@phdthesis{Grue1999, author = {Grue, Pernille}, title = {The physiological role of the two isoforms of DNA topoisomerase II in human cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-1369}, school = {Universit{\"a}t W{\"u}rzburg}, year = {1999}, abstract = {Unique functions of DNA topoisomerase IIalpha and IIbeta have been suggested. A human cell line which carries a homozygeous mutation of the nuclear localization sequence of the topoisomerase IIalpha gene expresses the isoform outside the nucleus at the onset of mitosis. At mitosis topoisomerase IIbeta diffused away from the chromatin despite the nuclear lack of the IIalpha-form. Chromosome condensation and disjunction was performed with the aid of cytosolic topoisomerase IIalpha which bound to the mitotic chromatin with low affinity. Consequently an increased rate of nondisjunction is observed in these cells. It is concluded that high affinity chromatin binding of topoisomerase IIalpha is essential for chromosome condensation/disjunction and that topoisomerase IIbeta does not adopt these functions. A centrosomal protein was recognized by topoisomerase IIalpha. This topoisomerase IIalpha-like protein resembles a modified form of topoisomerase IIalpha with an apparent size of 205 kDa compared to 170 kDa. The expression of the protein is constant in all stages of the cell cycle and it appears in proliferating as well as in resting cells. If there is not sufficient topoisomerase IIalpha present at mitosis the centrosomal proteins might adopt the function and a mitotic catastrophe in the cells could therefore be prevented.}, subject = {DNS-Gyrase}, language = {en} } @phdthesis{Christensen2003, author = {Christensen, Morten Overby}, title = {Dynamics of human DNA Topoisomerases I and II}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-4927}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2003}, abstract = {The first goal of this study was to develop cell lines with a stable expression of bio-fluorescent topo II and topo I. This was successfully achieved using a bicistronic vector system. Control experiments showed that proteins of expected size were expressed, and that GFP-tagged topos I, IIa, and IIb were active in the cells and fully integrated in the endogenous pools of the enzymes. These cell-lines provided a novel tool for investigating the cell biology of human DNA topoisomerases. Our most important finding was, that both types of mammalian topoisomerases are entirely mobile proteins that are in continuous and rapid flux between all compartments of the nucleus and between the cytososl and the chromosomes of mitotic cells. This was particularly surprising with regard to topo II, which is considered to be a structural component of the nuclear matrix and the chromosome scaffold. We must conclude that if this was the case, then these architectural structures appear to be much more dynamic than believed until now. In this context it should also be mentioned, that the alignment of topo II with the central axes of the chromosome arms, which has until now been considered a hall-mark of the enzyme's association with the chromosomal scaffold, is not seen in vivo and can be demonstrated to be to some extent an artefact of immunohistochemistry. Furthermore, we show that the two isoforms of topo II (a and b) have a different localisation during mitotic cell division, supporting the general concept that topo II functions at mitosis are exclusively assigned to the a-form, whereas at interphase the two isoenzymes work in concert. Despite unrestricted mobility within the entire nuclear space, topoisomerases I and II impose as mostly nucleolar proteins. We show that this is due to the fact that in the nucleoli they are moving slower than in the nucleoplasm. The decreased nucleolar mobility cannot be due to DNA-interactions, because compounds that fix topoisomerases to the DNA deplete them from the nucleoli. Interestingly, the subnucleolar distribution of topoisomerases I and II was complementary. The type II enzyme filled the entire nucleolar space, but excluded the fibrial centers, whereas topo I accumulated at the fibrial centers, an allocation directed by the enzyme's N-terminus. During mitosis, it also mediates association with the nucleolar organising regions of the acrocentric chromosomes. Thus, topo I stays associated with the rDNA during the entire cell-cycle and consistently colocalizes there with RNA-polymerase I. Finally, we show that certain cancer drugs believed to act by stabilising covalent catalytic DNA-intermediates of topoisomerases, do indeed immobilize the enzymes in living cells. Interestingly, these drugs do not target topoisomerases in the nucleoli but only in the nucleoplasm.}, subject = {Mensch}, language = {en} } @phdthesis{Visan2003, author = {Visan, Ioana Andreea}, title = {The CD23 receptor-regulation of expression and signal transduction}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-5556}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2003}, abstract = {Bisher sind zwei Isoformen des humanen CD23 (CD23a und CD23b) beschrieben. Beide unterscheiden sich lediglich in 6-7 Resten im N-terminalen, zytoplasmatischen Anteil. CD23a wird ausschließlich auf B-Zellen exprimiert, w{\"a}hrend CD23b sowohl auf B-Zellen als auch auf Monozyten, eosinophilen Granulozyten, Makrophagen und zahlreichen anderen Zelltypen durch Stimulation mit IL-4 induziert werden kann. Die beiden Isoformen vermitteln wahrscheinlich unterschiedliche Funktionen. CD23a gilt als Isoform, welche vornehmlich mit der Endozytose von IgE-Immunkomplexen und der Vermittlung von Antigen-Pr{\"a}sentation auf B-Zellen assoziiert ist. CD23b besitzt ein Phagozytose-Motiv und scheint bei der Phagozytose IgE besetzter Partikel, der Freisetzung von Zytokinen und der Bildung von Peroxiden eine Rolle zu spielen. Fr{\"u}here Untersuchungen legen die Vermutung nahe, dass die beiden Isoformen zwei getrennte Signal{\"u}bertragungswege miteinander verbinden. Die Gegen{\"u}berstellung von Ereignissen, welche in Zellen, die nur eine einer oder beide Isoformen von CD23 besitzen, stattfinden, legt die Vermutung nahe, dass CD23b cAMP und iNOS hochreguliert, wohingegen CD23a einen Anstieg des intrazellul{\"a}ren Kalziums vermittelt. Im ersten Teil unserer Untersuchungen haben wir die Regulation der B-Zell-spezifischen Expression von CD23a analysiert. Pax-5 ist ein auf B-Zellen beschr{\"a}nkter Transkriptionsfaktor, welcher f{\"u}r die fr{\"u}he und sp{\"a}te B-Zellentwicklung von entscheidender Bedeutung ist. M{\"o}gliche Pax-5 Bindungsstellen wurden in den proximalen Abschnitten des CD23a Promotors vermutet. Die Analyse des CD23a Promotors ergab drei mutmaßliche Pax-5 Bindungsstellen mit mehr als 50\% Homologie zur Konsensus-Sequenz. Eine dieser Bindungsstellen, namens CD23-1, kann mit einer hochaffinen Pax-5 Bindungsstelle konkurrieren oder direkt das Pax-5 Protein in Elektromobilit{\"a}ts Experimenten (EMSA) binden. Das Einf{\"u}gen von Mutationen an dieser Stelle verhindert die Bindung. Ein weiterer Versuch, bei dem die gesamte L{\"a}nge des CD23a Promotors durch {\"u}berlappende Peptide in einem kompetitiven Verfahren gegen{\"u}ber hoch affinen Bindungsstellen getestet wurde, zeigt ebenso CD23-1 als die einzige Stelle, welche direkt Pax-5 binden kann. In weiteren Experimenten f{\"u}hrte die Expression von Pax-5 in 293 Zellen zu einer 7fachen Aktivierung eines CD23a Kernpromotor Konstrukts. Die Kotransfektion zusammen mit STAT6 zeigte, dass Pax-5 mit diesem Transkriptionsfaktor kooperiert, indem es die Transkriptionsrate eines vergr{\"o}ßerten CD23a Promotorkonstrukts erh{\"o}ht. Von besonderer Bedeutung ist die Tatsache, dass die ektope Expression von Pax-5 in der monozyt{\"a}ren Zelllinie U-937, die normalerweise nur die CD23b Isoform exprimiert, dann zu einer Expression von CD23a nach Stimulation mit IL-4 und PMA f{\"u}hrte. Unsere Ergebnisse legen nahe, dass Pax-5 in der auf B-Zellen beschr{\"a}nkten Expression der CD23 Isoform eine Schl{\"u}sselrolle zukommt. Im zweiten Teil des Projekts haben wir ein "Zwei-Hefen-Hybrid-System" (Cyto-Trap von Stratagene) verwendet, um nach zytoplasmatischen Interaktionspartnern f{\"u}r den CD23 Rezeptor zu suchen. Das System wurde modifiziert um eine hohe Effizienz an Transformation zu erzielen. Unterschiedliche „K{\"o}der"-Vektorkonstrukte wurden hergestellt. Das Screening wurde mittels einer humanen Milzbibliothek mit dem Zielvektor des Systems durchgef{\"u}hrt. Die anfangs benutzten Konstrukte -pSosCD23a und pSosCD23b - exprimierten sehr kurze (22 Aminos{\"a}uren) zytoplasmatischen Reste der Isoformen am C-terminalen Ende des Fusionsproteins (humanes SOS). Verbesserte Konstrukte (pSos CD23a+Linker und pSosCD23b+Linker) exprimierten den zytoplasmatischen Anteil von CD23a/b am N-terminalen Ende des humanen SOS und hatten folglich den N-terminalen Anteil als Andockstelle frei, entsprechend den Bedingungen in vivo. Eine flexible Verbindungsregion trennte die Fusionsproteine, um auf diese Weise die kurze Aminos{\"a}urekette deutlich „sichtbar" werden zu lassen. Ann{\"a}hernd drei Millionen Klone wurden mittels der verschiedenen Konstrukte untersucht. Dabei konnte keine tats{\"a}chlich positive Interaktion gefunden werden. Stattdessen fand sich eine vergleichsweise hohe Zahl falsch-positiver Klone. Diese wiederum wurden in einem zweiten "Zwei-Hefen-Hybrid-System" getestet. In Zukunft wird ein neues Konstrukt als K{\"o}der verwendet werden. Hierbei wurde ein Tyrosin-Rest im zytoplasmatischen Anteil von CD23a durch Glutamat ersetzt. Das System wurde bereits dazu verwendet, die Interaktion zwischen CD23 und p59fyn - einem Mitglied der Src-Familie von Proteinkinasen, welches mit CD23a assoziiert sein soll - zu testen. Jedoch konnte im CytoTrap "Zwei-Hefen-Hybrid-System" keine Wechselwirkung nachgewiesen werden. Zusammenfassend zeigt das zentrale Ergebnis der Arbeit, dass Pax-5 der Schl{\"u}sselregulator ist, der die B-Zell-spezifische Expression von CD23a erm{\"o}glicht. Zus{\"a}tzlich wurde ein "Zwei-Hefen-Hybrid-System" etabliert, mit dem zytoplasmatische Interaktionspartner f{\"u}r die CD23 Isoformen gefunden werden k{\"o}nnen.