TY - THES A1 - Grue, Pernille T1 - The physiological role of the two isoforms of DNA topoisomerase II in human cells T1 - Die Physiologische Rolle der beiden Isoformen der DNS Topoisomerase II in humanen Zellen N2 - 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. N2 - Die exakt Funktion der zwei Isoformen der DNS Topoisomerase II, genannt Topoisomerase IIalpha und Topoisomerase IIbeta ist bisher unbekannt. Eine humanen Zelllinie hatte eine homozygote Deletion in der Nukleären Lokalisations Sequenz im Topoisomerase IIalpha Gen. In dieser Zelllinie wurde Topoisomerase IIalpha während der Interphase außerhalb des Kerns exprimiert. Während der Mitose diffundierte die gesamte Topoisomerase IIbeta trotz intranukleärem Mangel an IIalpha-Isoform vom Chromatin ab. Die Kondensation der Chromosomen und die Disjunktion mit der Hilfe von zytosolischen Topoisomerase IIalpha fand statt, die sich mit niedriger Affinität an mitotisches Chromatin bindet. Folglich kann eine zunehmende Rate von non-Disjunktion in diesen Zellen festgestellt werden. Daraus kann geschlossen werden, daß die hohe Affinität der Chromatin-Bindung von Topoisomerase IIalpha essentiell für die chromosomomale Kondensation und Disjunktion ist. Außerdem konnte Topoisomerase IIbeta nicht die Funktionen der IIalpha-Isoform übernehmen. Ein zentrosomales Protein wird von der humanen Topoisomerase IIalpha erkannt. Das Topoisomerase IIalpha-ähnliche Protein gleicht einer modifizierten Form von Topoisomerase IIalpha mit einer vermeintlichen Größe von 205 kDa im Vergleich zu 170 kDa. Die Expression der Topoisomerase IIalpha ist konstant in allen Phasen des Zellzyklus und es taucht in proliferierenden und in ruhende Zellen auf. Folglich könnte aktive Topoisomerase II von diesen Pool an aktiven Enzymen bei Anfang der Mitose freigesetzt werden, um die fehlende Enzymaktivität zu ersetzen. KW - DNS-Gyrase KW - DNS-Topoisomerasen KW - Physiologie KW - Topoisomerase II alpha KW - Mitose KW - Kondensation KW - non-Disjunktion KW - zentrosomales Protein KW - topoisomerase II alpha KW - mitosis KW - condensation KW - non-disjunction KW - centrosomal protein Y1 - 1999 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-1369 ER - TY - THES A1 - Christensen, Morten Overby T1 - Dynamics of human DNA Topoisomerases I and II T1 - Dynamic von Human DNA Topoisomerases I and II N2 - 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. N2 - Diese Arbeit hatte zunächst zum Ziel, humane Zelllinien zu etablieren, in denen GFP-Chimären der humanen DNS-Topoiosmerasen I, IIa und IIb stabil und constitutiv exprimiert werden. Dies wurde mit Hilfe eines bicistronischen Expressionsvektors erreicht, der eine quasi physiologische Expression der GFP-Chimären in humanen Zellen ermöglichte. Wir zeigen, dass die chimärischen Proteine die erwartete Größe haben, aktiv sind, und vollständig in die jeweiligen endogenen Enzympopulationen integriert werden. Damit halten wir ein ideales Werkzeug zur Untersuchung der Zellbiologie der Topoisomerasen in Händen. Sowohl Topoisomerase I, als auch die beiden Typ II-Enzyme innerhalb des Zellkerns vollständig mobil sind und zwischen Nukleoplasma und Nukleolen, sowie zwischen Zytosol und Chromosmen mitotischer Zellen ständig austauschen. Dieser Befund ist insbesondere hinsichtlich der Topoisomerase II erstaunlich, da man bisher davon ausgeht, dass dieses Enzym eine zentrale Rolle bei der Konstituierung der Kernmatrix bzw. des Chromosomengerüstes spielt, was mit einem vollständig und rasch beweglichen Protein unvereinbar scheint. Falls Topoisomerase II tatsächlich eine solche Rolle spielen sollte, müssen die Kernmatrix und das Chromosomengerüst sehr viel dynamischere Strukturen sein, als bisher angenommen. Es sei in diesem Zusammenhang auch darauf hingewiesen, dass wir in der lebenden Zelle keine Konzentrierung der Topoisomerase entlang der zentralen Längsachsen der Chromosmenarme gesehen haben, was bisher als Markenzeichen von deren Gerüstfunktion galt. Vielmehr konnten wir zeigen, dass eine solche axiale Anordnung überwiegend ein Artefakt immunhistologischer Methoden darstellt. Wir zeigen weiterhin, dass die beiden Isoformen der Topoisomerase II (a und b) während der Zellteilung unterschiedlich lokalisiert sind, was mit dem generellen Konzept zusammenpasst, dass nur die a-Form mitotische Funktionen wahrnimmt, während die beiden Isoenzyme in der Interphase konzertiert arbeiten. Ungeachtet ihrer unbegrenzten Mobilität innerhalb des gesamten Zellkerns, imponieren Topoiosmerase I und II in der lebende Zelle als überwiegend nukleoläre Proteine, was damit zusammenhängt, dass sie sich hier etwas langsamer bewegen, als im Nukleoplasma. Diese relative Abbremsung kann nicht auf DNS-Interaktionen beruhen, weil chemische Susbtanzen, die Topoisomerasen an der DNS fixieren, eine Entleerung der Nukleolen bewirken. Interessanterweise ist die subnukleoläre Verteilung von Topoisomerase I und II komplementär. Die Typ II- Enzyme füllen den gesamten nukleolären Raum aus, sparen aber die fibrillären Zentren aus, während das Typ I- Enzym fast ausschließlich an den fibrillären Zentren zu finden ist. Diese Assoziation wird durch den N-Terminus des Enzyms vermittelt, der darüber hinaus während der Mitose auch die Bindung an die nukelolären Organisationszentren der akrozentrischen Chromosomen bewirkt. So bleibt Topoisomerase I über den gesamten Zellzyklus hinweg mit der rDNS physisch verbunden und kolokalisiert hier mit der RNS-Polymerase I. Schließlich konnten wir zeigen, das bestimmte Tumnortherapeutika, von denen man annimt, dass sie über eine Stabilisierung der kovalenten katalytischen DNS-Intermediate der Topoiosmerasen wirken, diese Enzyme in der lebenden Zelle tatsächlich immobil machen. Interssanterweise treffen diese Substanzen überwiegend im Nukleolplasma und nicht in den Nukleolen. KW - Mensch KW - DNS-Topoisomerasen KW - Molekulargenetik KW - Topoisomerase I KW - Topoisomerase II KW - Mobilitet KW - Drogen KW - Krebs KW - Topoisomerases I KW - Topoisomerase II KW - Mobility KW - Drugs KW - Cancer Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-4927 ER - TY - THES A1 - Visan, Ioana Andreea T1 - The CD23 receptor-regulation of expression and signal transduction N2 - 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, während 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-Präsentation 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. Frühere Untersuchungen legen die Vermutung nahe, dass die beiden Isoformen zwei getrennte Signalübertragungswege miteinander verbinden. Die Gegenüberstellung 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 intrazellulären 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 beschränkter Transkriptionsfaktor, welcher für die frühe und späte B-Zellentwicklung von entscheidender Bedeutung ist. Mögliche 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 Elektromobilitäts Experimenten (EMSA) binden. Das Einfügen von Mutationen an dieser Stelle verhindert die Bindung. Ein weiterer Versuch, bei dem die gesamte Länge des CD23a Promotors durch überlappende Peptide in einem kompetitiven Verfahren gegenüber hoch affinen Bindungsstellen getestet wurde, zeigt ebenso CD23-1 als die einzige Stelle, welche direkt Pax-5 binden kann. In weiteren Experimenten führte 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 vergrößerten CD23a Promotorkonstrukts erhöht. Von besonderer Bedeutung ist die Tatsache, dass die ektope Expression von Pax-5 in der monozytären Zelllinie U-937, die normalerweise nur die CD23b Isoform exprimiert, dann zu einer Expression von CD23a nach Stimulation mit IL-4 und PMA führte. Unsere Ergebnisse legen nahe, dass Pax-5 in der auf B-Zellen beschränkten Expression der CD23 Isoform eine Schlüsselrolle zukommt. Im zweiten Teil des Projekts haben wir ein “Zwei-Hefen-Hybrid-System“ (Cyto-Trap von Stratagene) verwendet, um nach zytoplasmatischen Interaktionspartnern für den CD23 Rezeptor zu suchen. Das System wurde modifiziert um eine hohe Effizienz an Transformation zu erzielen. Unterschiedliche „Köder“-Vektorkonstrukte wurden hergestellt. Das Screening wurde mittels einer humanen Milzbibliothek mit dem Zielvektor des Systems durchgeführt. Die anfangs benutzten Konstrukte –pSosCD23a und pSosCD23b – exprimierten sehr kurze (22 Aminosäuren) 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 Aminosäurekette deutlich „sichtbar“ werden zu lassen. Annähernd drei Millionen Klone wurden mittels der verschiedenen Konstrukte untersucht. Dabei konnte keine tatsächlich 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 Köder 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 Schlüsselregulator ist, der die B-Zell-spezifische Expression von CD23a ermöglicht. Zusätzlich wurde ein “Zwei-Hefen-Hybrid-System“ etabliert, mit dem zytoplasmatische Interaktionspartner für die CD23 Isoformen gefunden werden können. N2 - Two isoforms of human CD23 (CD23a and CD23b) have been described. They differ by only 6-7 residues in the N-terminal cytoplasmic tail. CD23a is restrictively expressed on B-cells while CD23b is inducible on B-cells, as well as monocytes, eosinophils, macrophages and a variety of other cell types, after IL-4 stimulation. The two isoforms seems to have different functions. CD23a appears to be the isoform associated with endocytosis of IgE immune complexes and mediating antigen presentation on B-cells. CD23b has a phagocytosis motif and seems to be involved in the phagocytosis of IgE-coated particles, cytokine release and the generation of superoxides. Previous studies indicate that the two isoforms connect to different signal transduction pathways. Comparing the cells that express only one or both CD23 isoforms suggests that CD23b is involved in upregulating cAMP and iNOS, whereas CD23a mediates an increase in intracellular calcium. In the main part of the study we investigated how the CD23a B-cell specific expression is regulated. Pax-5 is a B-cell restricted transcription factor with an essential role in early and late B-cell development. Putative Pax-5 binding sites have been predicted in the CD23a proximal promoter. Analyses of the CD23a promoter revealed three putative Pax-5 binding sites with more than 50% homology to the consensus sequence. One of these sites, named CD23-1 can compete a high affinity Pax-5 binding site or can directly bind Pax-5 protein in electrophoretic mobility shift assays. Introducing mutations into this site abrogates the binding. A different approach, in which overlapping peptides covering the length of the CD23a promoter were tested in competition assays against a high affinity binding site, also revealed CD23-1 as the only site that directly binds Pax-5 protein. Expression of Pax-5 in 293 cells resulted in a 7-fold activation of a CD23a core promoter construct. Co-transfection together with STAT6 showed that Pax-5 cooperates with this transcription factor in enhancing the level of transcription of a CD23a extended promoter construct. Most importantly, ectopic expression of Pax-5 in the monocytic cell line U-937 that regularly expresses only the CD23b isoform enabled a significant CD23a expression after stimulation with IL-4 and PMA. Our results suggest that Pax-5 is a key regulator of the B-cell restricted expression of the CD23a isoform. In the second part of the project, we used a yeast two-hybrid system (CytoTrapTM from Stratagene) in order to look for cytoplasmic interaction partners for the CD23 receptor. The system was established in order to reach a high efficiency of transformation and different bait vector constructs were made. The screening was performed using a human spleen library cloned in the target vector of the system. The first bait constructs used (pSosCD23a and pSosCD23b) expressed the very short (22 amino acids) cytoplasmic tails of the isoforms at the C-terminal end of the fusion protein (human SOS). Improved bait constructs, (pSosCD23a+Linker and pSos CD23b+Linker) expressed the cytoplasmic tail of CD23a/b at the N-terminal side of the human SOS and had in consequence the N-terminal part free as a bait, as it occurs in vivo. A flexible linker region separated the fusion proteins in order to make the small amino acid bait chain more obvious. Approximately three million library clones were screened with these various constructs. No “true positive” interaction was detected. A relatively high number