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Würzburg, Germany

Koessler J.,Universitaetsklinikum Wuerzburg
Platelets | Year: 2011

Insufficient response on antiplatelet medication has become an intensively discussed issue because of the risk factor of recurrent adverse cardiovascular events. However, the monitoring of antiplatelet therapy requires appropriate, robust and reliable test methods. For the measurement of thienopyridine effects, the manufacturer of the PFA-100® System provides the INNOVANCE® PFA P2Y * cartridge. We tested this cartridge for its capacity to detect the inhibition of the P2Y receptor, which is the target for thienopyridine medication (e.g. clopidogrel). We compared the INNOVANCE® PFA P2Y * results with those obtained by the receptor specific flow cytometric vasodilator stimulated phosphoprotein (VASP) assay that expresses the status of the P2Y receptor as "platelet reactivity index" (PRI). The in vitro addition of the P2Y receptor antagonist cangrelor (AR-C69931MX) to citrated human whole blood resulted in a dose-dependent prolongation of closure times (CTs) of the INNOVANCE® PFA P2Y * cartridge correlating with decreased PRI levels. In volunteers, the intake of a 600 mg clopidogrel loading dose caused an increase of the CTs in all volunteers, although some of these volunteers were identified as "poor responders" by the VASP assay (no significant reduction of PRI levels). In 50 patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) and under dual antiplatelet therapy, the new cartridge had a detection rate of 84% (CT 106 s as cut-off) for clopidogrel medication. After dividing the 50 patients into two groups according to their response to clopidogrel INNOVANCE® PFA P2Y * recognized all "responders" (defined by a PRI > 50%) using >106 s as cut-off but the specificity for a "good response" was only 42% because several "poor responders" (defined by a PRI > 50%) also showed CTs above the cut-off. The best correlation (substantial agreement) between the results of INNOVANCE® PFA P2Y * and of the VASP phosphorylation assay was achieved using CT > 200 s and PRI < 55% as cut-offs. Then, the sensitivity of INNOVANCE® PFA P2Y * was 97% and the specificity for a "good response" 65%. In summary, INNOVANCE® PFA P2Y * showed a high sensitivity for the detection of P2Y receptor blockade, but had only a limited specificity for a "good response" to clopidogrel. Therefore, this new cartridge is a useful tool to rule out P2Y receptor inhibition, if normal or only slightly prolonged CTs are obtained. Its predictive value for risk assessment of thromboembolic events, e.g. after coronary stent implantation, needs to be evaluated in clinical trials. Source


Schwaerzer G.K.,Free University of Berlin | Hiepen C.,Free University of Berlin | Schrewe H.,Charite - Medical University of Berlin | Schrewe H.,Max Planck Institute for Molecular Genetics | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2012

Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS). SYNS is characterized by progressive symphalangism, carpal/tarsal fusions, deafness and mild facial dysmorphism. Here we present a novel molecular mechanism of a GDF5 mutation affecting chondrogenesis and osteogenesis. GDF5-S94N exhibits impaired binding to BMPRII causing alleviated Smad and non-Smad signaling and reduced chondrogenic differentiation of ATDC5 cells. Surprisingly, chondrogenesis in mouse micromass cultures was strongly enhanced by GDF5-S94N. By using quantitative techniques (SPR, reporter gene assay, ALP assay, qPCR), we uncovered that this gain of function is caused by strongly reduced affinity of GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack of noggin inhibition. Thus, since noggin is upregulated during chondrogenic differentiation, GDF5-S94N exceeds the GDF5 action, which results in the phenotypic outcome of SYNS. The detailed molecular characterization of GDF5-S94N as a noggin-resistant growth factor illustrates the potential of GDF5 mutants in applications with defined therapeutical needs. © 2012 American Society for Bone and Mineral Research. Source


Koessler J.,Universitaetsklinikum Wuerzburg | Ehrenschwender M.,Universitaetsklinikum Wuerzburg | Ehrenschwender M.,University of Regensburg | Kobsar A.,Universitaetsklinikum Wuerzburg | Brunner K.,Universitaetsklinikum Wuerzburg
Platelets | Year: 2012

Recently, the INNOVANCE® PFA P2Y (P2Y) cartridge of the PFA-100® system (Siemens Healthcare Diagnostics, Marburg, Germany) has been developed for the monitoring of adenosine diphosphate (ADP) P2Y12 receptor inhibition in patients under dual antiplatelet therapy. The aim of this study was to evaluate the influence of pre-existing defects in primary haemostasis on the P2Y cartridge independent from specific antiplatelet medication. Therefore, the closure time (CT) of the P2Y cartridge was measured in a cohort of 176 patients with assumed bleeding disorders and compared with the results of established methods for the assessment of primary haemostasis. Von Willebrand disease (VWD) was found in 25 patients (14). The detection rate of the P2Y cartridge regarding VWD was 64 and lower compared to the two conventional cartridges (collagen/epinephrine cartridge, CEPI, 80; collagen/ADP cartridge, CADP, 76). In the subgroup of VWD patients with VWF:RCo<60IU/dL (n22), the correlation analysis and the inter-rater agreement revealed only limited accordance with the two established cartridges. The correlation with the CADP cartridge (Cr0.767, R20.461; Kappa0.41) was higher than the correlation with the CEPI cartridge. Except for severe forms, platelet function disorders (9 patients, 5) did not prolong the CT of the P2Y cartridge. Interestingly, the P2Y cartridge was less interference-prone to unspecific medications (23 patients, 13). As the main conclusion, it must be taken into account that low von Willebrand factor activity can significantly influence the CTs of the P2Y cartridge when using it for the monitoring of antiplatelet therapy. Copyright © 2012 Informa UK Ltd. Source