}, subject = {Antigen CD23}, language = {en} } @phdthesis{Hallhuber2007, author = {Hallhuber, Matthias}, title = {Inhibition of Nuclear Import of Calcineurin Prevents the Development of Myocardial Hypertrophy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-23536}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {The Calcineurin/NFAT signaling cascade is a crucial transducer of cellular function. It has recently been emerged that in addition to the transcription factor NFAT, the phosphatase Calcineurin is also translocated to the nucleus. Our traditional understanding of Calcineurin activation via sustained high Ca2+-levels was also advanced by recent findings from this working group (AG Ritter), which showed that Calcineurin is activated by proteolysis of the C-terminal autoinhibitory domain. This leads to the constitutive activation and nuclear translocation of Calcineurin. Therefore, Calcineurin is not only responsible for dephosphorylating of NFAT in the cytosol thus enabling its nuclear import, its presence in the nucleus is also significant in ensuring the full transcriptional activity of NFAT. Formation of complexes between transcription factors and DNA regulates the transcriptional process. Therefore, the time that transcription factors remain nuclear is a major determinant of transcriptional activity. The movement of proteins over ~40 kDa into and out of the nucleus is governed by the nuclear pore complex (NPC). Transcription factors and enzymes that regulate the activity of these proteins are shuttled across the nuclear envelope by proteins that recognize nuclear localization signals (NLS) and nuclear export signals (NES) within the amino acid sequence of these transcription factors. In this study, the precise mechanisms of Calcineurin nuclear import and export were identified. Additionally to the nuclear localization sequence (NLS) and the nuclear export sequence (NES) within the sequence of Calcineurin, the respective nuclear cargo proteins, responsible for nuclear import, Importin\&\#946;1, and for nuclear export, CRM1, were identified. Inhibition of the Calcineurin/importin interaction by a competitive peptide, called Import Blocking Peptide (IBP), which mimicked the Calcineurin NLS, prevented nuclear entry of Calcineurin. A non-inhibitory control peptide showed no effect. Using this approach, it was able to prevent the development of myocardial hypertrophy. In Angiotensin II stimulated cardiomyocytes, both the transcriptional and the translational level was suppressed. Additionally, cell size and expression of Brain natriuretic peptide (as molecular marker for hypertrophy) were significantly reduced compared untreated controls. IBP worked dose-dependent, but did not affect the Calcineurin phosphatase activity. In conclusion, Calcineurin is not only capable of dephosphorylating NFAT, thus enabling its nuclear import, its presence in the nucleus is also important for full NFAT transcriptional activity. Using IBP to prevent the nuclear import of Calcineurin is a completely new approach to prevent the development of myocardial hypertrophy.}, language = {en} } @phdthesis{Padmapriya2008, author = {Padmapriya, Ponnuswamy}, title = {Insight into oxidative stress mediated by nitric oxide synthase (NOS) isoforms in atherosclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-30659}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {The principle product of each NOS is nitric oxide. However, under conditions of substrate and cofactor deficiency the enzymes directly catalyze superoxide formation. Considering this alternative chemistry of each NOS, the effects of each single enzyme on key events of atherosclerosis are difficult to predict. Here, we evaluate nitric oxide and superoxide production by all three NOS isoforms in atherosclerosis. ESR measurements of circulating and vascular wall nitric oxide production showed significantly reduced nitric oxide levels in apoE/eNOS double knockout (dko) and apoE/iNOS dko animals but not in apoE/nNOS dko animals suggesting that eNOS and iNOS majorly contribute to vascular nitric oxide production in atherosclerosis. Pharmacological inhibition and genetic deletion of eNOS and iNOS reduced vascular superoxide production suggesting that eNOS and iNOS are uncoupled in atherosclerotic vessels. Though genetic deletion of nNOS did not alter superoxide production, acute inhibition of nNOS showed that nNOS contributes significantly to superoxide production. In conclusion, uncoupling of eNOS occurs in apoE ko atherosclerosis but eNOS mediated superoxide production does not outweigh the protective effects of eNOS mediated nitric oxide production. We show that although nNOS is not a major contributor of the vascular nitric oxide formation, it prevents atherosclerosis development. Acute inhibition of nNOS showed a significant reduction of superoxide formation suggesting that nNOS is uncoupled. The exact mechanism of action of nNOS in atheroprotection is yet to be elucidated. Genetic deletion of iNOS reduced NADPH oxidase activity. Thus, iNOS has both direct and indirect proatherosclerotic effects, as it directly generates both nitric oxide and superoxide simultaneously resulting in peroxynitrite formation and indirectly modulates NADPH oxidase activity. We hypothesize that eNOS is coupled in the disease free regions of the vessel and contributes to nitric oxide generation whereas in the diseased region of the vessel it is uncoupled to produce superoxide (Figure 16). nNOS expressed in the smooth muscle cells of the plaque contributes to the local superoxide generation. iNOS expressed in smooth muscle cells and leukocytes of the plaque generates superoxide and nitric oxide simultaneously to produce the strong oxidant peroxynitrite.}, subject = {atherosclerosis}, language = {en} } @phdthesis{Govindaraj2009, author = {Govindaraj, Vijayakumar}, title = {Improved Cardiac Glucose Uptake: A Potential Mechanism for Estrogens to Prevent the Development of Cardiac Hypertrophy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-35911}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {The incidence of cardiovascular diseases including cardiac hypertrophy and failure in pre-menopausal women is lower compared to age-matched men but the risk of heart disease increases substantially after the onset of menopause. It has been postulated that female sex hormones play an important role in cardiovascular health in pre-menopausal women. In animal studies including spontaneously hypertensive (SHR) rats, the development of cardiac hypertrophy is attenuated by 17\&\#946;-estradiol treatment. Cardiac energy metabolism is crucial for normal function of the heart. In cardiac hypertrophy and heart failure, the myocardium undergoes a metabolic shift from fatty acid as primary cardiac energy source to glucose, which re-introduces the fetal type of metabolism that representing the glucose as a major source of energy. Many studies have reported that the disruption of the balance between glucose and fatty acid metabolism plays an important role in cardiac pathologies including hypertrophy, heart failure, diabetes, dilative cardiomyopathy and myocardial infarction. Glucose enters cardiomyocytes via GLUT1 and GLUT4 glucose transporters and GLUT4 is the major glucose transporter which is insulin-dependent. Cardiac-selective GLUT4 deficiency leads to cardiac hypertrophy. This shows that the decrease in cardiac glucose uptake may play a direct role in the pathogenesis of cardiac hypertrophy. Estrogens modulate glucose homeostasis in the liver and the skeletal muscle. But it is not known whether estrogens affect also cardiac glucose uptake which could provide another mechanism to explain the prevention of cardiac hypertrophy by female sex hormones. In the present study, SHR Rats were ovariectomized (OVX), not ovariectomized (sham) or ovariectomized and treated with subcutaneous 17\&\#946;-estradiol. After 6 weeks of treatment, body weight, the serum levels of estrogen, insulin, intra-peritoneal glucose tolerance test (IP-GTT), myocardial glucose uptake by FDG-PET (2-(18F)-fluoro-deoxyglucose (18FDG) and Positron Emission Tomography), cardiac glucose transporter expression and localization and cardiac hexokinase activity were analyzed. As results of this study, PET analysis of female SHR revealed decreased cardiac glucose uptake in OVX animals compared to intact that was normalized by estrogen supplementation. Interestingly, there was no change in global glucose tolerance among the treatment groups. Serum insulin levels and cardiac hexokinase activity were elevated by E2 substitution. The protein content of cardiac glucose transporters GLUT-4 and GLUT-1, and their translocation as determined by fractionation studies and immuno-staining did not show any significant change by ovariectomy and estrogen replacement. Also levels of insulin receptor substrate-1 (IRS-1) and its tyrosine phosphorylation, which is required for activation and translocation of GLUT4, was un-affected in all groups of SHR. Cardiac gene expression analysis in SHR heart showed that ei4Ebp1 and Frap1 genes which are involved in the mTOR signaling pathway, were differentially expressed upon estrogen treatment. These genes are known to be activated in presence of glucose in the heart. As a conclusion of this study, reduced myocardial FDG uptake in ovariectomized spontaneously hypertensive rat is normalized by 17\&\#946;-estradiol treatment. Increased myocardial hexokinase appears as a potential mechanism to explain increased myocardial glucose uptake by 17\&\#946;-estradiol. Increased cardiac glucose uptake in response to 17\&\#946;-estradiol in ovariectomized SHR may provide a novel mechanism to explain the reduction of cardiac hypertrophy in E2 treated SHR. Therefore, 17\&\#946;-estradiol improves cardiac glucose utilization in ovariectomized SHR which may give rise to possible mechanism for its protective effects against cardiac hypertrophy.