of “false positive” clones were obtained and checked in another two-hybrid system. A new bait construct, in which the tyrosine residue in the cytoplasmic tail of CD23a was replaced by a glutamic acid residue will be used for future screening. The system was also used in order to test the interaction between CD23 and p59fyn, a member of the Src family of protein kinases that was mentioned to associate with CD23a. No interaction was detected by using the CytoTrap two-hybrid system. In conclusion, the key result of the study demonstrates that Pax-5 is a main regulator of the B-cell specific expression of the CD23a isoform. In addition, a two-hybrid system was established and employed in order to look for cytoplasmic interaction partners for CD23. KW - Antigen CD23 KW - Promotor KW - Genregulation KW - CD23 KW - Pax-5 KW - Zwei-Hefen-Hybrid-System KW - Promotor Regulation KW - CD23 KW - Pax-5 KW - promoter regulation KW - two-hybrid system Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5556 ER - TY - THES A1 - Hallhuber, Matthias T1 - Inhibition of Nuclear Import of Calcineurin Prevents the Development of Myocardial Hypertrophy T1 - Inhibition des nukleären Imports von Calcineurin verhindert die Entwicklung myokardialer Hypertrophie N2 - 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, Importinβ1, 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. N2 - Die Calcineurin/NFAT – Signalkaskade spielt eine wichtige Rolle innerhalb der zellulären Funkionalität. Es wurde bereits gezeigt, dass neben NFAT auch die Phosphatase Calcineurin in den Zellkern transportiert wird. Die bisherigen Vorstellungen zur Aktivierung von Calcineurin durch erhöhte intrazelluläre Ca2+-Konzentrationen wurden durch aktuellste Ergebnisse dieser Arbeitsgruppe (AG Ritter) neu diskutiert. Es wurde gezeigt, dass Calcineurin durch gezielte Proteolyse der autoinhibitorischen Domäne konstitutiv aktiviert werden kann und in den Zellkern transportiert wird. Calcineurin ist daher nicht nur verantwortlich für die im Zytosol stattfindende Dephosphorylierung von NFAT, sondern übernimmt auch eine wichtige Funktion im Zellkern. Die nukleäre Lokalisation von Calcineurin ist essentiell für die vollständige transkriptionelle Aktivität von NFAT. Die Komplexbildung zwischen Transkriptionsfaktoren und DNA reguliert die Transkription. Aus diesem Grund spielt die nukleäre Verweildauer diverser Transkriptionsfaktoren eine tragende Rolle. Der Transport von Proteinen (> 40 kDa) in den und aus dem Zellkern erfolgt über nukleäre Porenkomplexe, wobei die zu transportierenden Proteine mittels nukleärer Lokalisationssequenzen (NLS) / nukleärer Exportsequencen (NES) durch die entsprechenden Transportportproteine (Karyopherine) erkannt werden. In dieser Arbeit wurden die genauen Mechanismen des Imports und des Exports von Calcineurin identifiziert. Zusätzlich konnten die NLS/NES von Calcineurin und die entsprechenden Karyopherine, Importinβ1 für den Import bzw. CRM1 für den Export, ermittelt werden. Die Inhibition der Calcineurin/Importin Interaktion durch ein kompetitives Peptid, welches als Import Blocking Peptide (IBP) bezeichnet wurde und der NLS von Calcineurin entspricht, verhinderte den nukleären Import von Calcineurin. Durch diesen Mechanismus war es möglich, die Entwicklung kardialer Hypertrophie zu verhindern. In Angiotensin II stimulierten Kardiomyozyten konnten sowohl die transkriptionelle, als auch die translationelle Aktivität reduziert werden. Des Weiteren wurden das Zellwachstum und die Expression von BNP unterdrückt. Das Blockpeptid wirkte konzentrationsabhängig, beeinflusste aber die Phosphatase-Eigenschaft von Calcineurin nicht. Zusammenfassend lässt sich sagen, dass Calcineurin, nicht nur verantwortlich für die Dephosphorylierung von NFAT ist, sondern die nukleäre Lokalisierung ebenfalls eine entscheidende Rolle für die volle transkriptionelle Aktivität von NFAT spielt. Die Verwendung von IBP, um den nukleären Import von Calcineurin zu verhindern, stellt ein völlig neues Konzept dar, die Entwicklung kardialer Hypertrophie zu unterdrücken. KW - Calcineurin KW - Inhibition KW - Blockpeptid KW - myokardiale Hypertrophie KW - Calcineurin KW - Inhibition KW - Blocking Peptide KW - Myocardial Hypertrophy Y1 - 2007 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-23536 ER - TY - THES A1 - Padmapriya, Ponnuswamy T1 - Insight into oxidative stress mediated by nitric oxide synthase (NOS) isoforms in atherosclerosis N2 - 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. N2 - Stickstoffmonoxid (NO) ist das prinzipielle Produkt aller Stickstoffmonoxid-Synthasen (NOS). Im Falle eines Mangels an Substrat (L-arginin) und Kofaktoren (Tetrahydrobiopterin, BH4) katalysieren die NOS-Enzyme direkt Superoxid (O2-). Diese Veränderung in der Radikalproduktion wird auch als Entkopplung der NOS bezeichnet. Die alternative Produktion von NO oder O2- durch die NOS bedingen, dass eine Voraussage über die Schlüsselfunktion der einzelnen Enzyme in der Entstehung der Atherosklerose schwierig ist. In unserer Studie evaluieren wir die Produktion von NO sowie O2- in atherosklerotischen Läsionen von apoE ko Mäusen und apoE/NOS doppel knockout (dko) Mäusen denen jeweils eine NOS-Isoform fehlt. Elektronen Spin Resonanz (ESR) Messungen konnten eine signifikante Reduktion sowohl des zirkulierenden, als auch der Gefäßwand eigenen Produktion von NO in apoE/eNOS dko und apoE/iNOS dko Mäusen zeigen, nicht jedoch in apoE/nNOS dko Mäusen. Dies lässt darauf schließen, dass eNOS und iNOS den hauptsächlichen Anteil der vaskulären NO-Produktion in atherosklerotischen Läsionen bewerkstelligen. Die pharmakologische Inhibierung wie auch die genetische Deletion von eNOS und iNOS führten ebenfalls zu einer reduzierten vaskulären O2- produktion, was die partielle Entkopplung beider Enzyme in atherosklerotisch veränderten Gefäßen nahe legt. Obwohl die chronische genetische Deletion von nNOS in apoE/nNOS dko die O2- Produktion nicht verändert, zeigte sich bei der akuten pharmakologischen Inhibierung von nNOS (durch L-NAANG) eine maßgebliche Beteiligung von nNOS an der O2- produktion in apoE ko Mäusen. Schlussfolgernd lässt sich sagen, dass in atherosklerotischen Gefäßen von apoE ko Tieren eine Entkopplung von eNOS statt findet, diese jedoch zu keinem Ausgleich der protektiven Effekte der eNOS vermittelten NO-Produktion führt. Unsere Ergebnisse in apoE/nNOS dko Mäusen zeigen eine atheroprotektive Rolle der nNOS, die sich nicht allein durch eine lokale, vaskuläre NO-Produktion durch das Enzym erklären lässt. Wir postulieren weitere systemisch atheroprotektive Eigenschaften der nNOS. Die signifikante Reduktion der Superoxidproduktion durch eine akute Inhibierung der nNOS weist auf eine Entkopplung der nNOS hin. Der exakte Wirkungsmechansimus von nNOS in der Atheroskleroseprävention ist weiterhin noch zu eruieren. Die genetische Deletion von iNOS führt zu einer reduzierten Aktivität der NADPH-Oxidase. Demnach sind für iNOS direkte sowie indirekte atherosklerosefördernde Effekte anzunehmen, da sie auf direktem Wege gleichzeitig NO und O2- produziert, was in einer Peroxynitritbildung resultiert. Wir stellen die Hypothese auf, dass eNOS in den läsionsfreien Gefäßregionen gekoppelt ist und dort seine atheroprotektiven Effekte durch die NO-Produktion vermittelt, während die eNOS in atherosklerotischen Läsionen entkoppelt vorliegt und hier O2- produziert (Fig. 16). iNOS, welches vor allem in den Plaques, in glatten Muskelzellen und Leukozyten zu finden ist, produziert gleichzeitig hohe Konzentrationen von O2- und NO, die als gemeinsames Endprodukt das stark oxidierende Peroxynitrit ergeben und die von uns dokumentierte proatherosklerotische Wirkung der iNOS vermittelt. KW - atherosclerosis KW - oxidative stress KW - Nitric oxide synthase KW - Atherosklerose KW - Stickstoffmonoxid Synthase KW - atherosclerosis KW - oxidative stress KW - Nitric oxide synthase Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30659 ER - TY - THES A1 - Govindaraj, Vijayakumar T1 - Improved Cardiac Glucose Uptake: A Potential Mechanism for Estrogens to Prevent the Development of Cardiac Hypertrophy N2 - 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 17β-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 17β-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 17β-estradiol treatment. Increased myocardial hexokinase appears as a potential mechanism to explain increased myocardial glucose uptake by 17β-estradiol. Increased cardiac glucose uptake in response to 17β-estradiol in ovariectomized SHR may provide a novel mechanism to explain the reduction of cardiac hypertrophy in E2 treated SHR. Therefore, 17β-estradiol improves cardiac glucose utilization in ovariectomized SHR which may give rise to possible mechanism for its protective effects against cardiac hypertrophy. N2 - Erkrankungen des kardiovaskulären Systems, wie beispielsweise Herzhypertrophie oder Herzinsuffizienz treten bei Frauen vor der Menopause im Vergleich zu gleichaltrigen Männern seltener auf. Das Risiko für eine solche kardiovaskuläre Erkrankung steigt jedoch drastisch mit dem Beginn der Menopause an. Aus diesem Grund wird angenommen, dass weibliche Geschlechtshormone kardioprotektive Wirkungen besitzen. Tierstudien an spontan hypertensiven Ratten (SHR) haben belegt, dass eine Herzhypertrophie durch die Behandlung der Tiere mit 17β-Estradiol abgemildert werden kann. Entscheidend für die Funktion des Myokards ist sein Energiemetabolimus, der sich im Verlauf einer Hypertrophie oder Herzinsuffizienz vom primären Fettsäurestoffwechsel auf Glucosemetabolismus umschaltet. Diese Situation entspricht der des fetalen Herzens. Viele Studien haben belegt, dass eine Störung der Balance zwischen Glucose- und Fettsäurestoffwechsel oftmals ein erstes Anzeichen für einen pathologischen Zustand des Herzens, wie z.B. Hypertrophie, Herzinsuffizienz, Diabetes, dilative Kardiomyopathie und Myokardinfarkt ist. Im gesunden Herzen gelangt Glucose über die zwei Glucosetransporter GLUT1 und GLUT4 in die Zellen des Myokards, wobei der insulinabhängige Glut4-Transporter der Hauptglucosetransporter ist. Eine GLUT4-Defizienz führt daher ebenfalls zu einer Herzhypertrophie was wiederum zeigt, dass eine verminderte Glucoseaufnahme im direkten Zusammenhang mit pathologischen Zuständen des Herzens steht. Bisherige Studien haben gezeigt, dass Östrogen an der Glucosehomöostase in Leber und Skelettmuskeln beteiligt ist. Jedoch ist wenig darüber bekannt, ob Östrogen ebenfalls in die kardiale Glucosehomöostase eingreift und inwiefern die kardioprotektive Wirkung des Östrogens in diesem Zusammenhang steht.In der vorliegenden Arbeit wurden weibliche SH-Ratten ovariektomiert (OVX), nicht ovariektomiert (sham) oder ovariektomiert und zusätzlich subkutan mit 17β-Estradiol behandelt. Nach einer Behandlungszeit von 6 Wochen wurden dann das Körpergewicht, die Serumspiegel von Östrogen, Insulin und IPGTT bestimmt, und die Glucoseaufnahme des Myokards mittels FDG-PET analysiert. Zusätzlich wurden Expression und zelluläre Lokalisation der kardialen Glucosetransporter sowie die kardiale Hexokinaseaktivität untersucht. Es konnte gezeigt werden, dass sich eine verminderte Glucoseaufnahme des Herzens bei ovariektomierten Tieren durch Östrogen-Supplementation normalisieren lässt. Eine Abweichung bezüglich der Glucosetoleranz der einzelnen Gruppen konnte nicht beobachtet werden. Jedoch konnte ein erhöhter Insulinspiegel des Serums und eine erhöhte kardiale Aktivität des Enzyms Hexokinase durch die Behandlung mit Östrogen bei den ovariektomierten Tieren beschrieben werden. Durch Fraktionierungen und immunhistologische Untersuchungen konnte kein signifikanter Unterschied in Bezug auf die Menge sowie die Translokation der Glucosetransporter GLUT1 und GLUT4 im Myokard zwischen den einzelnen Behandlungen der Tiere beschrieben werden. Ferner konnte zwischen den einzelnen Tiergruppen auch kein Unterschied zwischen dem Insulin Rezeptor Substrat-1 (IRS-1) und seiner Tyrosin-phosphorylierten Form festgestellt werden, die für die Aktivierung und Translokation des GLUT4 benötigt werden. Analysen der Genexpression in den Herzen der SH-Ratten konnten allerdings zeigen, dass die Gene ei4Ebp1 und Frap1, die im mTOR Signalweg involviert sind, bei den Östrogen-supplementierten Tieren ein abweichendes Expressionsmuster aufweisen. Über diese Gene ist