Del Guerra A.,University of Pisa | Bardies M.,French Institute of Health and Medical Research | Belcari N.,University of Pisa | Caruana C.J.,University of Malta | And 7 more authors.
Physica Medica | Year: 2013

Purpose: To provide a guideline curriculum covering theoretical and practical aspects of education and training for Medical Physicists in Nuclear Medicine within Europe. Material and methods: National training programmes of Medical Physics, Radiation Physics and Nuclear Medicine physics from a range of European countries and from North America were reviewed and elements of best practice identified. An independent panel of experts was used to achieve consensus regarding the content of the curriculum. Results: Guidelines have been developed for the specialist theoretical knowledge and practical experience required to practice as a Medical Physicist in Nuclear Medicine in Europe. It is assumed that the precondition for the beginning of the training is a good initial degree in Medical Physics at master level (or equivalent). The Learning Outcomes are categorised using the Knowledge, Skill and Competence approach along the lines recommended by the European Qualifications Framework. The minimum level expected in each topic in the theoretical knowledge and practical experience sections is intended to bring trainees up to the requirements expected of a Medical Physicist entering the field of Nuclear Medicine. Conclusions: This new joint EANM/EFOMP European guideline curriculum is a further step to harmonise specialist training of Medical Physicists in Nuclear Medicine within Europe. It provides a common framework for national Medical Physics societies to develop or benchmark their own curricula. The responsibility for the implementation and accreditation of these standards and guidelines resides within national training and regulatory bodies. © 2012 Associazione Italiana di Fisica Medica. Source


Koessler J.,Universitaetsklinikum Wuerzburg | Kobsar A.L.,Universitaetsklinikum Wuerzburg | Rajkovic M.S.,Universitaetsklinikum Wuerzburg | Rajkovic M.S.,Universitaetsklinikum Greifswald | And 7 more authors.
Platelets | Year: 2011

Insufficient response on antiplatelet medication has become an intensively discussed issue because of the risk factor of recurrent adverse cardiovascular events. However, the monitoring of antiplatelet therapy requires appropriate, robust and reliable test methods. For the measurement of thienopyridine effects, the manufacturer of the PFA-100® System provides the INNOVANCE® PFA P2Y* cartridge. We tested this cartridge for its capacity to detect the inhibition of the P2Y12 receptor, which is the target for thienopyridine medication (e.g. clopidogrel). We compared the INNOVANCE® PFA P2Y* results with those obtained by the receptor specific flow cytometric vasodilator stimulated phosphoprotein (VASP) assay that expresses the status of the P2Y12 receptor as "platelet reactivity index" (PRI). The in vitro addition of the P2Y12 receptor antagonist cangrelor (AR-C69931MX) to citrated human whole blood resulted in a dose-dependent prolongation of closure times (CTs) of the INNOVANCE® PFA P2Y* cartridge correlating with decreased PRI levels. In volunteers, the intake of a 600 mg clopidogrel loading dose caused an increase of the CTs in all volunteers, although some of these volunteers were identified as "poor responders" by the VASP assay (no significant reduction of PRI levels). In 50 patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) and under dual antiplatelet therapy, the new cartridge had a detection rate of 84% (CT 106 s as cut-off) for clopidogrel medication. After dividing the 50 patients into two groups according to their response to clopidogrel INNOVANCE® PFA P2Y* recognized all "responders" (defined by a PRI > 50%) using >106 s as cut-off but the specificity for a "good response" was only 42% because several "poor responders" (defined by a PRI > 50%) also showed CTs above the cut-off. The best correlation (substantial agreement) between the results of INNOVANCE® PFA P2Y* and of the VASP phosphorylation assay was achieved using CT > 200 s and PRI < 55% as cut-offs. Then, the sensitivity of INNOVANCE® PFA P2Y* was 97% and the specificity for a "good response" 65%. In summary, INNOVANCE® PFA P2Y* showed a high sensitivity for the detection of P2Y12 receptor blockade, but had only a limited specificity for a "good response" to clopidogrel. Therefore, this new cartridge is a useful tool to rule out P2Y12 receptor inhibition, if normal or only slightly prolonged CTs are obtained. Its predictive value for risk assessment of thromboembolic events, e.g. after coronary stent implantation, needs to be evaluated in clinical trials. © 2011 Informa UK Ltd All rights reserved. Source

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