}, subject = {estrogen}, language = {en} } @phdthesis{Fiedler2010, author = {Fiedler, Jan}, title = {Endothelial microRNA-24 contributes to capillary density in the infarcted heart}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-49809}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {Cardiovascular disease is the most common mortality risk in the industrialized world. Myocardial infarction (MI) results in the irreversible loss of cardiac muscle, triggering pathophysiological remodelling of the ventricle and development of heart failure. Insufficient myocardial capillary density within the surviving myocardium after MI has been identified as a critical event in this process, although the underlying molecular signalling pathways of cardiac angiogenesis are mechanistically not well understood. The discovery of microRNAs (miRNAs, miRs), small non-coding RNAs with 19-25 nucleotides in length, has introduced a new level of the regulation of cardiac signalling pathways. MiRNAs regulate gene expression post-transcriptionally by binding to their complementary target messenger RNAs (mRNAs) and represent promising therapeutic targets for gene therapy. Here, it is shown that cardiac miR-24 is primarily expressed in cardiac endothelial cells and upregulated following MI in mice and hypoxic conditions in vitro. Enhanced miR-24 expression induces endothelial cell apoptosis and impairs endothelial capillary network formation. These effects on endothelial cell biology are at least in part mediated through targeting of transcription factor GATA2, histone deacetylase H2A.X, p21-activated kinase PAK4 and Ras p21 protein activator RASA1. Mechanistically, target repression abolishes respective and secondary downstream signalling cascades. Here it is shown that endothelial GATA2 is an important mediator of cell cycle, apoptosis and angiogenesis at least in part by regulation of cytoprotective heme oxygenase 1 (HMOX1). Moreover, additional control of endothelial apoptosis is achieved by the direct miR-24 target PAK4. Its kinase function is essential for anti-apoptotic Bad phosphorylation in endothelial cells. In a mouse model of MI, blocking of endothelial miR-24 by systemic administration of a specific antagonist (antagomir) enhances capillary density in the infarcted heart and preserves cardiac function. The current findings indicate miR-24 to act as a critical regulator of endothelial cell apoptosis and angiogenesis. Modulation of miR-24 may be potentially a suitable strategy for therapeutic intervention in the setting of ischemic heart diseases.}, subject = {Herzinfarkt}, language = {en} } @article{BauerNadler2010, author = {Bauer, Wolfgang R. and Nadler, Walter}, title = {Thermodynamics of Competitive Molecular Channel Transport: Application to Artificial Nuclear Pores}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68484}, year = {2010}, abstract = {In an analytical model channel transport is analyzed as a function of key parameters, determining efficiency and selectivity of particle transport in a competitive molecular environment. These key parameters are the concentration of particles, solvent-channel exchange dynamics, as well as particle-in-channel- and interparticle interaction. These parameters are explicitly related to translocation dynamics and channel occupation probability. Slowing down the exchange dynamics at the channel ends, or elevating the particle concentration reduces the in-channel binding strength necessary to maintain maximum transport. Optimized in-channel interaction may even shift from binding to repulsion. A simple equation gives the interrelation of access dynamics and concentration at this transition point. The model is readily transferred to competitive transport of different species, each of them having their individual in-channel affinity. Combinations of channel affinities are determined which differentially favor selectivity of certain species on the cost of others. Selectivity for a species increases if its in-channel binding enhances the species' translocation probablity when compared to that of the other species. Selectivity increases particularly for a wide binding site, long channels, and fast access dynamics. Recent experiments on competitive transport of in-channel binding and inert molecules through artificial nuclear pores serve as a paradigm for our model. It explains qualitatively and quantitatively how binding molecules are favored for transport at the cost of the transport of inert molecules.}, subject = {Thermodynamik}, language = {en} } @phdthesis{Burkard2010, author = {Burkard, Natalie}, title = {Signal{\"u}bertragungswege und Pr{\"a}ventionsm{\"o}glichkeiten der kardialen Hypertrophie : conditional overexpression of neuronal nitric oxide synthase is cardioprotective in ischemia-reperfusion}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-51832}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {Zusammenfassung: Wie fr{\"u}her schon gezeigt, wird der L-Typ Ca2+-Kanal durch eine induzierbare, myokardspezifische {\"U}berexpression der neuronalen Stickstoffmonoxidsynthase (nNOS) inhibiert. Gleichzeitig bewirkt diese {\"U}berexpression eine verminderte kardiale Kontraktilit{\"a}t1 (Burkard N. et al. (2007). Circ Res 100, 32-44). nNOS interagiert mit vielen verschiedenen Kompartimenten und Kan{\"a}len innerhalb der Zelle. In dieser Arbeit wurde gezeigt, dass eine nNOS {\"U}berexpression nach Isch{\"a}mie-Reperfusion kardioprotektiv wirkt. Dieses wird durch eine Inhibition der Mitochondrienfunktion und durch eine Verminderung der reaktiven Sauerstoffspezies (ROS) erm{\"o}glicht. In einer fr{\"u}heren Arbeit wurde der Effekt der induzierbaren und myokardspezifischen {\"U}berexpression von nNOS unter physiologischen Bedingungen am transgenen Tiermodell untersucht. Diese Arbeit besch{\"a}ftigt sich nun mit der {\"U}berexpression von nNOS unter pathophysiologischen (Isch{\"a}mie-Reperfusion) Bedingungen. Ein Isch{\"a}mie-Reperfusions-Schaden bewirkt bei Wildtyp-M{\"a}usen, sowie bei transgener nNOS {\"U}berexpression eine Anreicherung von nNOS in den Mitochondrien. Elektronenmikroskopische Aufnahmen von Mausmyokard haben gezeigt, dass bei {\"U}berexpression nNOS zus{\"a}tzlich in den Mitochondrien lokalisiert ist. Diese Translokation von nNOS in die Mitochondrien ist abh{\"a}ngig von HSP90. Isch{\"a}mie- Reperfusionsexperimente an isolierten M{\"a}useherzen zeigten einen kardioprotektiven Effekt der nNOS {\"U}berexpression (30min post ischemia, LVDP 27.0±2.5mmHg vs. 45.2±1.9mmHg, n=12, p<0.05). Dieser positive Effekt konnte bei der Bestimmung der Infarktgr{\"o}ße best{\"a}tigt werden. nNOS {\"u}berexprimierende M{\"a}use hatten eine kleinere Infarktgr{\"o}ße nach Isch{\"a}mie-Reperfusion (36.6±8.4 relative \% vs. 61.1±2.9 relative \%, n=8, p<0.05). Die {\"U}berexpression von nNOS bewirkte ebenfalls einen signifikanten Anstieg des mitochondrialen Nitrit-Levels, begleitet von einer Verminderung der Cytochrom C Oxidase Aktivit{\"a}t (72.0±8.9units/ml in nNOS overexpressing mice vs. 113.2±17.1units/ml in non-induced mice, n=12, p<0.01), was zu einer Hemmung der Mitochondrienfunktion f{\"u}hrt. Dementsprechend war der Sauerstoffverbrauch (gemessen an isolierten Herzmuskelstreifen) schon unter basalen Bedingungen beinNOS {\"U}berexpression vermindert (0.016±0.0015 vs. 0.024±0.006ml[O2] x mm-3 x min-1, n=13, p<0.05). Außerdem war die ROS Konzentration in Herzen von nNOS {\"u}berexprimierenden M{\"a}usen signifikant vermindert (6.14±0.685 vs. 14.53±1.7μM, n=8, p<0.01). Die Zugabe von verschiedenen Inhibitoren, Western Blot- und Aktivit{\"a}tsuntersuchungen zeigten schließlich, dass diese niedrigere ROS Konzentration durch eine verminderte Xanthin Oxidoreduktase Aktivit{\"a}t hervorgerufen wurde. Zusammenfassend hat diese Arbeit gezeigt, dass eine induzierbare und myokardspezifische {\"U}berexpression von nNOS unter pathophysiologischen Bedingungen (Isch{\"a}mie-Reperfusion) kardioprotektiv wirkt. Zus{\"a}tzlich zu der Verminderung des myokardialen Ca2+-{\"U}berschusses nach Reperfusion k{\"o}nnte dieser protektive Effekt durch eine Hemmung der Mitochondrienfunktion bedingt sein, schließlich wird der Sauerstoffverbrauch schon unter basalen Bedingungen reduziert}, subject = {Herzhypertrophie}, language = {en} } @article{JohanssenHahnerSaegeretal.2010, author = {Johanssen, Sarah and Hahner, Stefanie and Saeger, Wolfgang and Quinkler, Marcus and Beuschlein, Felix and Dralle, Henning and Haaf, Michaela and Kroiss, Matthias and Jurowich, Christian and Langer, Peter and Oelkers, Wolfgang and Spahn, Martin and Willenberg, Holger S. and Maeder, Uwe and Allolio, Bruno and Fassnacht, Martin}, title = {Deficits in the Management of Patients With Adrenocortical Carcinoma in Germany}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85897}, year = {2010}, abstract = {Background: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. Methods: Data from the German ACC registry were analyzed with regard to the patients' preoperative diagnostic evaluation, histopathological reporting, and clinical followup. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). Results: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21\% of them underwent no hormonal evaluation before surgery, and 59\% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48\% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13\% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11\% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. Conclusion: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers.}, language = {en} } @phdthesis{Kehlenbrink2010, author = {Kehlenbrink, Sylvia}, title = {Inhibiting Gluconeogenesis (GNG) Prevents the Effects of Free Fatty Acids (FFA) on Hepatic Glucose Effectiveness (GE)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-48389}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {Free fatty acids (FFA) modulate the effectiveness of glucose to suppress endogenous glucose production (EGP), and increased FFA levels contribute importantly to the loss of glucose effectiveness in type 2 diabetes mellitus (T2DM). Elevating FFA levels in nondiabetic (ND) subjects for at least 6h both increases gluconeogenesis (GNG) and impairs glucose effectiveness. Therefore, we wished to define the extent to which an increase in GNG is responsible for the loss of glucose effectiveness and whether EGP can be inhibited in the presence of elevated plasma FFA by inhibiting GNG with ethanol. To determine the effect of inhibiting GNG on glucose effectiveness, EGP ([3-3H]-glucose) was measured during three separate 7h normoglycemic/hyperglycemic pancreatic clamp studies (somatostatin; basal glucagon/GH/insulin replacement) in n=7 ND subjects (1F/6M; age=45±5 yr; BMI=27.6±3.0 kg/m2). Following an initial 210 min interval of euglycemia (5 mmol/l), blood glucose levels were raised to hyperglycemic levels (10 mmol/l) from t=210-420 min. The first pancreatic clamp study was a baseline study with saline infusions (Lip-/Et-). Lipid emulsion (Liposyn 20\%) was infused throughout the second and third study types (Lip+ and Lip+/Et+) to increase FFA to T2DM levels (~ 500 mmol/l). In addition to Liposyn, ethanol (Et) was infused during hyperglycemia in the third study type (Lip+/Et+), using a pharmacokinetic algorithm to attain GNG-inhibiting ethanol levels of 80 mg/dl within 20 min. Under baseline conditions, hyperglycemia suppressed EGP by 61\%. After raising plasma FFA to T2DM levels, suppression of EGP by hyperglycemia was impaired in Lip+ (34\% decrease). During the Lip+/Et+ co-infusion studies the infusion of ethanol enhanced suppression of EGP by hyperglycemia (65.8\% decrease, P=0.004 vs. Lip+) and thus restored glucose effectiveness (P=0.6 vs. Lip-/Et-). Thus, our results confirm the striking effects of elevated plasma FFA to impair glucose effectiveness and suggest that increased GNG contributes importantly to this loss of regulation. Inhibiting GNG could be an effective means of lowering EGP and improving glucose effectiveness in T2DM.}, subject = {Gluconeogenese}, language = {en} } @article{ArltBiehlTayloretal.2011, author = {Arlt, Wiebke and Biehl, Michael and Taylor, Angela E. and Hahner, Stefanie and Lib{\´e}, Rossella and Hughes, Beverly A. and Schneider, Petra and Smith, David J. and Stiekema, Han and Krone, Nils and Porfiri, Emilio and Opocher, Giuseppe and Bertherat, Jer{\^o}me and Mantero, Franco and Allolio, Bruno and Terzolo, Massimo and Nightingale, Peter and Shackleton, Cedric H. L. and Bertagna, Xavier and Fassnacht, Martin and Stewart, Paul M.}, title = {Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors}, series = {The Journal of Clinical Endocrinology \& Metabolism}, volume = {96}, journal = {The Journal of Clinical Endocrinology \& Metabolism}, number = {12}, doi = {10.1210/jc.2011-1565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154682}, pages = {3775 -- 3784}, year = {2011}, abstract = {Context: Adrenal tumors have a prevalence of around 2\% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2-11\% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values. Objective: Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy. Design: Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19-84 yr) and 45 ACC patients (20-80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26-201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids. Results: Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90\% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88\% (area under the curve = 0.96) when using only the nine most differentiating markers. Conclusions: Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas.}, language = {en} } @article{AsciertoWorschechYuetal.2011, author = {Ascierto, Maria Libera and Worschech, Andrea and Yu, Zhiya and Adams, Sharon and Reinboth, Jennifer and Chen, Nanhai G and Pos, Zoltan and Roychoudhuri, Rahul and Di Pasquale, Giovanni and Bedognetti, Davide and Uccellini, Lorenzo and Rossano, Fabio and Ascierto, Paolo A and Stroncek, David F and Restifo, Nicholas P and Wang, Ena and Szalay, Aladar A and Marincola, Francesco M}, title = {Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68}, series = {BMC Cancer}, volume = {11}, journal = {BMC Cancer}, number = {451}, doi = {10.1186/1471-2407-11-451}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141503}, pages = {1-14}, year = {2011}, abstract = {Background: Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo. Methods: In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection. Results: We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection. Conclusions: Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection.}, language = {en} } @article{FassnachtJohanssenAllolio2011, author = {Fassnacht, Martin and Johanssen, Sarah and Allolio, Bruno}, title = {Statements Cannot Be Substantiated : In Reply}, series = {Deutsches {\"A}rzteblatt International}, volume = {108}, journal = {Deutsches {\"A}rzteblatt International}, number = {19}, doi = {10.3238/arztebl.2011.0339b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142597}, pages = {339-340}, year = {2011}, abstract = {No abstract available.}, language = {en} } @article{SackWendeNaegeleetal.2011, author = {Sack, Stefan and Wende, Christian Michael and N{\"a}gele, Herbert and Katz, Amos and Bauer, Wolfgang Rudolf and Barr, Craig Scott and Malinowski, Klaus and Schwacke, Harald and Leyva, Francisco and Proff, Jochen and Berdyshev, Sergey and Paul, Vincent}, title = {Potential value of automated daily screening of cardiac resynchronization therapy defibrillator diagnostics for prediction of major cardiovascular events: results from Home-CARE (Home Monitoring in Cardiac Resynchronization Therapy) study}, series = {European Journal of Heart Failure}, volume = {13}, journal = {European Journal of Heart Failure}, number = {9}, doi = {10.1093/eurjhf/hfr089}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141709}, pages = {1019-1027}, year = {2011}, abstract = {Aim To investigate whether diagnostic data from implanted cardiac resynchronization therapy defibrillators (CRT-Ds) retrieved automatically at 24 h intervals via a Home Monitoring function can enable dynamic prediction of cardiovascular hospitalization and death. Methods and results Three hundred and seventy-seven heart failure patients received CRT-Ds with Home Monitoring option. Data on all deaths and hospitalizations due to cardiovascular reasons and Home Monitoring data were collected prospectively during 1-year follow-up to develop a predictive algorithm with a predefined specificity of 99.5\%. Seven parameters were included in the algorithm: mean heart rate over 24 h, heart rate at rest, patient activity, frequency of ventricular extrasystoles, atrial-atrial intervals (heart rate variability), right ventricular pacing impedance, and painless shock impedance. The algorithm was developed using a 25-day monitoring window ending 3 days before hospitalization or death. While the retrospective sensitivities of the individual parameters ranged from 23.6 to 50.0\%, the combination of all parameters was 65.4\% sensitive in detecting cardiovascular hospitalizations and deaths with 99.5\% specificity (corresponding to 1.83 false-positive detections per patient-year of follow-up). The estimated relative risk of an event was 7.15-fold higher after a positive predictor finding than after a negative predictor finding. Conclusion We developed an automated algorithm for dynamic prediction of cardiovascular events in patients treated with CRT-D devices capable of daily transmission of their diagnostic data via Home Monitoring. This tool may increase patients' quality of life and reduce morbidity, mortality, and health economic burden, it now warrants prospective studies.