bekannt, dass sie in der Gegenwart von Glucose im Herzen aktiviert werden und bei der Entstehung einer Herzhypertrophie mitwirken. Basierend auf den PET-Analysen und der Hexokinaseaktivität lässt sich als Resultat dieser Arbeit aussagen, dass Östrogen die kardiale Glucoseaufnahme in SH-Ratten fördert. Diese Ergebnisse könnten einen Hinweis auf einen noch unbekannten Mechanismus geben, um die protektive Wirkung des Östrogens im Hinblick auf die Herzhypertrophie zu erklären. Hinsichtlich der Tatsache, dass keine Veränderungen in der Translokation der GLUT4-Transporter in der Plasmamembran bei den einzelnen Behandlungen der Tiere zu verzeichnen sind, jedoch Veränderungen der Glucoseaufnahme durch die PET-Analysen dargestellt werden konnten, besteht jedoch noch Erklärungsbedarf. Es liegen diverse Studien vor, die diesen Unterschied damit erklären könnten, dass der GLUT4-Transporter in einer inaktiven Form in der Plasmamembran vorliegt bis die Glucoseaufnahme durch den GLUT4-Transporter mittels der Insulin Signaltransduktionskaskade reguliert wird. KW - estrogen KW - estrogen receptor KW - cardiac hypertrophy KW - cardiac metabolism KW - Glut4 KW - estrogen KW - estrogen receptor KW - cardiac hypertrophy KW - cardiac metabolism KW - Glut4 KW - estrogen KW - estrogen receptor KW - cardiac hypertrophy KW - cardiac metabolism KW - Glut4 Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-35911 ER - TY - THES A1 - Fiedler, Jan T1 - Endothelial microRNA-24 contributes to capillary density in the infarcted heart N2 - 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. N2 - Kardiovaskuläre Erkrankungen sind die häufigste Todesursache in der industrialisierten Welt. Nach Myokardinfarkt (MI) kommt es zum Verlust kardialen Gewebes und zu pathologischen Umbauprozessen im Herzen, die oftmals in einer Herzinsuffizienz münden. Dabei spielt eine insuffiziente Gefäßversorgung im überlebenden Myokard eine wichtige Rolle. Zugrunde liegende molekulare Mechanismen oder gentherapeutische Strategien zur Verbesserung der Angiogenese nach MI sind jedoch nur unzureichend verstanden und etabliert. Die Entdeckung sogenannter microRNAs (miRNAs, miRs), kleiner nicht-kodierender RNAs mit einer Länge von 19-25 Nukleotiden, zeigt eine neue Ebene der Komplexität bei der Regulation kardiovaskulärer Signalwege auf. So regulieren miRNAs die Genexpression posttranskriptional durch inhibitorische Bindung an komplementäre messenger RNAs. Die Modulation von miRNAs und damit nachfolgenden Gen-Netzwerken könnte daher ein wichtiger Baustein bei der Entwicklung neuer Therapiestrategien in der kardiovaskulären Medizin werden. In dieser Arbeit wird gezeigt, dass kardiale miR-24 überwiegend in kardialen Endothelzellen exprimiert ist und nach Myokardinfarkt im Mausmodell sowie nach Hypoxie in vitro hochreguliert wird. Die verstärkte miR-24-Expression induziert endotheliale Apoptose und vermindert die Kapillarbildungsfähigkeit endothelialer Zellen in einem Angiogeneseassay. Diese funktionalen Defekte werden über die Repression des Transkriptionsfaktors GATA2, der Histon-Deacetylase H2A.X, der p21-aktivierten Kinase PAK4 und dem p21 Protein-Aktivator RASA1 vermittelt. GATA2 wird in dieser Arbeit als wichtiger Faktor für die Zellzykluskontrolle, Apoptose und Angiogenese beschrieben, wobei die Regulation direkter Effektoren wie Hämoxygenase 1 (HMOX1) essentiell ist. Weiterhin wird über die miR-24-abhängige Modulation von PAK4 endotheliale Apoptose kontrolliert. PAK4 weist eine anti-apoptotische Funktion auf, indem es zu einer Phosphorylierung des Proteins Bad führt. Die spezifische Repression endogener miR-24 durch einen Antagonisten (Antagomir) in einem murinen MI-Modell erhöht die Kapillardichte im infarzierten Gewebe und verbessert die kardiale Funktion. Zusammenfassend zeigen die Erkenntnisse dieser Arbeit eine wichtige Funktion für miR-24 bei der Regulation endothelialer Apoptose und Angiogenese. Die Modulation von miR-24 könnte ein interessantes neues therapeutisches Konzept zur Verbesserung der Angiogenese nach MI darstellen. KW - Herzinfarkt KW - miRNS KW - Angiogenese KW - miRNA infarcted heart Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49809 ER - TY - JOUR A1 - Bauer, Wolfgang R. A1 - Nadler, Walter T1 - Thermodynamics of Competitive Molecular Channel Transport: Application to Artificial Nuclear Pores N2 - 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. KW - Thermodynamik KW - Transport KW - Molekül KW - Molecular Channel Transport KW - Artificial Nuclear Pores KW - Thermodynamics Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68484 ER - TY - THES A1 - Burkard, Natalie T1 - Signalübertragungswege und Präventionsmöglichkeiten der kardialen Hypertrophie : conditional overexpression of neuronal nitric oxide synthase is cardioprotective in ischemia-reperfusion T1 - Konditionale Überexpression der neuronalen NO-Synthase wirkt kardioprotektiv bei Ischämie-Reperfusion N2 - Zusammenfassung: Wie früher schon gezeigt, wird der L-Typ Ca2+-Kanal durch eine induzierbare, myokardspezifische Überexpression der neuronalen Stickstoffmonoxidsynthase (nNOS) inhibiert. Gleichzeitig bewirkt diese Überexpression eine verminderte kardiale Kontraktilität1 (Burkard N. et al. (2007). Circ Res 100, 32-44). nNOS interagiert mit vielen verschiedenen Kompartimenten und Kanälen innerhalb der Zelle. In dieser Arbeit wurde gezeigt, dass eine nNOS Überexpression nach Ischämie-Reperfusion kardioprotektiv wirkt. Dieses wird durch eine Inhibition der Mitochondrienfunktion und durch eine Verminderung der reaktiven Sauerstoffspezies (ROS) ermöglicht. In einer früheren Arbeit wurde der Effekt der induzierbaren und myokardspezifischen Überexpression von nNOS unter physiologischen Bedingungen am transgenen Tiermodell untersucht. Diese Arbeit beschäftigt sich nun mit der Überexpression von nNOS unter pathophysiologischen (Ischämie-Reperfusion) Bedingungen. Ein Ischämie-Reperfusions-Schaden bewirkt bei Wildtyp-Mäusen, sowie bei transgener nNOS Überexpression eine Anreicherung von nNOS in den Mitochondrien. Elektronenmikroskopische Aufnahmen von Mausmyokard haben gezeigt, dass bei Überexpression nNOS zusätzlich in den Mitochondrien lokalisiert ist. Diese Translokation von nNOS in die Mitochondrien ist abhängig von HSP90. Ischämie- Reperfusionsexperimente an isolierten Mäuseherzen zeigten einen kardioprotektiven Effekt der nNOS Überexpression (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 Infarktgröße bestätigt werden. nNOS überexprimierende Mäuse hatten eine kleinere Infarktgröße nach Ischämie-Reperfusion (36.6±8.4 relative % vs. 61.1±2.9 relative %, n=8, p<0.05). Die Überexpression von nNOS bewirkte ebenfalls einen signifikanten Anstieg des mitochondrialen Nitrit-Levels, begleitet von einer Verminderung der Cytochrom C Oxidase Aktivität (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 führt. Dementsprechend war der Sauerstoffverbrauch (gemessen an isolierten Herzmuskelstreifen) schon unter basalen Bedingungen beinNOS Überexpression 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 überexprimierenden Mäusen signifikant vermindert (6.14±0.685 vs. 14.53±1.7μM, n=8, p<0.01). Die Zugabe von verschiedenen Inhibitoren, Western Blot- und Aktivitätsuntersuchungen zeigten schließlich, dass diese niedrigere ROS Konzentration durch eine verminderte Xanthin Oxidoreduktase Aktivität hervorgerufen wurde. Zusammenfassend hat diese Arbeit gezeigt, dass eine induzierbare und myokardspezifische Überexpression von nNOS unter pathophysiologischen Bedingungen (Ischämie-Reperfusion) kardioprotektiv wirkt. Zusätzlich zu der Verminderung des myokardialen Ca2+-Überschusses nach Reperfusion könnte dieser protektive Effekt durch eine Hemmung der Mitochondrienfunktion bedingt sein, schließlich wird der Sauerstoffverbrauch schon unter basalen Bedingungen reduziert N2 - Summary: I previously demonstrated that conditional overexpression of the neuronal nitric oxide synthase (nNOS) inhibited L-type Ca2+-channels and decreased myocardial contractility1 (Burkard N. et al. (2007). Circ Res 100, 32-44). However, nNOS has multiple targets within the cardiac myocyte and it is possible that interesting biological functions of this protein remain to be elucidated. In this study, I showed that nNOS overexpression has a cardioprotective effect after ischemia-reperfusion injury by inhibiting mitochondrial function and reducing the generation of reactive oxygen species (ROS). The effect of conditional nNOS overexpression in cardiac myocytes in ischemiareperfusion injury was assessed. Ischemia-reperfusion injury in WT mice resulted in nNOS accumulation in the mitochondria. Similary, transgenic nNOS overexpression caused nNOS abundance in mitochondria. Electron microscopy of mouse myocardium from nNOS overexpressing mice showed that after induction of its expression, nNOS is additionally localised in mitochondria. nNOS translocation into mitochondria was dependent on HSP90. Ischemia-reperfusion experiments in isolated hearts showed a cardioprotective effect of nNOS overexpression (30min post-ischemia, LVDP 27.0±2.5mmHg in non-induced animals vs. 45.2±1.9mmHg in nNOS overexpressing mice, n=12, p<0.05). Consistently with this finding, in vivo the infarct size within the area at risk was significantly decreased in nNOS overexpressing mice compared to non-induced animals (36.6±8.4 relative % vs. 61.1±2.9 relative %, n=12, p<0.05). nNOS overexpression also caused a significant increase in mitochondrial nitrite levels accompanied by a decrease of cytochrome c oxidase activity (72.0±8.9units/ml in nNOS overexpressing mice vs. 113.2±17.1units/ml in non-induced mice, n=12, p<0.01) resulting in an inhibition of mitochondrial function. Accordingly, O2-consumption (MVO2) in isolated heart muscle stripes was decreased in nNOS overexpressing mice, already under resting conditions (0.016±0.0015 vs. 0.024±0.006ml[O2] x mm-3 x min-1, n=13, p<0.05). Additionally, this study showed that the ROS concentration was significantlydecreased in hearts of nNOS overexpressing mice compared to non-induced animals (6.14±0.685 vs. 14.53±1.7μM, n=8, p<0.01). Application of different inhibitors, Western Blot analysis and activity assays showed that the lower ROS concentration in nNOS overexpressing mice was caused by inhibition of the xanthine oxidoreductase (XOR) activity by the increased abundance of nNOS expression. In summary, this study demonstrated that the conditional transgenic overexpression of nNOS resulted in myocardial protection after ischemia-reperfusion injury. Besides reduction of myocardial Ca2+-overload after reperfusion this might be caused by inhibition of mitochondrial function through nNOS, which reduced myocardial oxygen consumption already under baseline conditions (Burkard N. conditionally accepted by KW - Herzhypertrophie KW - Signaltransduktion KW - Prävention KW - kardioprotektiv KW - Ischämie-Reperfusion KW - nNOS KW - cardioprotection KW - ischemia-reperfusion KW - nNOS Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-51832 ER - TY - JOUR A1 - Johanssen, Sarah A1 - Hahner, Stefanie A1 - Saeger, Wolfgang A1 - Quinkler, Marcus A1 - Beuschlein, Felix A1 - Dralle, Henning A1 - Haaf, Michaela A1 - Kroiss, Matthias A1 - Jurowich, Christian A1 - Langer, Peter A1 - Oelkers, Wolfgang A1 - Spahn, Martin A1 - Willenberg, Holger S. A1 - Maeder, Uwe A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Deficits in the Management of Patients With Adrenocortical Carcinoma in Germany N2 - 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. Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-85897 ER - TY - THES A1 - Kehlenbrink, Sylvia T1 - Inhibiting Gluconeogenesis (GNG) Prevents the Effects of Free Fatty Acids (FFA) on Hepatic Glucose Effectiveness (GE) T1 - Die Inhibierung der Glukoneogenese verhindert die Beeinträchtigung freier Fettsäuren auf die hepatische Glukoseeffektivität N2 - 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. N2 - Freie Fettsäuren (FFA) modulieren die Fähigkeit von Glukose die endogene Glukoseproduktion (EGP) zu unterdrücken und spielen eine wichtige Rolle bei dem Verlust der Glukoseeffektivität bei Typ-2-Diabetes mellitus (T2DM). Die Erhöhung freier Fettsäuren in Nicht-Diabetikern (ND) für mindestens 6 Stunden steigert die Glukoneogenese (GNG) und beeinträchtigt die Glukoseeffektivität. Ziel dieser Studien war es daher zu erkennen inwiefern die GNG für den Verlust der Glukoseeffektivität verantwortlich ist und ob die EGP in der Gegenwart von erhöhten FFA, durch die Inhibierung der GNG mit Ethanol, gehemmt werden kann. Um die Auswirkung der Hemmung der GNG auf die Glukoseeffektivität zu bestimmen haben wir die EGP ([3-3H]-glucose) während drei verschiedener normoglykämischen/ hyperglykämischen ‘Pancreatic Clamp’ Studien (Infusion von Somatostatin; Ersetzung basaler Konzentrationen von Glukagon, GH, und Insulin) von jeweils 7 Stunden Dauer in n=7 ND Probanden (1W/6M; Alter=45±5 Jahre; BMI=27.6±3.0 kg/m2) gemessen. Nach einer initialen Phase der Euglykämie (Blutglukosekonzentration bei 5 mmol/l; t=0-210 Minuten) wurde für den Zeitintervall t=210-420 Minuten die Blutglukosekonzentration auf 10 mmol/l erhöht. Die erste ‘Pancreatic Clamp’ Studie war eine Kontrollstudie mit Infusion einer NaCl-Lösung (Lip-/Et-). Eine Lipidemulsion (Liposyn 20%) wurde während der zweiten und dritten Studie (Lip+ und Lip+/Et-) infundiert, um die FFA Plasmaspiegel auf Konzentrationen zu erhöhen, die charakteristisch für den T2DM sind (~ 500 mmol/l). In Ergänzung zu Liposyn wurde Ethanol (Et) während der hyperglykämischen Phase der dritten Studie (Lip+/Et+) zugeführt. Mittels eines pharmakokinetischen Algorithmus wurden innerhalb von 20 Minuten Ethanolwerte erreicht die die GNG hemmen (~80 mg/dl). In den Kontrollstudien verminderte sich die EGP um 61% mit Einsetzen der Hyperglykämie. Nach Infusion von Liposyn in den Lip+ Studien verminderte sich die EGP in Folge der Hyperglykämie jedoch nur um 34%. Die GNG wurde rasch durch die Infusion von Ethanol in den Lip+/Et+ Studien gehemmt und verbesserte signifikant die hyperglykämie-induzierte Suppression der EGP (65% Verminderung der EGP, P=0.004 vs. Lip+). Dadurch wurde die normale Glukoseeffektivität wiederhergestellt (P=0.6 vs. Lip-/Et-). Diese Ergebnisse bestätigen die markante Rolle erhöhter Plasma FFA-Spiegel für die Beeinträchtigung der Glukoseeffektivität und deuten auf die Zentrale Rolle der GNG für den Verlust dieser Regulierung hin. Die Inhibierung der GNG könnte eine effektive Maßnahme sein, die EGP bei T2DM zu vermindern und die Glukoseeffektivität wiederherzustellen. KW - Gluconeogenese KW - Freie Fettsäuren KW - Diabetes mellitus KW - Glukoseeffektivität KW - Gluconeogenesis KW - free fatty acids KW - type 2 diabetes mellitus KW - glucose effectiveness Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-48389 ER - TY - JOUR A1 - Arlt, Wiebke A1 - Biehl, Michael A1 - Taylor, Angela E. A1 - Hahner, Stefanie A1 - Libé, Rossella A1 - Hughes, Beverly A. A1 - Schneider, Petra A1 - Smith, David J. A1 - Stiekema, Han A1 - Krone, Nils A1 - Porfiri, Emilio A1 - Opocher, Giuseppe A1 - Bertherat, Jerôme A1 - Mantero, Franco A1 - Allolio, Bruno A1 - Terzolo, Massimo A1 - Nightingale, Peter A1 - Shackleton, Cedric H. L. A1 - Bertagna, Xavier A1 - Fassnacht, Martin A1 - Stewart, Paul M. T1 - Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors JF - The Journal of Clinical Endocrinology & Metabolism N2 - 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. KW - adrenal cortex hormones KW - urine KW - adrenal cortex neoplasms KW - mass spectrometry KW - metabolomics Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154682 VL - 96 IS - 12 SP - 3775 EP - 3784 ER - TY - JOUR A1 - Ascierto, Maria Libera A1 - Worschech, Andrea A1 - Yu, Zhiya A1 - Adams, Sharon A1 - Reinboth, Jennifer A1 - Chen, Nanhai G A1 - Pos, Zoltan A1 - Roychoudhuri, Rahul A1 - Di Pasquale, Giovanni A1 - Bedognetti, Davide A1 - Uccellini, Lorenzo A1 - Rossano, Fabio A1 - Ascierto, Paolo A A1 - Stroncek, David F A1 - Restifo, Nicholas P A1 - Wang, Ena A1 - Szalay, Aladar A A1 - Marincola, Francesco M T1 - Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68 JF - BMC Cancer N2 - 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. KW - gene-therapy KW - adenovirus KW - receptor KW - identification KW - infection KW - CD9 KW - panel Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141503 VL - 11 IS - 451 ER - TY - JOUR A1 - Fassnacht, Martin A1 - Johanssen, Sarah A1 - Allolio, Bruno T1 - Statements Cannot Be Substantiated : In Reply JF - Deutsches Ärzteblatt International N2 - No abstract available. KW - Medicine Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142597 VL - 108 IS - 19 ER - TY - JOUR A1 - Sack, Stefan A1 - Wende, Christian Michael A1 - Nägele, Herbert A1 - Katz, Amos A1 - Bauer, Wolfgang Rudolf A1 - Barr, Craig Scott A1 - Malinowski, Klaus A1 - Schwacke, Harald A1 - Leyva, Francisco A1 - Proff, Jochen A1 - Berdyshev, Sergey A1 - Paul, Vincent T1 - 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 JF - European Journal of Heart Failure N2 - 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. KW - Remote device monitoring KW - Multiparameter predictor KW - Cardiovascular hospitalizations KW - Heart failure KW - Home monitoring KW - Cardiac resynchronization therapy defibrillator Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141709 VL - 13 IS - 9 ER - TY - JOUR A1 - Williams, Tatjana A1 - Machann, Wolfram A1 - Kühler, Leif A1 - Hamm, Henning A1 - Müller-Höcker, Josef A1 - Zimmer, Michael A1 - Ertl, Georg A1 - Ritter, Oliver A1 - Beer, Meinrad A1 - Schönberger, Jost T1 - Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma JF - Clinical Research in Cardiology N2 - 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. KW - Desmoplakin KW - Juvenile biventricular cardiomyopathy KW - Palmoplantar keratoderma Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141198 VL - 100 IS - 12 ER - TY - JOUR A1 - Allignol, Arthur A1 - Schumacher, Martin A1 - Wanner, Christoph A1 - Drechsler, Christiane A1 - Beyersmann, Jan T1 - Understanding competing risks: a simulation point of view JF - BMC Medical Research Methodology N2 - 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. KW - Cumulative incidence function KW - Clinical-trials KW - Sample-sizes KW - Regression KW - Subdistribution KW - Hazards KW - Model KW - Probabilities KW - Tests Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142811 VL - 11 IS - 86 ER - TY - JOUR A1 - Edelmann, Frank A1 - Wachter, Rolf A1 - Düngen, Hans-Dirk A1 - Störk, Stefan A1 - Richter, Annette A1 - Stahrenberg, Raoul A1 - Neumann, Till A1 - Lüers, Claus A1 - Angermann, Christiane E. A1 - Mehrhof, Felix A1 - Gelbrich, Götz A1 - Pieske, Burkert T1 - Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline JF - Cardiovascular Diabetology N2 - 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. KW - Preserved Ejection Fraction KW - Diastocic Dysfunction KW - Myocardial-Infarction KW - Hyperkalemia KW - Eplerenone KW - Mortality KW - Predictors KW - Framingham KW - Morbidity KW - Outcomes Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140397 VL - 10 IS - 15 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Meinitzer, Andreas A1 - Pilz, Stefan A1 - Krane, Vera A1 - Tomaschitz, Andreas A1 - Ritz, Eberhard A1 - März, Winfried A1 - Wanner, Christoph T1 - Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients JF - European Journal of Heart Failure N2 - 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. KW - Homoarginine KW - Sudden cardiac death KW - Heart failure KW - Amino acids KW - Haemodialysis Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140495 VL - 13 IS - 8 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Dexneit, Thomas A1 - Reichardt, Sybille D. A1 - Michel, Kai D. A1 - van den Brandt, Jens A1 - Schmull, Sebastian A1 - Kraus, Luitgard A1 - Beyer, Melanie A1 - Mlynski, Robert A1 - Wortmann, Sebastian A1 - Allolio, Bruno A1 - Reichardt, Holger M. A1 - Fassnacht, Martin T1 - Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells \(In\) \(Vivo\) JF - PLoS One N2 - 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. KW - Systemic-Lupus-Erythematosus KW - Immunological Self-Tolerance KW - Multiple-Sclerosis KW - Suppressive Function KW - Autoimmune-Diseases KW - FoxP3 Expression KW - Dendritic Cells KW - Immune-System KW - Sex-Hormones KW - Antigen 4 Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140822 VL - 6 IS - 9 ER - TY - JOUR A1 - Fassnacht, Martin A1 - Sbiera, Silviu A1 - Dexneit, Thomas A1 - Reichardt, Sybille D. A1 - Michel, Kai D. A1 - van den Brandt, Jens A1 - Schmull, Sebastian A1 - Kraus, Luitgard A1 - Beyer, Melanie A1 - Mlynski, Robert A1 - Wortmann, Sebastian A1 - Allolio, Bruno A1 - Reichardt, Holger M. T1 - Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells In Vivo N2 - 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 naı¨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. KW - Medizin Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-74749 ER - TY - THES A1 - Liu, Dan T1 - Regional Myocardial Deformation in Adult Patients with Isolated Left Ventricular Non-compaction Cardiomyopathy T1 - Regionale Myokardfunktion bei erwachsenen Patienten mit isolierter ventrikulärer Non-Compaction-Kardiomyopathie N2 - 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. N2 - Isolierte ventrikuläre Non-Compaction-Kardiomyopathie (IVNM) ist eine angeborene myokardiale Erkrankung, gekennzeichnet durch Hypertrabekularisierung mit tiefen intertrabekulären Recessus des linken Ventrikels. Da ausgeprägte Trabekularisierung auch in anderen Kardiomyopathien wie der DCM oder sogar beim Gesunden vorkommt, gibt dieser unspezifische Befund dem Kliniker oft Rätsel auf. Ziel der vorliegenden Studie ist eine umfassende Untersuchung der regionalen myokardialen Wanddeformierungseigenschaften bei erwachsenen Patienten mit isolierter IVNM mittels Strain Rate Imaging und 2D Speckle Tracking. Die Annahme war, dass das Wissen um die Deformationseigenschaften bei IVNM helfen würde, diese von der DCM abzugrenzen. In die Studie wurden 14 Patienten mit IVNM, 15 mit DCM und 15 Gesunde als Kontrollgruppe eingeschlossen. Die jeweiligen Gruppen wurden nach Alter und Geschlecht angeglichen. Alle Patienten erhielten eine Standard 2D Echokardiographie. Gewebedoppler (TDI) wurde im apikalen Vier- und Zweikammerblick sowie in der apikalen langen Achse an allen ventrikulären Wänden durchgeführt. Analysiert wurden Daten aus Deformationsaufnahmen sowie TDI und Grey-scale-Bildern. Klinische und standard-echokardiographische Befunde bei IVNM und DCM waren vergleichbar. Bei Patienten mit IVNM war die Hypertrabekularisierung vor allem im apikalen und den mittleren Segmenten des linken Ventrikels lokalisiert, deutlich mehr als bei den Patienten des DCM-Kollektives. Das Non-Compaction Ausmaß korrelierte nur schwach mit der globalen linksventrikulären systolischen Funktion (LVEF). Ebenso verhielt es sich mit der mittels Strain Rate Imaging ermittelten regionalen linksventrikulären Funktion. Die regionale myokardiale systolische Deformation bei IVNM Patienten war links- und rechtsventrikulär sowohl longitudinal als auch radial signifikant vermindert. Auffällige Unterschiede zwischen den IVNM- und DCM-Kollektiven fanden sich in der longitudinalen myokardialen Funktion. Hier zeigten IVNM-Patienten vom Apex zur Basis zunehmende Strain- und Strain-Rate-Gradienten, wohingegen DCM-Patienten gleichmäßig über alle Segmente reduzierte Strain und Strain-Rate Werte aufwiesen. Die mittels 2D Speckle Tracking erhobenen Werte deckten sich mit den Ergebnissen aus den Gewebedoppler Aufnahmen. Die myokardiale kontraktions-Synchronie war bei beiden Patientenkollektiven gestört. Die Zeit bis zum Erreichen der systolischen Spitzengeschwindigkeit war bei beiden Gruppen verlängert. Die myokardialen Asynchronien waren in beiden Gruppen ähnlich und sind aus diesem Grund differentialdiagnostisch nicht hilfreich. Zusammenfassend lässt sich feststellen, dass IVNM und DCM Kardiomyopathien mit reduzierter regionaler myokardialer Funktion sind, die eine mechanische Asynchronie aufweisen. Nichtsdestotrotz kann man die Differentialdiagnose über eine Analyse der Hypertrabekularisierung sowie der regionalen myokardialen Deformierungsmuster stellen. KW - Ultraschallkardiographie KW - Gewebedoppler KW - Non-Compaction Kardiomyopathie KW - Speckle tracking KW - left ventricular non-compaction KW - speckle tracking Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-55838 ER - TY - JOUR A1 - Kasang, Christa A1 - Kalluvya, Samuel A1 - Majinge, Charles A1 - Stich, August A1 - Bodem, Jochen A1 - Kongola, Gilbert A1 - Jacobs, Graeme B. A1 - Mlewa, Mathias A1 - Mildner, Miriam A1 - Hensel, Irina A1 - Horn, Anne A1 - Preiser, Wolfgang A1 - van Zyl, Gert A1 - Klinker, Hartwig A1 - Koutsilieri, Eleni A1 - Rethwilm, Axel A1 - Scheller, Carsten A1 - Weissbrich, Benedikt T1 - HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Naïve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High JF - PLoS One N2 - 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-naïve population. Methods and Findings HIVDR was determined in 88 sequentially enrolled ART-naïve 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-naïve 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-naïve 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-naïve HIV-infected population. KW - Tanzania KW - antimicrobial resistance KW - antiretroviral therapy KW - HIV KW - sequence databases KW - mutation databases KW - antiretrovirals KW - HIV diagnosis and management Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137988 VL - 6 IS - 8 ER - TY - JOUR A1 - Kistler, Andreas D. A1 - Siwy, Justyna A1 - Frank, Breunig A1 - Jeevaratnam, Praveen A1 - Scherl, Alexander A1 - Mullen, William A1 - Warnock, David G. A1 - Wanner, Christoph A1 - Hughes, Derralynn A. A1 - Mischak, Harald A1 - Wüthrich, Rudolf P. A1 - Serra, Andreas L. T1 - A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy JF - PLoS ONE N2 - 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. KW - Chronic kidney-disease KW - Onset hypertrophic cardiomyopathy KW - Mass-spectrometry KW - Alpha-galactosidase KW - Hemodialysis-patients KW - Clinical proteomics KW - Young-patients KW - Discovery KW - Globotriaosylceramide KW - Prevalence Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133526 VL - 6 IS - 6 ER - TY - JOUR A1 - Edelmann, Frank A1 - Stahrenberg, Raoul A1 - Gelbrich, Götz A1 - Durstewitz, Kathleen A1 - Angermann, Christiane E. A1 - Düngen, Hans-Dirk A1 - Scheffold, Thomas A1 - Zugck, Christian A1 - Maisch, Bernhard A1 - Regitz-Zagrosek, Vera A1 - Hasenfuß, Gerd A1 - Pieske, Burkert M. A1 - Wachter, Rolf T1 - Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction JF - Clinical Research in Cardiology N2 - 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. KW - Heart failure with preserved ejection fraction KW - Heart failure with reduced ejection fraction KW - Comorbidities KW - Physical impairment Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134354 VL - 100 IS - 9 ER - TY - JOUR A1 - Carsten A., Böger A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M. A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M. A1 - Kutalik, Zoltán A1 - Wichmann, H.-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G. A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André A1 - Hofman, Albert A1 - Beckmann, Jacques S. A1 - Krämer, Bernhard K. A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I. A1 - Heid, Iris M. A1 - Fox, Caroline S. A1 - Kao, W.H. T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD JF - PLoS Genetics N2 - 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. KW - Chronic Kidney-disease KW - Stage renal-disease KW - Glomerular-filtration-rate KW - Diabetic-nephropathy KW - General-population KW - African-americans KW - Risk KW - Progression KW - Mortality KW - Variants Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133758 VL - 7 IS - 9 ER - TY - JOUR A1 - Güder, Gülmisal A1 - Brenner, Susanne A1 - Angermann, Christiane E. A1 - Ertl, Georg A1 - Held, Matthias A1 - Sachs, Alfred P. A1 - Lammers, Jan Willem A1 - Zanen, Peter A1 - Hoes, Arno W. A1 - Störk, Stefan A1 - Rutten, Frans H. T1 - "GOLD or lower limit of normal definition? a comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study" N2 - 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. KW - Medizin KW - COPD diagnosis KW - lower limit of normal KW - GOLD KW - validation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75193 ER - TY - JOUR A1 - Reiter, Theresa A1 - Ritter, Oliver A1 - Prince, Martin R. A1 - Nordbeck, Peter A1 - Wanner, Christoph A1 - Nagel, Eike A1 - Bauer, Wolfgang R. T1 - Minimizing Risk of Nephrogenic systemic fibrosis in Cardiovascular Magnetic Resonance N2 - 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. KW - CMR Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75068 ER - TY - JOUR A1 - Reiter, Theresa A1 - Ritter, Oliver A1 - Nordbeck, Peter A1 - Beer, Meinrad A1 - Bauer, Wolfgang Rudolf T1 - MRI-guided ablation of wide complex tachycardia in a univentricular heart JF - World Journal of Cardiology N2 - 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. KW - magnetic resonsance imaging KW - ablation KW - Fontan’s Operation KW - ventricular tachycardia KW - univentricular heart Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123165 VL - 4 IS - 8 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis – the membrane study JF - BMC Nephrology N2 - 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. KW - hemodialysis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124052 VL - 13 IS - 50 ER - TY - JOUR A1 - Nordbeck, Peter A1 - Beer, Meinrad A1 - Köstler, Herbert A1 - Ladd, Mark E. A1 - Quick, Harald H. A1 - Bauer, Wolfgang R. A1 - Ritter, Oliver T1 - Cardiac catheter ablation under real-time magnetic resonance guidance JF - European Heart Journal N2 - 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 … KW - magnetic resonance Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125638 VL - 33 IS - 15 ER - TY - JOUR A1 - Warnock, David G. A1 - Ortiz, Alberto A1 - Mauer, Michael A1 - Linthorst, Gabor E. A1 - Oliveira, João P. A1 - Serra, Andreas L. A1 - Maródi, László A1 - Mignani, Renzo A1 - Vujkovac, Bojan A1 - Beitner-Johnson, Dana A1 - Lemay, Roberta A1 - Cole, J. Alexander A1 - Svarstad, Einar A1 - Waldek, Stephen A1 - Germain, Dominique P. A1 - Wanner, Christoph T1 - Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation JF - Nephrology Dialysis Transplantation N2 - 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. KW - proteinuria KW - enzyme replacement therapy KW - alpha galactosidase KW - Fabry disease KW - genetic renal disease Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124697 VL - 27 IS - 3 ER - TY - JOUR A1 - Kiryluk, Krzysztof A1 - Yifu, Li A1 - Sanna-Cherchi, Simone A1 - Rohanizadegan, Mersedeh A1 - Suzuki, Hitoshi A1 - Eitner, Frank A1 - Snyder, Holly J. A1 - Choi, Murim A1 - Hou, Ping A1 - Scolari, Francesco A1 - Izzi, Claudia A1 - Gigante, Maddalena A1 - Gesualdo, Loreto A1 - Savoldi, Silvana A1 - Amoroso, Antonio A1 - Cusi, Daniele A1 - Zamboli, Pasquale A1 - Julian, Bruce A. A1 - Novak, Jan A1 - Wyatt, Robert J. A1 - Mucha, Krzysztof A1 - Perola, Markus A1 - Kristiansson, Kati A1 - Viktorin, Alexander A1 - Magnusson, Patrik K. A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - Boland, Anne A1 - Metzger, Marie A1 - Thibaudin, Lise A1 - Wanner, Christoph A1 - Jager, Kitty J. A1 - Goto, Shin A1 - Maixnerova, Dita A1 - Karnib, Hussein H. A1 - Nagy, Judit A1 - Panzer, Ulf A1 - Xie, Jingyuan A1 - Chen, Nan A1 - Tesar, Vladimir A1 - Narita, Ichiei A1 - Berthoux, Francois A1 - Floege, Jürgen A1 - Stengel, Benedicte A1 - Zhang, Hong A1 - Lifton, Richard P. A1 - Gharavi, Ali G. T1 - Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis JF - PLoS Genetics N2 - 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. KW - linkage KW - genome-wide association KW - multiple sclerosis KW - renal disease KW - New mexico KW - recombination hotspot KW - italian population KW - natural history KW - HLA KW - glomerulonephritis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130195 VL - 8 IS - 6 ER - TY - JOUR A1 - Betz, Boris A1 - Schneider, Reinhard A1 - Kress, Tobias A1 - Schick, Martin Alexander A1 - Wanner, Christoph A1 - Sauvant, Christoph T1 - Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury JF - PPAR Research N2 - 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. KW - dysfunction KW - activated-receptor gamma KW - ischemia-reperfusion injury KW - failure KW - kidney KW - agnoists KW - mices KW - inos KW - pathophysiology KW - pioglitazone Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130872 VL - 2012 IS - Article ID 219319 ER - TY - JOUR A1 - Ponnuswamy, Padmapriya A1 - Schröttle, Angelika A1 - Ostermeier, Eva A1 - Grüner, Sabine A1 - Huang, Paul L. A1 - Ertl, Georg A1 - Hoffmann, Ulrich A1 - Nieswandt, Bernhard A1 - Kuhlencordt, Peter J. T1 - eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice JF - PLoS One N2 - 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. KW - platelet adhesion KW - lesion formation KW - nitric oxide synthase KW - endothelial cell interactions KW - double knockout mice KW - apolipoprotein E KW - deficient mice KW - in vivo KW - accelerated atherosclerosis KW - leukocyte adhesion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134866 VL - 7 IS - 1 ER - TY - JOUR A1 - Reiter, Theresa A1 - Gensler, Daniel A1 - Ritter, Oliver A1 - Weiss, Ingo A1 - Geistert, Wolfgang A1 - Kaufmann, Ralf A1 - Hoffmeister, Sabine A1 - Friedrich, Michael T. A1 - Wintzheimer, Stefan A1 - Düring, Markus A1 - Nordbeck, Peter A1 - Jakob, Peter M. A1 - Ladd, Mark E. A1 - Quick, Harald H. A1 - Bauer, Wolfgang R. T1 - Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures JF - Journal of Cardiovascular Magnetic Resonance N2 - 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. KW - EP Procedures KW - radiofrequency ablation KW - contact force KW - lesion size KW - MRI KW - temperature KW - tissue KW - wires KW - model KW - ablation KW - safety KW - catheter tip KW - MR guidance Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134927 VL - 14 IS - 12 ER - TY - JOUR A1 - Ronchi, Cristina L. A1 - Leich, Ellen A1 - Sbiera, Silviu A1 - Weismann, Dirk A1 - Rosenwald, Andreas A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways JF - Neoplasia N2 - 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. KW - kinase KW - comparative genomic hybridization KW - high-resolution analysis KW - Cushings syndrome KW - neutral loss KW - tumors KW - serum KW - expression KW - carcinoma KW - catenin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134953 VL - 14 IS - 3 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study JF - BMC Nephrology N2 - 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. KW - XA KW - low molecular weight KW - severe renal insufficiency KW - unfractionated heparin KW - standard heparin KW - enoxaparin KW - metaanalysis KW - coagulation KW - fragmin KW - sodium Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134845 VL - 13 IS - 50 ER - TY - JOUR A1 - Rahimi, Kazem A1 - Bhala, Neeraj A1 - Kamphuisen, Pieter A1 - Emberson, Jonathan A1 - Biere-Rafi, Sara A1 - Krane, Vera A1 - Robertson, Michele A1 - Wikstrand, John A1 - McMurray, John T1 - Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials JF - PLoS Medicine N2 - 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. KW - deep-vein thrombosis KW - cardiovascular disease KW - placebo-controlled trial KW - coronary-heart-disease KW - coa reductase inhibitors KW - lipid-lowering therapy KW - high-dose atorvastatin KW - myocardial-infarction KW - primary prevention KW - double-blind Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134279 VL - 9 IS - 9 ER - TY - JOUR A1 - de Zeeuw, Dick A1 - Akizawa, Tadao A1 - Agarwal, Rajiv A1 - Audhya, Paul A1 - Bakris, George L. A1 - Chin, Melanie A1 - Krauth, Melissa A1 - Lambers Heerspink, Hiddo J. A1 - Meyer, Colin J. A1 - McMurray, John J. A1 - Parving, Hans-Henrik A1 - Pergola, Pablo E. A1 - Remuzzi, Giuseppe A1 - Toto, Robert D. A1 - Vaziri, Nosratola D. A1 - Wanner, Christoph A1 - Warnock, David G. A1 - Wittes, Janet A1 - Chertow, Glenn M. T1 - Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON) JF - American Journal of Nephrology N2 - 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. KW - clinical trial KW - diabetes mellitus KW - glomerular filtration rate KW - trial design KW - bardoxolone methyl KW - Nrf2 KW - end-stage renal disease KW - cardiovascular death KW - chronic kidney disease Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196832 SN - 0250-8095 SN - 1421-9670 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 37 IS - 3 ER - TY - JOUR A1 - Dörhöfer, Lena A1 - Lammert, Alexander A1 - Krane, Vera A1 - Gorski, Mathias A1 - Banas, Bernhard A1 - Wanner, Christoph A1 - Krämer, Bernhard