy.

In vivo (molecular) imaging of the vessel wall of large arteries at subcellular resolution is crucial for unraveling vascular pathophysiology. We previously showed the applicability of two-photon laser scanning microscopy (TPLSM) in mounted arteries ex vivo. However, in vivo TPLSM has thus far suffered from in-frame and between-frame motion artifacts due to arterial movement with cardiac and respiratory activity.

Small-molecule inhibitors of vascular adhesion protein-1 reduce the accumulation of myeloid cells into tumors and attenuate tumor growth in mice.

Vascular adhesion protein-1 (VAP-1) is an endothelial, cell surface-expressed oxidase involved in leukocyte traffic. The adhesive function of VAP-1 can be blocked by anti-VAP-1 Abs and small-molecule inhibitors. However, the effects of VAP-1 blockade on antitumor immunity and tumor progression are unknown.

Molecular imaging of tumor angiogenesis using alphavbeta3-integrin targeted multimodal quantum dots.

Molecular imaging of angiogenesis is urgently needed for diagnostic purposes such as early detection, monitoring of (angiostatic) therapy and individualized therapy. Multimodality molecular imaging is a promising and refined technique to study tumor angiogenesis, which has so far been largely unexplored due to the lack of suitable multimodal contrast agents. Here, we report on the application of a novel alphavbeta3-specific quantum dot-based nanoparticle, which has been optimized for both optical and magnetic resonance detection of tumor angiogenesis.

Two-photon microscopy on vital carotid arteries: imaging the relationship between collagen and inflammatory cells in atherosclerotic plaques.

We used two-photon laser scanning microscopy (TPLSM) to demonstrate for the first time its potential in studying relational details at the cellular level of atherogenesis in intact, viable mouse carotid arteries. Isolated and mounted arteries of ApoE-/-mice, aged 15 or 21 weeks (7 and 13 weeks on western diet), were imaged after labeling with specific fluorescent markers for cell nuclei, inflammatory cells, collagen, and lipids. Data were compared with C57BL6/J mice fed a chow diet.

A transgenic Tie2-GFP athymic mouse model; a tool for vascular biology in xenograft tumors.

We report the generation of a transgenic Tie2-GFP athymic nude mouse, carrying green fluorescent blood vessels throughout the body. This transgenic mouse is a tool for studies in vascular biology, and is especially of interest for imaging of tumor angiogenesis and the study of anti-angiogenesis strategies in (human) xenografts. Intravital microscopy identified the presence of blood conducting structures that are not lined by endothelial cells.

Imaging collagen in intact viable healthy and atherosclerotic arteries using fluorescently labeled CNA35 and two-photon laser scanning microscopy.

We evaluated CNA35 as a collagen marker in healthy and atherosclerotic arteries of mice after both ex vivo and in vivo administration and as a molecular imaging agent for the detection of atherosclerosis. CNA35 conjugated with fluorescent Oregon Green 488 (CNA35/OG488) was administered ex vivo to mounted viable muscular (uterine), elastic (carotid), and atherosclerotic (carotid) arteries and fresh arterial rings. Two-photon microscopy was used for imaging.

The endothelial glycocalyx: composition, functions, and visualization.

This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins, covering the endothelium luminally. Both endothelium- and plasma-derived soluble molecules integrate into this mesh.

Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications.

Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocyte-vessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation.

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis.

The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment.

Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors.

Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immunohistochemistry in two mouse tumor models.

The glycoprotein VI-phospholipase Cgamma2 signaling pathway controls thrombus formation induced by collagen and tissue factor in vitro and in vivo.

Objective: Both collagen and tissue factor can be initiating factors in thrombus formation. We investigated the signaling pathway of collagen-induced platelet activation in interaction with tissue factor-triggered coagulation during the thrombus-forming process.

Methods And Results: In murine blood flowing over collagen, platelet exposure of phosphatidylserine and procoagulant activity, but not adhesion, completely relied on each of the following signaling modules: glycoprotein VI (GPVI), FcR gamma-chain, Src kinases, adaptor protein LAT, and phospholipase Cgamma2 (PLCgamma2).

Preservation of rat cremaster muscle microcirculation after prolonged cold storage and transplantation.

Background: Microvascular surgery for the reconstruction of complex defects involves an ischemic period, which may cause flap failure as the result of ischemia/reperfusion injury. We assessed the microvascular consequences of rat cremaster muscle transplantation after prolonged periods of cold storage in HTK-Bretschneider solution (HTK).

Materials And Methods: Cremaster muscle transplantations were performed immediately or after 8 or 24 h of cold storage (4 degrees C) in HTK or saline.

Do preservation solutions protect rat cremaster microcirculation during ischemia and reperfusion?

Background: Our aim was to investigate the potential of the preservation solution Celsior to protect rat cremaster muscle microcirculation during ischemia and reperfusion, and to compare its effects with those of HTK (histidine-tryptophan-ketoglutarate-Bretschneider solution). Because of its anti-oxidant contents, we expected Celsior to be more protective than HTK.

Materials And Methods: Capillary perfusion and leukocyte-endothelium interactions were examined in rat cremaster muscle using intravital microscopy.

Regulation of microvascular thromboembolism in vivo.

Atherothrombosis and embolization are main causes of morbidity and mortality in the Western world. To optimize treatment, better understanding of the factors involved in thromboembolism in vivo is needed. The course and outcome of a thromboembolic process are determined by the local balance between anti and prothrombotic factors.

Effect of HTK on the microcirculation in the rat cremaster muscle during warm ischemia and reperfusion.

Histidine-tryptophan-ketoglutarate (HTK) preserves rat muscle function during cold storage. We examined the effect of HTK perfusion on preservation of microvascular function during 4 h of warm ischemia and subsequent reperfusion (I/R) in the rat cremaster muscle. Leukocyte-endothelium interactions, capillary perfusion, and arteriole diameters were quantified prior to HTK-perfusion and/or ischemia, and at 0, 1, and 2 h after restoration of blood flow.