}, language = {en} } @article{WilliamsMachannKuehleretal.2011, author = {Williams, Tatjana and Machann, Wolfram and K{\"u}hler, Leif and Hamm, Henning and M{\"u}ller-H{\"o}cker, Josef and Zimmer, Michael and Ertl, Georg and Ritter, Oliver and Beer, Meinrad and Sch{\"o}nberger, Jost}, title = {Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma}, series = {Clinical Research in Cardiology}, volume = {100}, journal = {Clinical Research in Cardiology}, number = {12}, doi = {10.1007/s00392-011-0345-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141198}, pages = {1087-1093}, year = {2011}, abstract = {Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death.}, language = {en} } @article{AllignolSchumacherWanneretal.2011, author = {Allignol, Arthur and Schumacher, Martin and Wanner, Christoph and Drechsler, Christiane and Beyersmann, Jan}, title = {Understanding competing risks: a simulation point of view}, series = {BMC Medical Research Methodology}, volume = {11}, journal = {BMC Medical Research Methodology}, number = {86}, doi = {10.1186/1471-2288-11-86}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142811}, pages = {1-13}, year = {2011}, abstract = {Background: Competing risks methodology allows for an event-specific analysis of the single components of composite time-to-event endpoints. A key feature of competing risks is that there are as many hazards as there are competing risks. This is not always well accounted for in the applied literature. Methods: We advocate a simulation point of view for understanding competing risks. The hazards are envisaged as momentary event forces. They jointly determine the event time. Their relative magnitude determines the event type. 'Empirical simulations' using data from a recent study on cardiovascular events in diabetes patients illustrate subsequent interpretation. The method avoids concerns on identifiability and plausibility known from the latent failure time approach. Results: The 'empirical simulations' served as a proof of concept. Additionally manipulating baseline hazards and treatment effects illustrated both scenarios that require greater care for interpretation and how the simulation point of view aids the interpretation. The simulation algorithm applied to real data also provides for a general tool for study planning. Conclusions: There are as many hazards as there are competing risks. All of them should be analysed. This includes estimation of baseline hazards. Study planning must equally account for these aspects.}, language = {en} } @article{EdelmannWachterDuengenetal.2011, author = {Edelmann, Frank and Wachter, Rolf and D{\"u}ngen, Hans-Dirk and St{\"o}rk, Stefan and Richter, Annette and Stahrenberg, Raoul and Neumann, Till and L{\"u}ers, Claus and Angermann, Christiane E. and Mehrhof, Felix and Gelbrich, G{\"o}tz and Pieske, Burkert}, title = {Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline}, series = {Cardiovascular Diabetology}, volume = {10}, journal = {Cardiovascular Diabetology}, number = {15}, doi = {10.1186/1475-2840-10-15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140397}, pages = {1-8}, year = {2011}, abstract = {Background: To assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function. Methods: 3304 patients with heart failure from 9 different studies were included (mean age 63 +/- 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (>= 50\%) and 994 patients in the whole cohort suffered from diabetes. Results: The majority (>90\%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function. Conclusions: Diabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function.}, language = {en} } @article{DrechslerMeinitzerPilzetal.2011, author = {Drechsler, Christiane and Meinitzer, Andreas and Pilz, Stefan and Krane, Vera and Tomaschitz, Andreas and Ritz, Eberhard and M{\"a}rz, Winfried and Wanner, Christoph}, title = {Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients}, series = {European Journal of Heart Failure}, volume = {13}, journal = {European Journal of Heart Failure}, number = {8}, doi = {10.1093/eurjhf/hfr056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140495}, pages = {852-859}, year = {2011}, abstract = {Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95\% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95\% CI 2.0-4.9), attenuating slightly in multivariate models (HR 2.4; 95\% CI 1.5-3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.}, language = {en} } @article{SbieraDexneitReichardtetal.2011, author = {Sbiera, Silviu and Dexneit, Thomas and Reichardt, Sybille D. and Michel, Kai D. and van den Brandt, Jens and Schmull, Sebastian and Kraus, Luitgard and Beyer, Melanie and Mlynski, Robert and Wortmann, Sebastian and Allolio, Bruno and Reichardt, Holger M. and Fassnacht, Martin}, title = {Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells \(In\) \(Vivo\)}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0024345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140822}, pages = {e24345}, year = {2011}, abstract = {Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5\% vs 3.4 +/- 1.5\%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3\%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0\%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5\%; * p < 0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.}, language = {en} } @article{FassnachtSbieraDexneitetal.2011, author = {Fassnacht, Martin and Sbiera, Silviu and Dexneit, Thomas and Reichardt, Sybille D. and Michel, Kai D. and van den Brandt, Jens and Schmull, Sebastian and Kraus, Luitgard and Beyer, Melanie and Mlynski, Robert and Wortmann, Sebastian and Allolio, Bruno and Reichardt, Holger M.}, title = {Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells In Vivo}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74749}, year = {2011}, abstract = {Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and na{\i}¨ve mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.861.86104 cells/ml vs. 336116104 in control mice) and spleen (dexamethasone: 2.861.96105/spleen vs. 956226105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.061.5\% vs 3.461.5\%*; AITR+: 0.660.4 vs 0.560.3\%, CD127low: 4.061.3 vs 5.063.0\%* and CTLA4+: 13.8611.5 vs 15.6612.5\%; * p,0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers.}, subject = {Medizin}, language = {en} } @phdthesis{Liu2011, author = {Liu, Dan}, title = {Regional Myocardial Deformation in Adult Patients with Isolated Left Ventricular Non-compaction Cardiomyopathy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-55838}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Isolated left ventricular non-compaction cardiomyopathy (LVNC) is a congenital myocardial disease characterized by excessive and prominent trabeculations in the left ventricle with deep intertrabecular recesses. Trabeculation is, however, a non specific finding which is present not only in LVNC but also in other cardiomyopathies like dilated cardiomyopathy (DCM) and even in healthy controls, therefore, differential diagnosis keeps puzzling clinicians. Therefore the present study aimed to comprehensively explore regional myocardial deformation properties in adult patients with isolated LVNC using strain and strain rate imaging derived from tissue Doppler imaging and 2D speckle tracking. It was proposed that the knowledge of deformation properties in LVNC would help to differentiate patients with LVNC and DCM. A total of 14 patients with LVNC, 15 patients with DCM, and 15 healthy controls were included in this study. The groups were matched for age and gender. Standard 2D echocardiography was performed in all subjects, and tissue Doppler imaging (TDI) of all ventricular walls was acquired using parasternal long axis, apical 4-chamber, 2-chamber, and apical long axis views. Deformation imaging data derived from both TDI and grey scale images were analyzed. Clinical and standard echocardiographic findings in patients with LVNC and DCM were similar. In patients with LVNC, hypertrabeculation was mostly located in the apical and mid segments of the left ventricle and strikingly more than in patients with DCM. The extent of non-compaction was poorly related to global left ventricular systolic function (LVEF) as well as regional myocardial function assessed by strain rate imaging. Regional myocardial systolic deformation in patients with LVNC was significantly impaired in the left and right ventricles in both longitudinal and radial direction. There was a striking difference on longitudinal myocardial systolic function between LVNC and DCM patients, i.e., an increasing strain and strain rate gradient from apex to base in patients with LVNC, whereas patients with DCM displayed a homogeneously decreased strain and strain rate in all segments. Results derived from 2D speckle tracking method were consistent with those from TDI method. Analysis of myocardial mechanical asynchrony revealed a lack of myocardial contraction synchrony in the LVNC and DCM patients. The time to systolic peak velocity was obviously delayed in these two patient groups. However, the mechanical asynchrony features were similar in patients with LVNC and DCM and could not serve for differential diagnosis. In conclusion, LVNC and DCM are both cardiomyopathies presenting reduced regional myocardial function and mechanical asynchrony. Nevertheless differential diagnosis can be made by analysis of hypertrabeculation as well as analysis of regional myocardial deformation pattern.