K. A1 - Heid, Iris M. A1 - Böger, Carsten A. T1 - Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2 JF - BMC Medical Genetics N2 - 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. KW - chronic kidney-disease KW - stage renal-disease KW - glomerular-filtration-rate KW - genome-wide association KW - blood-glucose control KW - genetics KW - serum creatinine KW - cardiovascular disease KW - replacement therapy KW - United States KW - risk factors KW - diabetes mellitus type 2 KW - diabetic nephropathy KW - end stage renal disease KW - cardiovascular morbidity KW - diabetes complications KW - epidemiology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122040 SN - 1471-2350 VL - 14 IS - 25 ER - TY - JOUR A1 - Brandenburg, Vincent M. A1 - Kramann, Rafael A1 - Koos, Ralf A1 - Krueger, Thilo A1 - Schurgers, Leon A1 - Mühlenbruch, Georg A1 - Hübner, Sinah A1 - Gladziwa, Ulrich A1 - Drechler, Christiane A1 - Ketteler, Markus T1 - Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study JF - BMC Nephrology N2 - 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. KW - coronary calcification KW - cardiovascular disease KW - aortic valve disease KW - calcium KW - mortality KW - sclerostin KW - aortic valve KW - bone formation KW - computed tomography KW - fetuin A KW - risk factors KW - GLA protein UCMGP KW - kidney-disease CKD KW - coronary-artery calcification KW - hemodialysis KW - mineral metabolism KW - vascular calcification KW - renal osteodystrophy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122070 SN - 1471-2369 VL - 14 IS - 219 ER - TY - JOUR A1 - Eisele, Marion A1 - Blozik, Eva A1 - Störk, Stefan A1 - Träder, Jens-Martin A1 - Herrmann-Lingen, Christoph A1 - Scherer, Martin T1 - 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 JF - BMC Family Practice N2 - 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. KW - anxiety KW - depression KW - health care research KW - heart failure KW - prevalence KW - observational study KW - prognosis KW - quality of life KW - hospitalization KW - treatment KW - mortality KW - task force KW - health questionnaire KW - cardiovascular care KW - validity KW - scale KW - validation KW - outcomes KW - standardization KW - population Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121881 SN - 1471-2296 VL - 14 IS - 180 ER - TY - JOUR A1 - Weidemann, Frank A1 - Sanchez-Nino, Maria D. A1 - Politei, Juan A1 - Oliveira, João-Paulo A1 - Wanner, Christoph A1 - Warnock, David G. A1 - Oritz, Alberto T1 - Fibrosis: a key feature of Fabry disease with potential therapeutic implications JF - Orphanet Journal of Rare Diseases N2 - 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. KW - Fabry KW - fibrosis KW - podocyte KW - Lyso-Gb3 KW - kidney KW - enzyme replacement therapy KW - alpha-galactosidase-A KW - focal semental glomerulosclerosis KW - cardiovascular magnetic-resonance KW - left-ventricular hypertrophy KW - biopsy findings KW - agalsidase-beta KW - natural-history data KW - cardiac energy metabolism KW - randomized controlled trial Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124773 SN - 1750-1172 VL - 8 IS - 116 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Ritz, Eberhard A1 - Tomaschitz, Andreas A1 - Pilz, Stefan A1 - Schönfeld, Stephan A1 - Blouin, Katja A1 - Bidlingmaier, Martin A1 - Hammer, Fabian A1 - Krane, Vera A1 - März, Winfried A1 - Allolio, Bruno A1 - Fassnacht, Martin A1 - Wanner, Christoph T1 - Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients JF - European Heart Journal N2 - 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. KW - mortality KW - kidney disease KW - cardiovascular events KW - sudden cardiac death KW - cortisol KW - aldosterone Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132562 VL - 34 ER - TY - JOUR A1 - Blömer, Nadja A1 - Pachel, Christina A1 - Hofmann, Urlich A1 - Nordbeck, Peter A1 - Bauer, Wolfgang A1 - Mathes, Denise A1 - Frey, Anna A1 - Bayer, Barbara A1 - Vogel, Benjamin A1 - Ertl, Georg T1 - 5-Lipoxygenase facilitates healing after myocardial infarction JF - Basic Research in Cardiology N2 - 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. KW - lipoxygenase KW - myocardial infarction KW - extracellular matrix remodeling KW - inflammation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132602 VL - 108 IS - 4 ER - TY - JOUR A1 - Frantz, Stefan A1 - Klaiber, Michael A1 - Baba, Hideo A. A1 - Oberwinkler, Heinz A1 - Völker, Katharina A1 - Gaßner, Birgit A1 - Bayer, Barbara A1 - Abeßer, Marco A1 - Schuh, Kai A1 - Feil, Robert A1 - Hofmann, Franz A1 - Kuhn, Michaela T1 - Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I JF - European Heart Journal N2 - 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. KW - cyclic KW - GMPcGMP-dependent protein kinase I KW - cardiac hypertrophy KW - natriuretic peptide KW - Ca2+i handling Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134693 VL - 34 ER - TY - JOUR A1 - Haring, Bernhard A1 - Leng, Xiaoyan A1 - Robinson, Jennifer A1 - Johnson, Karen C. A1 - Jackson, Rebecca D. A1 - Beyth, Rebecca A1 - Wactawski-Wende, Jean A1 - Wyler von Ballmoos, Moritz A1 - Goveas, Joseph S. A1 - Kuller, Lewis H. A1 - Wassertheil-Smoller, Sylvia T1 - Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study JF - Journal of the American Heart Association N2 - 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. KW - postmenopausal women KW - cognitive decline KW - cardiovascular diseases Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129487 VL - 2 IS - e000369 ER - TY - JOUR A1 - Weidemann, F. A1 - Niemann, M. A1 - Stork, S. A1 - Breunig, F. A1 - Beer, M. A1 - Sommer, C. A1 - Herrmann, S. A1 - Ertl, G. A1 - Wanner, C. T1 - Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications JF - Journal of Internal Medicine N2 - 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. KW - Fabry disease KW - α-galactosidase A KW - dialysis KW - prognosis KW - stroke KW - sudden cardiac death Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132075 VL - 247 IS - 4 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Schmiedeke, Benjamin A1 - Niemann, Markus A1 - Schmiedeke, Daniel A1 - Krämer, Johannes A1 - Turkin, Irina A1 - Blouin, Katja A1 - Emmert, Andrea A1 - Pilz, Stefan A1 - Obermayer-Pietsch, Barbara A1 - Wiedemann, Frank A1 - Breunig, Frank A1 - Wanner, Christoph T1 - Potential role of vitamin D deficiency on Fabry cardiomyopathy JF - Journal of Inherited Metabolic Disease N2 - 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. KW - Fabry patient KW - urinary protein excretion KW - hypertrophic cardiomyopathy KW - renal fibrosis KW - left ventricular mass KW - LV mass KW - diabetic mouse KW - septal hypertrophy KW - Fabry nephropathy KW - cardiac hypertrophy KW - cornea verticillata KW - enzyme replacement therapy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132102 VL - 37 IS - 2 ER - TY - JOUR A1 - Hofmann, Ulrich A1 - Frantz, Stefan T1 - How can we cure a heart "in flame"? A translational view on inflammation in heart failure JF - Basic Research in Cardiology N2 - The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-a led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective. KW - cytokines KW - immuno-modulation KW - heart failure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134497 VL - 108 IS - 356 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Niemann, Markus A1 - Herrmann, Sebastian A1 - Cikes, Maja A1 - Störk, Stefan A1 - Beer, Meinrad A1 - Gaudron, Philipp Daniel A1 - Morbach, Caroline A1 - Knop, Stefan A1 - Geissinger, Eva A1 - Ertl, Georg A1 - Bijnens, Bart A1 - Weidemann, Frank T1 - Impact of Regional Left Ventricular Function on Outcome for Patients with AL Amyloidosis JF - PLoS ONE N2 - Objectives The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy. Background Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome. Methods LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days. Results Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35% vs. compensated 78%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14%, mild 27%, intermediate 67%, and severe 64%). Mid-septum LSsys<11% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival. Conclusions Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy. KW - regression analysis KW - ejection fraction KW - echocardiography KW - cardiac transplantation KW - deformation KW - amyloidosis KW - prognosis KW - stem cell transplantation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130293 VL - 8 IS - 3 ER - TY - JOUR A1 - Schneider, Andreas A1 - Schneider, Markus P. A1 - Scharnagl, Hubert A1 - Jardine, Alan G. A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes JF - BMC Nephrology N2 - Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients. Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers. Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance. Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies. KW - type 2 diabetes KW - heodialysis patients Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128695 VL - 14 IS - 67 ER - TY - JOUR A1 - Quinkler, Marcus A1 - Beuschlein, Felix A1 - Hahner, Stefanie A1 - Meyer, Gesine A1 - Schöfl, Christof A1 - Stalla, Günter K. T1 - Adrenal Cortical Insufficiency-a Life Threatening Illness With Multiple Etiologies JF - Deutsches Ärzteblatt International N2 - Background: The clinical signs of adrenal cortical insufficiency (incidence, ca. 25 per million per year; prevalence, ca. 400 per million) are nonspecific, and misdiagnoses are therefore common. Glucocorticoid substitution therapy has been in use for 50 years but is not a wholly adequate treatment. Our understanding of this disease remains incomplete in many ways. Methods: We selectively searched the Medline database for publications on adrenal cortical insufficiency, with particular attention to studies from the year 2000 onward (search terms: "adrenal insufficiency" or "Addison's disease" or "hypopituitarism"). Results: Hydrocortisone substitution therapy is often given in doses of 10-25 mg/day, timed according to the circadian rhythm. Gastrointestinal and other, febrile infections account for 30-50% of life-threatening adrenocortical crises. Such crises affect 8 of 100 persons with adrenal cortical insufficiency per year and must be treated by the immediate administration of glucocorticoids and fluids. When persons with adrenal cortical insufficiency are acutely ill or are otherwise under unusual stress, they may need additional amounts of hydrocortisone, often in the range of 5-10 mg but occasionally as high as 200 mg. The sustained administration of excessive amounts of steroid can shorten patients' lives by several years. Inappropriate substitution therapy can cause other major medical conditions, such as metabolic syndrome and osteoporosis. Conclusion: Important measures for the prevention of adrenocortical crises include improved care by treating physicians, education of patients and their families, the provision of emergency identifying documents, and the prescription of glucocorticoid emergency kits. KW - short term KW - subjective health-status KW - modified-release hydrocortisone KW - glucocorticoid replacement regimens KW - Addisons disease KW - therapeutic management KW - hypopituitary patients KW - premature mortality KW - circadian therapy KW - adult patients Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131662 VL - 110 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Kolleritz, Barbara A1 - Meinitzer, Andreas A1 - März, Winfried A1 - Ritz, Eberhard A1 - König, Paul A1 - Neyer, Ulrich A1 - Pilz, Stefan A1 - Wanner, Christoph A1 - Kronenberg, Florian T1 - Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study JF - PLoS ONE N2 - Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06). Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations. KW - risk KW - alkaline phosphatase KW - cardiovascular events KW - nictric-oxide KW - induced insulin-release KW - creatine synthesis KW - renal function KW - heart failure KW - rat kidney KW - L-arginine Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130979 VL - 8 IS - 5 ER - TY - JOUR A1 - Korb, Doreen A1 - Tng, Priscilla Y. A1 - Milenkovic, Vladimir M. A1 - Reichhart, Nadine A1 - Strauss, Olaf A1 - Ritter, Oliver A1 - Fischer, Tobias A1 - Benz, Peter M. A1 - Schuh, Kai T1 - Identification of PDZ domain containing proteins interacting with \(Ca_v1.2\) and PMCA4b JF - ISRN Cell Biology N2 - PDZ (PSD-95/Disc large/Zonula occludens-1) protein interaction domains bind to cytoplasmic protein C-termini of transmembrane proteins. In order to identify new interaction partners of the voltage-gated L-type \(Ca^{2+}\) channel Cav1.2 and the plasma membrane \(Ca^{2+}\) ATPase 4b (PMCA4b), we used PDZ domain arrays probing for 124 PDZ domains. We confirmed this byGST pulldowns and immunoprecipitations. In PDZ arrays, strongest interactionswith \(Ca_v1.2\) and PMCA4b were found for the PDZ domains of SAP-102, MAST-205, MAGI-1, MAGI-2, MAGI-3, and ZO-1. We observed binding of the \(Ca_v1.2\) C-terminus to PDZ domains of NHERF1/2, Mint-2, and CASK. PMCA4b was observed to interact with Mint-2 and its known interactions with Chapsyn-110 and CASK were confirmed. Furthermore, we validated interaction of \(Ca_v1.2\) and PMCA4b with NHERF1/2, CASK,MAST-205 and MAGI-3 viaimmunoprecipitation. We also verified the interaction of \(Ca_v1.2\) and nNOS and hypothesized that nNOS overexpression might reduce \(Ca^{2+}\) influx through \(Ca_v1.2\). To address this, we measured \(Ca^{2+}\) currents in HEK 293 cells co-expressing \(Ca_v1.2\) and nNOS and observed reduced voltage-dependent \(Ca_v1.2\) activation. Taken together, we conclude that \(Ca_v1.2\) and PMCA4b bind promiscuously to various PDZ domains, and that our data provides the basis for further investigation of the physiological consequences of these interactions. KW - Cell Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130585 IS - Article ID 265182 ER - TY - JOUR A1 - Frey, A. A1 - Ertl, G. A1 - Angermann, C. E. A1 - Hofmann, U. A1 - Störk, S. A1 - Frantz, S. T1 - Complement C3c as a Biomarker in Heart Failure JF - Mediators of Inflammation N2 - Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF). Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. Methods and Results. Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17%of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. Conclusion. Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure. KW - medicine Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129668 VL - 2013 IS - Article ID 716902 ER - TY - JOUR A1 - Pachel, Christina A1 - Mathes, Denise A1 - Bayer, Barbara A1 - Dienesch, Charlotte A1 - Wangorsch, Gaby A1 - Heitzmann, Wolfram A1 - Lang, Isabell A1 - Ardehali, Hossein A1 - Ertl, Georg A1 - Dandekar, Thomas A1 - Wajant, Harald A1 - Frantz, Stefan T1 - Exogenous Administration of a Recombinant Variant of TWEAK Impairs Healing after Myocardial Infarction by Aggravation of Inflammation JF - PLoS ONE N2 - Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium. KW - apoptosis KW - myocardial infarction KW - neutrophils KW - cytokines KW - inflammation KW - myocardium KW - heart KW - extracellular matrix Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129889 VL - 8 IS - 11 ER - TY - JOUR A1 - Nordbeck, Peter A1 - Bönhof, Leoni A1 - Hiller, Karl-Heinz A1 - Voll, Sabine A1 - Arias-Loza, Paula A1 - Seidlmaier, Lea A1 - Williams, Tatjana A1 - Ye, Yu-Xiang A1 - Gensler, Daniel A1 - Pelzer, Theo A1 - Ertl, Georg A1 - Jakob, Peter M. A1 - Bauer, Wolfgang R. A1 - Ritter, Oliver T1 - Impact of Thoracic Surgery on Cardiac Morphology and Function in Small Animal Models of Heart Disease: A Cardiac MRI Study in Rats JF - PLoS ONE N2 - Background Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. Methods Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. Results Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. Conclusion Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients. KW - heart rate KW - body weight KW - surgical and invasive medical procedures KW - magnetic resonance imaging KW - blood KW - vascular surgery KW - myocardial infarction KW - cardiac ventricles Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130064 VL - 8 IS - 8 ER - TY - JOUR A1 - Palkovits, Miklós A1 - Šebeková, Katarína A1 - Klenovics, Kristina Simon A1 - Kebis, Anton A1 - Fazeli, Gholamreza A1 - Bahner, Udo A1 - Heidland, August T1 - Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine JF - PLoS ONE N2 - The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances. KW - brain natriuretic peptide KW - kidneys KW - cognitive impairment KW - central nervous system KW - chronic kidney disease KW - neurons KW - homeostasis KW - blood pressure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130108 VL - 8 IS - 6 ER - TY - JOUR A1 - Haring, Bernhard A1 - Leng, Xiaoyan A1 - Robinson, Jennifer A1 - Johnson, Karen C. A1 - Jackson, Rebecca D. A1 - Beyth, Rebecca A1 - Wactawski-Wende, Jean A1 - Wyler von Ballmoos, Moritz A1 - Goveas, Joseph S. A1 - Kuller, Lewis H. A1 - Wassertheil-Smoller, Sylvia T1 - Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women’s Health Initiative Memory Study N2 - 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. KW - cardiovascular diseases KW - cognitive decline KW - postmenopausal women Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111376 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Ronchi, Cristina L. A1 - Leich, Ellen A1 - Henzel, Katharina A1 - Rosenwald, Andreas A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence? JF - PLoS ONE N2 - Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors. KW - adenomas KW - cancer diagnosis KW - cancer detection KW - carcinogenesis KW - carcinomas KW - chromosomes KW - genetic loci KW - malignant tumors KW - notch signaling Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97218 ER - TY - JOUR A1 - Chopra, Martin A1 - Lang, Isabell A1 - Salzmann, Steffen A1 - Pachel, Christina A1 - Kraus, Sabrina A1 - Bäuerlein, Carina A. A1 - Brede, Christian A1 - Jordán Garrote, Ana-Laura A1 - Mattenheimer, Katharina A1 - Ritz, Miriam A1 - Schwinn, Stefanie A1 - Graf, Carolin A1 - Schäfer, Viktoria A1 - Frantz, Stefan A1 - Einsele, Hermann A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1 JF - PLoS ONE N2 - Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome. KW - Bioluminescence KW - cancer treatment KW - cell staining KW - cytokines KW - immune cells KW - metastasis KW - regulatory T cells KW - T cells Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97246 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Kahn, Ann-Kathrin A1 - Kramer, Daniela A1 - Zeller, Daniel A1 - Casanova-Molla, Jordi A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Katsarava, Zaza A1 - Sommer, Claudia T1 - Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case–control study JF - BMC Neurology N2 - Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). Methods In this case–control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. Results All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. Conclusion Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction. KW - Fabry disease KW - Pain-related evoked potentials KW - Small fiber neuropathy KW - A-delta fibers Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96527 UR - http://www.biomedcentral.com/1471-2377/13/47 ER - TY - JOUR A1 - Gassenmaier, Tobias A1 - Gorski, Armin A1 - Aleksic, Ivan A1 - Deubner, Nikolas A1 - Weidemann, Frank A1 - Beer, Meinrad T1 - Impact of cardiac magnet resonance imaging on management of ventricular septal rupture after acute myocardial infarction JF - World Journal of Cardiology N2 - A 74-year-old man was admitted to the cardiac catheterization laboratory with acute myocardial infarction. After successful angioplasty and stent implantation into the right coronary artery, he developed cardiogenic shock the following day. Echocardiography showed ventricular septal rupture. Cardiac magnet resonance imaging (MRI) was performed on the critically ill patient and provided detailed information on size and localization of the ruptured septum by the use of fast MRI sequences. Moreover, the MRI revealed that the ventricular septal rupture was within the myocardial infarction area, which was substantially larger than the rupture. As the patient’s condition worsened, he was intubated and had intra-aortic balloon pump implanted, and extracorporeal membrane oxygenation was initiated. During the following days, the patient’s situation improved, and surgical correction of the ventricular septal defect could successfully be performed. To the best of our knowledge, this case report is the first description of postinfarction ventricular septal rupture by the use of cardiac MRI in an intensive care patient with cardiogenic shock and subsequent successful surgical repair. KW - Cardiac magnetic resonance imaging KW - Ventricular septal rupture KW - Myocardial infarction KW - surgical repair KW - Extracorporeal membrane oxygenation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96562 ER - TY - JOUR A1 - Winter, Patrick A1 - Kampf, Thomas A1 - Helluy, Xavier A1 - Gutjahr, Fabian T. A1 - Meyer, Cord B. A1 - Rommel, Eberhard A1 - Bauer, Wolfgang R. A1 - Jakob, Peter M. A1 - Herold, Volker T1 - Fast retrospectively triggered local pulse-wave velocity measurements in mice with CMR-microscopy using a radial trajectory JF - Journal of Cardiovascular Magnetic Resonance N2 - Background The aortic pulse-wave velocity (PWV) is an important indicator of cardiovascular risk. In recent studies MRI methods have been developed to measure this parameter noninvasively in mice. Present techniques require additional hardware for cardiac and respiratory gating. In this work a robust self-gated measurement of the local PWV in mice without the need of triggering probes is proposed. Methods The local PWV of 6-months-old wild-type C57BL/6J mice (n=6) was measured in the abdominal aorta with a retrospectively triggered radial Phase Contrast (PC) MR sequence using the flow-area (QA) method. A navigator signal was extracted from the CMR data of highly asymmetric radial projections with short repetition time (TR=3 ms) and post-processed with high-pass and low-pass filters for retrospective cardiac and respiratory gating. The self-gating signal was used for a reconstruction of high-resolution Cine frames of the aortic motion. To assess the local PWV the volume flow Q and the cross-sectional area A of the aorta were determined. The results were compared with the values measured with a triggered Cartesian and an undersampled triggered radial PC-Cine sequence. Results In all examined animals a self-gating signal could be extracted and used for retrospective breath-gating and PC-Cine reconstruction. With the non-triggered measurement PWV values of 2.3±0.2 m/s were determined. These values are in agreement with those measured with the triggered Cartesian (2.4±0.2 m/s) and the triggered radial (2.3±0.2 m/s) measurement. Due to the strong robustness of the radial trajectory against undersampling an acceleration of more than two relative to the prospectively triggered Cartesian sampling could be achieved with the retrospective method. Conclusion With the radial flow-encoding sequence the extraction of a self-gating signal is feasible. The retrospective method enables a robust and fast measurement of the local PWV without the need of additional trigger hardware. KW - pulse-wave velocity KW - mouse KW - self-gating KW - phase-contrast CMR KW - non-triggered KW - retrospective KW - radial KW - aorta Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96602 UR - http://jcmr-online.com/content/15/1/88 ER - TY - THES A1 - Devine, Eric T1 - Increased removal of protein bound uremic toxins through reversible modification of the ionic strength during hemodiafiltration T1 - Erhöhte Elimination proteingebundener Urämietoxine durch reversible Modifikation der Ionenstärke während der Hämodiafiltration N2 - A large number of metabolic waste products accumulate in the blood of patients with renal failure. Since these solutes have deleterious effects on the biological functions, they are called uremic toxins and have been classified in three groups: 1) small water soluble solutes (MW < 500 Da), 2) small solutes with known protein binding (MW < 500 Da), and 3) middle molecules (500 Da < MW < 60 kDa). Protein bound uremic toxins are poorly removed by conventional hemodialysis treatments because of their high protein binding and high distribution volume. The prototypical protein bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are associated with