}, subject = {Ultraschallkardiographie}, language = {en} } @article{KasangKalluvyaMajingeetal.2011, author = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mlewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt}, title = {HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Na{\"i}ve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0023091}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137988}, pages = {e23091}, year = {2011}, abstract = {Background The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-na{\"i}ve population. Methods and Findings HIVDR was determined in 88 sequentially enrolled ART-na{\"i}ve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions ART-na{\"i}ve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-na{\"i}ve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-na{\"i}ve HIV-infected population.}, language = {en} } @article{KistlerSiwyFranketal.2011, author = {Kistler, Andreas D. and Siwy, Justyna and Frank, Breunig and Jeevaratnam, Praveen and Scherl, Alexander and Mullen, William and Warnock, David G. and Wanner, Christoph and Hughes, Derralynn A. and Mischak, Harald and W{\"u}thrich, Rudolf P. and Serra, Andreas L.}, title = {A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0020534}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133526}, pages = {e20534}, year = {2011}, abstract = {Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2\% sensitivity and 97.8\% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.}, language = {en} } @article{EdelmannStahrenbergGelbrichetal.2011, author = {Edelmann, Frank and Stahrenberg, Raoul and Gelbrich, G{\"o}tz and Durstewitz, Kathleen and Angermann, Christiane E. and D{\"u}ngen, Hans-Dirk and Scheffold, Thomas and Zugck, Christian and Maisch, Bernhard and Regitz-Zagrosek, Vera and Hasenfuß, Gerd and Pieske, Burkert M. and Wachter, Rolf}, title = {Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction}, series = {Clinical Research in Cardiology}, volume = {100}, journal = {Clinical Research in Cardiology}, number = {9}, doi = {10.1007/s00392-011-0305-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134354}, pages = {755-764}, year = {2011}, abstract = {Background Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far. Methods and results The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p < 0.001) and higher SF-36 PF score (54.4 ± 28.3 vs. 54.4 ± 27.7, p < 0.001). All comorbidities were significantly (p < 0.05) more frequent in HFrEF, except hypertension and obesity, which were more frequent in HFpEF (p < 0.001). Adjusting for age and gender, COPD, anemia, hyperuricemia, atrial fibrillation, renal dysfunction, cerebrovascular disease and diabetes had a similar (p for interaction > 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r 2) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10\% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF. Conclusion The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF.}, language = {en} } @article{CarstenAGorskiLietal.2011, author = {Carsten A., B{\"o}ger and Gorski, Mathias and Li, Man and Hoffmann, Michael M. and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O'Seaghdha, Conall M. and Kutalik, Zolt{\´a}n and Wichmann, H.-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G. and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\´e} and Hofman, Albert and Beckmann, Jacques S. and Kr{\"a}mer, Bernhard K. and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I. and Heid, Iris M. and Fox, Caroline S. and Kao, W.H.}, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {9}, doi = {10.1371/journal.pgen.1002292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133758}, pages = {e1002292}, year = {2011}, abstract = {Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.}, language = {en} } @article{GuederBrennerAngermannetal.2012, author = {G{\"u}der, G{\"u}lmisal and Brenner, Susanne and Angermann, Christiane E. and Ertl, Georg and Held, Matthias and Sachs, Alfred P. and Lammers, Jan Willem and Zanen, Peter and Hoes, Arno W. and St{\"o}rk, Stefan and Rutten, Frans H.}, title = {"GOLD or lower limit of normal definition? a comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study"}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75193}, year = {2012}, abstract = {Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28\%) patients, and the three LLNs misclassified 114 (46\%), 96 (39\%), and 98 (40\%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 \% predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50\% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.}, subject = {Medizin}, language = {en} } @article{ReiterRitterPrinceetal.2012, author = {Reiter, Theresa and Ritter, Oliver and Prince, Martin R. and Nordbeck, Peter and Wanner, Christoph and Nagel, Eike and Bauer, Wolfgang R.}, title = {Minimizing Risk of Nephrogenic systemic fibrosis in Cardiovascular Magnetic Resonance}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75068}, year = {2012}, abstract = {Nephrogenic Systemic Fibrosis is a rare condition appearing only in patients with severe renal impairment or failure and presents with dermal lesions and involvement of internal organs. Although many cases are mild, an estimated 5 \% have a progressive debilitating course. To date, there is no known effective treatment thus stressing the necessity of ample prevention measures. An association with the use of Gadolinium based contrast agents (GBCA) makes Nephrogenic Systemic Fibrosis a potential side effect of contrast enhanced magnetic resonance imaging and offers the opportunity for prevention by limiting use of gadolinium based contrast agents in renal failure patients. In itself toxic, Gadolinium is embedded into chelates that allow its safe use as a contrast agent. One NSF theory is that Gadolinium chelates distribute into the extracellular fluid compartment and set Gadolinium ions free, depending on multiple factors among which the duration of chelates exposure is directly related to the renal function. Major medical societies both in Europe and in North America have developed guidelines for the usage of GBCA. Since the establishment of these guidelines and the increased general awareness of this condition, the occurrence of NSF has been nearly eliminated. Giving an overview over the current knowledge of NSF pathobiochemistry, pathogenesis and treatment options this review focuses on the guidelines of the European Medicines Agency, the European Society of Urogenital Radiology, the FDA and the American College of Radiology from 2008 up to 2011 and the transfer of this knowledge into every day practice.}, subject = {CMR}, language = {en} } @article{ReiterRitterNordbecketal.2012, author = {Reiter, Theresa and Ritter, Oliver and Nordbeck, Peter and Beer, Meinrad and Bauer, Wolfgang Rudolf}, title = {MRI-guided ablation of wide complex tachycardia in a univentricular heart}, series = {World Journal of Cardiology}, volume = {4}, journal = {World Journal of Cardiology}, number = {8}, doi = {10.4330/wjc.v4.i8.260}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123165}, pages = {260-263}, year = {2012}, abstract = {Magnetic resonance imaging can be used for preprocedural assessment of complex anatomy for radiofrequency (RF) ablations, e.g., in a univentricular heart. This case report features the treatment of a young patient with a functionally univentricular heart who suffered from persistent sudden onset tachycardia with wide complexes that required RF ablation as treatment.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124052}, year = {2012}, abstract = {Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9\% (n = 2/106; 95\% confidence interval [CI] 0.23-6.65\%); no major bleeding. 1.9\% had moderate/severe clotting in the lines/bubble catcher and 2.8\% in the dialyser at week 8. 15.7 ± 14.3\% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95\%CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0\% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34\%) had at least one episode of minor bleeding. 4) 85.3\% of patients had any adverse event, 9.2\% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.}, language = {en} } @article{NordbeckBeerKoestleretal.2012, author = {Nordbeck, Peter and Beer, Meinrad and K{\"o}stler, Herbert and Ladd, Mark E. and Quick, Harald H. and Bauer, Wolfgang R. and Ritter, Oliver}, title = {Cardiac catheter ablation under real-time magnetic resonance guidance}, series = {European Heart Journal}, volume = {33}, journal = {European Heart Journal}, number = {15}, doi = {10.1093/eurheartj/ehs139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125638}, year = {2012}, abstract = {One of the main shortcomings of interventional electrophysiology (EP) is its inability to generate sufficient soft tissue contrast for intra-procedural visualization of the myocardium and the surrounding tissue, using conventional imaging techniques. Interventional cardiovascular magnetic resonance imaging (MRI) aims at bringing about significant improvements to the complex and decisive EP interventions far beyond the capabilities of currently available supportive imaging techniques used to surmount the drawbacks of fluoroscopy, as MRI not only allows of precise three-dimensional exposure of the cardiovascular morphology, but also proves to be a promising technique exclusively suitable for direct visualization of arrhythmogenic substrate and therapeutic effects. The major challenge posed by clinical …}, language = {en} } @article{WarnockOrtizMaueretal.2012, author = {Warnock, David G. and Ortiz, Alberto and Mauer, Michael and Linthorst, Gabor E. and Oliveira, Jo{\~a}o P. and Serra, Andreas L. and Mar{\´o}di, L{\´a}szl{\´o} and Mignani, Renzo and Vujkovac, Bojan and Beitner-Johnson, Dana and Lemay, Roberta and Cole, J. Alexander and Svarstad, Einar and Waldek, Stephen and Germain, Dominique P. and Wanner, Christoph}, title = {Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation}, series = {Nephrology Dialysis Transplantation}, volume = {27}, journal = {Nephrology Dialysis Transplantation}, number = {3}, organization = {Fabry Registry}, doi = {10.1093/ndt/gfr420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124697}, pages = {1042-1049}, year = {2012}, abstract = {Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95\% confidence interval (95\% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95\% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.}, language = {en} } @article{KirylukYifuSannaCherchietal.2012, author = {Kiryluk, Krzysztof and Yifu, Li and Sanna-Cherchi, Simone and Rohanizadegan, Mersedeh and Suzuki, Hitoshi and Eitner, Frank and Snyder, Holly J. and Choi, Murim and Hou, Ping and Scolari, Francesco and Izzi, Claudia and Gigante, Maddalena and Gesualdo, Loreto and Savoldi, Silvana and Amoroso, Antonio and Cusi, Daniele and Zamboli, Pasquale and Julian, Bruce A. and Novak, Jan and Wyatt, Robert J. and Mucha, Krzysztof and Perola, Markus and Kristiansson, Kati and Viktorin, Alexander and Magnusson, Patrik K. and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Stefansson, Kari and Boland, Anne and Metzger, Marie and Thibaudin, Lise and Wanner, Christoph and Jager, Kitty J. and Goto, Shin and Maixnerova, Dita and Karnib, Hussein H. and Nagy, Judit and Panzer, Ulf and Xie, Jingyuan and Chen, Nan and Tesar, Vladimir and Narita, Ichiei and Berthoux, Francois and Floege, J{\"u}rgen and Stengel, Benedicte and Zhang, Hong and Lifton, Richard P. and Gharavi, Ali G.}, title = {Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {6}, doi = {10.1371/journal.pgen.1002765}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130195}, pages = {e1002765}, year = {2012}, abstract = {IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5x10\(^{-32}\) 3x10\(^{-10}\), with heterogeneity detected only at the PSMB9/TAP1 locus (I\(^{-2}\) = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5x10\(^{-4}\)). A seven-SNP genetic risk score, which explained 4.7\% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3x10\(^{-128}\)). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.}, language = {en} } @article{BetzSchneiderKressetal.2012, author = {Betz, Boris and Schneider, Reinhard and Kress, Tobias and Schick, Martin Alexander and Wanner, Christoph and Sauvant, Christoph}, title = {Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury}, series = {PPAR Research}, volume = {2012}, journal = {PPAR Research}, number = {Article ID 219319}, doi = {10.1155/2012/219319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130872}, pages = {12}, year = {2012}, abstract = {Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60 min). Following 24 h of reperfusion, inulin-and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury.}, language = {en} } @article{PonnuswamySchroettleOstermeieretal.2012, author = {Ponnuswamy, Padmapriya and Schr{\"o}ttle, Angelika and Ostermeier, Eva and Gr{\"u}ner, Sabine and Huang, Paul L. and Ertl, Georg and Hoffmann, Ulrich and Nieswandt, Bernhard and Kuhlencordt, Peter J.}, title = {eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0030193}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134866}, pages = {e30193}, year = {2012}, abstract = {Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial-(L/E) and platelet/endothelial-(P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme. Principal Findings: Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE\(^{-/-}\)/eNOS\(^{-/-}\)), while P/E-interactions did not differ, compared to apoE\(^{-/-}\). eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE\(^{-/-}\) vessels. Conclusion: Overt plaque formation, increased vascular inflammation and L/E-interactions are associated with significant reduction of superoxide production in apoE\(^{-/-}\)/eNOS\(^{-/-}\) vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE\(^{-/-}\) atherosclerosis but does not negate the enzyme's strong protective effects.}, language = {en} } @article{ReiterGenslerRitteretal.2012, author = {Reiter, Theresa and Gensler, Daniel and Ritter, Oliver and Weiss, Ingo and Geistert, Wolfgang and Kaufmann, Ralf and Hoffmeister, Sabine and Friedrich, Michael T. and Wintzheimer, Stefan and D{\"u}ring, Markus and Nordbeck, Peter and Jakob, Peter M. and Ladd, Mark E. and Quick, Harald H. and Bauer, Wolfgang R.}, title = {Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {14}, journal = {Journal of Cardiovascular Magnetic Resonance}, number = {12}, doi = {10.1186/1532-429X-14-12}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134927}, year = {2012}, abstract = {Background: One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating. Methods: A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip. Results: A maximum temperature rise of 22.4 degrees C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2 degrees C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8 degrees C. Conclusion: Up to a maximum of 22.4 degrees C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner.}, language = {en} } @article{RonchiLeichSbieraetal.2012, author = {Ronchi, Cristina L. and Leich, Ellen and Sbiera, Silviu and Weismann, Dirk and Rosenwald, Andreas and Allolio, Bruno and Fassnacht, Martin}, title = {Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways}, series = {Neoplasia}, volume = {14}, journal = {Neoplasia}, number = {3}, doi = {10.1593/neo.111758}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134953}, pages = {206}, year = {2012}, abstract = {The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89\% were less than 100 kb, and 28\% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>= 20\% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134845}, year = {2012}, abstract = {Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9\% (n = 2/106; 95\% confidence interval [CI] 0.23-6.65\%); no major bleeding. 1.9\% had moderate/severe clotting in the lines/bubble catcher and 2.8\% in the dialyser at week 8.15.7 +/- 14.3\% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95\% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0\% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34\%) had at least one episode of minor bleeding. 4) 85.3\% of patients had any adverse event, 9.2\% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.}, language = {en} } @article{RahimiBhalaKamphuisenetal.2012, author = {Rahimi, Kazem and Bhala, Neeraj and Kamphuisen, Pieter and Emberson, Jonathan and Biere-Rafi, Sara and Krane, Vera and Robertson, Michele and Wikstrand, John and McMurray, John}, title = {Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials}, series = {PLoS Medicine}, volume = {9}, journal = {PLoS Medicine}, number = {9}, doi = {10.1371/journal.pmed.1001310}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134279}, pages = {e1001310}, year = {2012}, abstract = {Background: It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins. Methods and Findings: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9\%] statin versus 521 [1.0\%] control, odds ratio [OR] = 0.89, 95\% CI 0.78-1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95\% CI 0.72-1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95\% CI 0.76-1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9\%] versus 461 [1.0\%], OR = 0.93 [95\% CI 0.82-1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0\%] versus 202 [1.0\%], OR = 0.98, 95\% CI 0.80-1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Conclusions: The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out. Please see later in the article for the Editors' Summary.}, language = {en} } @article{deZeeuwAkizawaAgarwaletal.2013, author = {de Zeeuw, Dick and Akizawa, Tadao and Agarwal, Rajiv and Audhya, Paul and Bakris, George L. and Chin, Melanie and Krauth, Melissa and Lambers Heerspink, Hiddo J. and Meyer, Colin J. and McMurray, John J. and Parving, Hans-Henrik and Pergola, Pablo E. and Remuzzi, Giuseppe and Toto, Robert D. and Vaziri, Nosratola D. and Wanner, Christoph and Warnock, David G. and Wittes, Janet and Chertow, Glenn M.}, title = {Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)}, series = {American Journal of Nephrology}, volume = {37}, journal = {American Journal of Nephrology}, number = {3}, issn = {0250-8095}, doi = {10.1159/000346948}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196832}, pages = {212-222}, year = {2013}, abstract = {Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.}, language = {en} } @article{DoerhoeferLammertKraneetal.2013, author = {D{\"o}rh{\"o}fer, Lena and Lammert, Alexander and Krane, Vera and Gorski, Mathias and Banas, Bernhard and Wanner, Christoph and Kr{\"a}mer, Bernhard K. and Heid, Iris M. and B{\"o}ger, Carsten A.}, title = {Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2}, series = {BMC Medical Genetics}, volume = {14}, journal = {BMC Medical Genetics}, number = {25}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122040}, year = {2013}, abstract = {Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.}, language = {en} } @article{BrandenburgKramannKoosetal.2013, author = {Brandenburg, Vincent M. and Kramann, Rafael and Koos, Ralf and Krueger, Thilo and Schurgers, Leon and M{\"u}hlenbruch, Georg and H{\"u}bner, Sinah and Gladziwa, Ulrich and Drechler, Christiane and Ketteler, Markus}, title = {Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study}, series = {BMC Nephrology}, volume = {14}, journal = {BMC Nephrology}, number = {219}, issn = {1471-2369}, doi = {10.1186/1471-2369-14-219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122070}, year = {2013}, abstract = {Background: Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. Methods: We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 +/- 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR). Results: CAC (Agatston score > 100) and any AVC were present in 65\% and in 40\% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 +/- 0.81 vs 0.76 +/- 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 +/- 0.84 vs 1.35 +/- 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves. Conclusion: We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.}, language = {en} } @article{EiseleBlozikStoerketal.2013, author = {Eisele, Marion and Blozik, Eva and St{\"o}rk, Stefan and Tr{\"a}der, Jens-Martin and Herrmann-Lingen, Christoph and Scherer, Martin}, title = {Recognition of depression and anxiety and their association with quality of life, hospitalization and mortality in primary care patients with heart failure - study protocol of a longitudinal observation study}, series = {BMC Family Practice}, volume = {14}, journal = {BMC Family Practice}, number = {180}, issn = {1471-2296}, doi = {10.1186/1471-2296-14-180}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121881}, year = {2013}, abstract = {Background: International disease management guidelines recommend the regular assessment of depression and anxiety in heart failure patients. Currently there is little data on the effect of screening for depression and anxiety on the quality of life and the prognosis of heart failure (HF). We will investigate the association between the recognition of current depression/anxiety by the general practitioner (GP) and the quality of life and the patients' prognosis. Methods/Design: In this multicenter, prospective, observational study 3,950 patients with HF are recruited by general practices in Germany. The patients fill out questionnaires at baseline and 12-month follow-up. At baseline the GPs are interviewed regarding the somatic and psychological comorbidities of their patients. During the follow-up assessment, data on hospitalization and mortality are provided by the general practice. Based on baseline data, the patients are allocated into three observation groups: HF patients with depression and/or anxiety recognized by their GP (P+/+), those with depression and/or anxiety not recognized (P+/-) and patients without depression and/or anxiety (P-/-). We will perform multivariate regression models to investigate the influence of the recognition of depression and/or anxiety on quality of life at 12 month follow-up, as well as its influences on the prognosis (hospital admission, mortality). Discussion: We will display the frequency of GP-acknowledged depression and anxiety and the frequency of installed therapeutic strategies. We will also describe the frequency of depression and anxiety missed by the GP and the resulting treatment gap. Effects of correctly acknowledged and missed depression/anxiety on outcome, also in comparison to the outcome of subjects without depression/anxiety will be addressed. In case results suggest a treatment gap of depression/anxiety in patients with HF, the results of this study will provide methodological advice for the efficient planning of further interventional research.}, language = {en} } @article{WeidemannSanchezNinoPoliteietal.2013, author = {Weidemann, Frank and Sanchez-Nino, Maria D. and Politei, Juan and Oliveira, Jo{\~a}o-Paulo and Wanner, Christoph and Warnock, David G. and Oritz, Alberto}, title = {Fibrosis: a key feature of Fabry disease with potential therapeutic implications}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {116}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-116}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124773}, year = {2013}, abstract = {Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.}, language = {en} } @article{DrechslerRitzTomaschitzetal.2013, author = {Drechsler, Christiane and Ritz, Eberhard and Tomaschitz, Andreas and Pilz, Stefan and Sch{\"o}nfeld, Stephan and Blouin, Katja and Bidlingmaier, Martin and Hammer, Fabian and Krane, Vera and M{\"a}rz, Winfried and Allolio, Bruno and Fassnacht, Martin and Wanner, Christoph}, title = {Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, doi = {10.1093/eurheartj/ehs361}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132562}, pages = {578-585}, year = {2013}, abstract = {Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54\% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95\% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95\% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95\% CI: 1.01-2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.}, language = {en} } @article{BloemerPachelHofmannetal.2013, author = {Bl{\"o}mer, Nadja and Pachel, Christina and Hofmann, Urlich and Nordbeck, Peter and Bauer, Wolfgang and Mathes, Denise and Frey, Anna and Bayer, Barbara and Vogel, Benjamin and Ertl, Georg}, title = {5-Lipoxygenase facilitates healing after myocardial infarction}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {4}, doi = {10.1007/s00395-013-0367-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132602}, year = {2013}, abstract = {Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{-/-}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{-/-}\) bone marrow in 5-LOX\(^{-/-}\) animals), indicating that an altered function of 5-LOX\(^{-/-}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{-/-}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{-/-}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.}, language = {en} } @article{FrantzKlaiberBabaetal.2013, author = {Frantz, Stefan and Klaiber, Michael and Baba, Hideo A. and Oberwinkler, Heinz and V{\"o}lker, Katharina and Gaßner, Birgit and Bayer, Barbara and Abeßer, Marco and Schuh, Kai and Feil, Robert and Hofmann, Franz and Kuhn, Michaela}, title = {Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134693}, pages = {1233-1244}, year = {2013}, abstract = {Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI. Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.}, language = {en} } @article{HaringLengRobinsonetal.2013, author = {Haring, Bernhard and Leng, Xiaoyan and Robinson, Jennifer and Johnson, Karen C. and Jackson, Rebecca D. and Beyth, Rebecca and Wactawski-Wende, Jean and Wyler von Ballmoos, Moritz and Goveas, Joseph S. and Kuller, Lewis H. and Wassertheil-Smoller, Sylvia}, title = {Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study}, series = {Journal of the American Heart Association}, volume = {2}, journal = {Journal of the American Heart Association}, number = {e000369}, doi = {10.1161/JAHA.113.000369}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129487}, year = {2013}, abstract = {Background-—Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning. Methods and Results-—Prospective follow-up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self-report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini-mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow-up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95\% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95\% CI: 1.40, 3.15 or HR, 1.97; 95\% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95\% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity. Conclusions-—CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.}, language = {en} } @article{WeidemannNiemannStorketal.2013, author = {Weidemann, F. and Niemann, M. and Stork, S. and Breunig, F. and Beer, M. and Sommer, C. and Herrmann, S. and Ertl, G. and Wanner, C.}, title = {Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications}, series = {Journal of Internal Medicine}, volume = {247}, journal = {Journal of Internal Medicine}, number = {4}, doi = {10.1111/joim.12077}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132075}, pages = {331-4}, year = {2013}, abstract = {The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7\%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.}, language = {en} } @article{DrechslerSchmiedekeNiemannetal.2013, author = {Drechsler, Christiane and Schmiedeke, Benjamin and Niemann, Markus and Schmiedeke, Daniel and Kr{\"a}mer, Johannes and Turkin, Irina and Blouin, Katja and Emmert, Andrea and Pilz, Stefan and Obermayer-Pietsch, Barbara and Wiedemann, Frank and Breunig, Frank and Wanner, Christoph}, title = {Potential role of vitamin D deficiency on Fabry cardiomyopathy}, series = {Journal of Inherited Metabolic Disease}, volume = {37}, journal = {Journal of Inherited Metabolic Disease}, number = {2}, doi = {10.1007/s10545-013-9653-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132102}, pages = {289-295}, year = {2013}, abstract = {Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 \% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.}, language = {en} }