the progression of chronic kidney disease, cardiovascular outcomes, and mortality of patients on maintenance hemodialysis. Furthermore, these two compounds are bound to albumin, the main plasma protein, via electrostatic and/or Van-der-Waals forces. The aim of the present thesis was to develop a dialysis strategy, based on the reversible modification of the ionic strength in the blood stream by increasing the sodium chloride (NaCl) concentration, in order to enhance the removal of protein bound substances, such as IS and pCS, with the ultimate goal to improve clinical patient outcomes. Enhancing the NaCl concentration ([NaCl]) in both human normal and uremic plasma was efficient to reduce the protein bound fraction of both IS and pCS by reducing their binding affinity to albumin. Increasing the ionic strength was feasible during modified pre-dilution hemodiafiltration (HDF) by increasing the [NaCl] in the substitution fluid. The NaCl excess was adequately removed within the hemodialyzer. This method was effective to increase the removal rate of both protein bound uremic toxins. Its ex vivo hemocompatibility, however, was limited by the osmotic shock induced by the high [NaCl] in the substituate. Therefore, modified pre-dilution HDF was further iterated by introducing a second serial cartridge, named the serial dialyzers (SDial) setup. This setting was validated for feasibility, hemocompatibility, and toxin removal efficiency. A better hemocompatibility at similar efficacy was obtained with the SDial setup compared with the modified pre-dilution HDF. Both methods were finally tested in an animal sheep model of dialysis to verify biocompatibility. Low hemolysis and no activation of both the complement and the coagulation systems were observed when increasing the [NaCl] in blood up to 0.45 and 0.60 M with the modified pre-dilution HDF and the SDial setup, respectively. In conclusion, the two dialysis methods developed to transitory enhance the ionic strength in blood demonstrated adequate biocompatibility and improved the removal of protein bound uremic toxins by decreasing their protein bound fraction. The concepts require follow-on clinical trials to assess their in vivo efficacy and their impact on long-term clinical outcomes. N2 - Eine große Zahl von Stoffwechselprodukten akkumuliert im Blut urämischer Patienten mit Nierenversagen. Da diese Moleküle schädliche Wirkungen auf die biologischen Funktionen haben, werden sie als Urämietoxine bezeichnet. Man teilt sie in drei Gruppen ein: 1) kleine wasserlösliche Substanzen (MG < 500 Da), 2) kleine, proteingebundene Substanzen (MG < 500 Da), 3) Mittelmoleküle (500 Da < MG < 60 kDa). Proteingebundene Urämietoxine werden wegen ihrer starken Proteinbindung und ihres Verteilungsvolumen durch klassische Hämodialyseverfahrens nur schlecht entfernt. Die prototypischen proteingebundenen Urämietoxine Indoxylsulfat (IS) und p-Cresylsulfat (pCS) sind bei chronischen niereninsuffizienten Patienten mit dem Fortschreiten der Niereninsuffizienz, Herz-Kreislauf-Erkrankungen und der Mortalität verbunden. Außerdem sind diese beiden Toxine an Albumin, dem wichtigsten Plasmaprotein, durch elektrostatische und/oder Van-der-Waals-Kräfte gebunden. Das Ziel der vorliegenden Arbeit war es, ein Dialyseverfahren basierend auf einer reversiblen Modifikation der Ionenstärke im Blut durch Erhöhung der Natriumchlorid (NaCl)-Konzentration zu entwickeln, um die Entfernung von proteingebundenen Molekülen wie IS und pCS zu erhöhen und dadurch eine Verbesserung des klinischen Verlauf der Patienten zu erreichen. Die Erhöhung der NaCl-Konzentration ([NaCl]) sowohl in normalem als auch in urämischem menschlichem Plasma war geeignet, um den proteingebundenen Anteil von IS und pCS durch Schwächung ihrer Bindungsaffinität zu Albumin zu verringern. Die Erhöhung der Ionenstärke während einer modifizierten Prädilutions-Hämodiafiltration (HDF) konnte durch eine Erhöhung der [NaCl] in der Substitutionslösung umgesetzt werden; dabei wurde der NaCl-Überschuss innerhalb des Dialysators vollständig entfernt. Dieses Verfahren war effektiv, um die Entfernungsrate beider proteingebundenen Urämietoxine zu steigern; seine Ex-vivo-Hämokompatibilität war allerdings aufgrund des osmotischen Schocks infolge der hohen [NaCl] im Substituat begrenzt. Deshalb wurde eine Iteration der modifizierten Prädilutions-HDF durch Einbau eines zweiten, seriellen Dialysators vorgenommen, bezeichnet als serielles Dialysator System (SDial). Diese letzte Methode wurde dann bezüglich der Durchführbarkeit, der Hämokompatibilität und Toxinentfernung validiert. Durch das SDial-System konnte, verglichen mit der modifizierten Prädilutions-HDF, eine bessere Hämokompatibilität bei ähnlicher Wirksamkeit erzielt werden. Beide Methoden, modifizierte Prädilutions-HDF und SDial System, wurden abschließend in ein Tierdialysemodell mit Schafen transferiert, wobei eine zufriedenstellende Biokompatibilität demonstriert werden konnte. Beide, zur vorübergehenden Erhöhung der Ionenstärke im Blut entwickelten Dialyseverfahren zeigten bei zufriedenstellender Biokompatibilität eine verbesserte Entfernung proteingebundener Urämietoxine durch Reduktion ihrer proteingebundenen Fraktion. In einem nächsten Schritt sind klinische Studien erforderlich, die diese Konzepte bezüglich ihrer In-vivo-Wirksamkeit und ihrer langfristigen Wirkung auf den Krankheitsverlauf untersuchen. KW - Hämodiafiltration KW - Ionenstärke KW - Proteinbindung KW - Urämietoxine KW - Hämodialyse KW - Biokompatibilität KW - Ionic strength KW - protein binding KW - uremic toxin KW - hemodialysis KW - biocompatibility KW - Urämie KW - Toxin KW - Ionenstärke KW - Blut Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-83583 ER - TY - THES A1 - Schlereth, Florian T1 - Expression of the DHEA/DHEAS-Shuttle in cell lines and foetal tissue of human liver, adrenal and cartilage T1 - Expression des DHEA/DHEAS-Shuttles in Zelllinien und fötalem Gewebe der menschlichen Leber, Nebenniere und Knorpel N2 - DHEA is a precursor for the male and female sex hormones testosterone and estradiol, which are mainly secreted from the testes and the ovary, respectively. In addition, epidemiological studies showed that low serum levels of DHEA and DHEAS correlate with the incidence of autoimmune disease, cancer and cardiovascular disease. In vitro, DHEA and DHEAS influenced glucose metabolism in a favourable manner. However, positive effects of DHEA substitution were only significant adrenal insufficiency in women. Steroid sulphotransferase 2A1 (SULT2A1) is the responsible enzyme for sulphonation of DHEA to DHEAS which is thought to be the inactive form of DHEA. In this role, SULT2A1 acts as a central regulator of steroid synthesis because sulphonation of DHEA withdraws the substrate for further downstream conversion. Another essential cofactor for sulphonation is PAPS, which is produced by the enzyme PAPS synthase (PAPSS) from ATP and anorganic sulphate. PAPSS exists in the different isoforms PAPSS1 and PAPSS2 and splice variants PAPSS2a and PAPSS2b. Changes in PAPSS activity are thought to influence sulphonation of DHEA significantly. However, neither regulation of PAPSS nor its influence on SULT2A1 have been investigated in human cell lines or humans. The main goal of this thesis was to analyze the enzyme expression of the DHEA/DHEA shuttle, i.e. mRNA and protein of SULT2A1, PAPSS1 and PAPSS2, in various human cell lines. Furthermore, I investigated which cell line could serve as a suitable model for further research regarding regulation of SULT2A1, PAPSS1 and PAPSS2. Here, I could show that the enzymes of the DHEA/DHEAS shuttle were expressed in the human adrenal cell line NCI-h295R as both mRNA and protein. In enzyme assays, I was able to prove conversion of DHEA to DHEAS as well as to different other steroids. However, applying Trilostane, a potent inhibitor of CYP3B, effectively directed conversion of DHEA to DHEAS. Using these findings, future experiments can investigate for example the influence of certain cytokines or endocrine disruptors on expression and activity of PAPSS1/2 and on sulphonation of DHEA. In particular, the relatively equal expression of PAPSS1 and PAPSS2 will enable us to do knock down experiments with siRNA to elucidate how the activity of one enzyme changes when the other one fails. Sulphonation of DHEA by SULT2A1 is thought to happen in the cytoplasm or more precisely in the Golgi apparatus. However, experiments in transfected cells have shown both a cytoplasmatic and a nuclear localisation when both enzymes were expressed at the same time. Immunocytochemistry revealed the same results in the adrenal cell line NCI-h295R, where both enzymes were expressed strongly in the nucleus. The physiological role is not clear and requires further research. Presumably, sulphate is activated in the nucleus. However, one could also speculate that a shift of PAPSS to the nucleus could generate a reservoir, which can be activated by re-localisation to the cytoplasm when more PAPS is needed. Expression of SULT2A1 in some foetal tissues has been investigated earlier. Whilst in adult human cartilage PAPSS1 is predominant, in newly born hamsters PAPSS2 is more abundantly expressed. The expression of PAPSS isoforms in highly sulphonating tissue has not been investigated in humans, so far. This work demonstrated a differential expression of SULT2A1, PAPSS1 and PAPSS2 in adult and foetal liver, adrenal and foetal cartilage tissue. In adult and foetal adrenal expression was similar. However, foetal and adult liver differed in the expression of SULT2A1, which was expressed much more in adult tissue. Most importantly, in foetal cartilage there was only a low expression of SULT2A1 and PAPS seems to mostly provided by PAPSS1, which was considerably higher expressed in cartilage than in other tissues. In contrast, PAPSS2 was mainly expressed in adult and foetal adrenal. Additionally, we reported a case of a female patient who had been investigated for hyperandrogenism. Two mutations in the PAPSS2 gene had led to massively reduced serum levels of DHEAS. One heterozygous mutation in the domain of the APS kinase of the PAPSS2 protein leads to substitution of one amino acid at position 48 (T48R). In vitro experiments showed a residual activity of 6% for this mutation. A second mutation in the ATP sulphurylase domain of PAPSS2 was found. The introduction of thymidine instead of cytidine leads to a stop codon, which is presumed to truncate the protein at position 329 (R329X). In vitro, no residual activity was seen for this mutation. The lack of PAPS reduces sulphonation of DHEA but also sulphonation of proteoglycanes, which leads to skeletal abnormalities. The abundance of DHEA enables massive downstream conversion to androgens leading to clinical features of hyperandrogenism. Regarding the bone abnormalities, it is interesting and surprising that activity of PAPSS1 compensated to a great extent in cartilage but was not able to keep up a more considerable sulphonation of DHEA. Possibly, the subcellular localisation might play a role in this scenario. N2 - DHEA ist eine Vorstufe der männlichen und weiblichen Sexualhormone Testosteron bzw. Oestradiol, welche hauptsächlich in den Testes bzw. Ovarien gebildet werden, aber auch in der Körperperipherie aus DHEA gebildet werden können. Desweiteren konnte in epidemiologischen Studien gezeigt werden, dass niedrige Spiegel von DHEA und DHEAS mit dem Auftreten von Autoimmunerkrankungen, Tumorerkrankungen und Herz-Kreislauf-Erkrankungen korrelieren. In vitro konnten beispielsweise günstige Effekte auf den Glukose-Stoffwechsel nachgewiesen werden. Allerdings konnte eine klinisch sinnvolle Gabe von DHEA nur im Rahmen einer Substitution bei Nebenniereninsuffizienz bei Frauen nachgewiesen werden. Verantwortlich für die Sulfonierung von DHEA ist vor allem die Steroid Sulfotransferase 2A1 (SULT2A1). DHEAS wird als inaktivierte Form von DHEA angesehen. SULT2A1 fungiert als zentraler Regulator der Steroid-Synthese, da durch Sulfonierung von DHEA zu DHEAS der weiteren Konversion das Substrat entzogen wird. Für diese Sulfonierung ist PAPS ein essentieller Kofaktor. Das Enzym PAPS-Synthase, von welchem unterschiedliche Splice-Varianten und Isoformen (PAPSS1 und PAPSS2a/b) vorliegen, stellen PAPS aus ATP und anorganischem Sulfat her. Eine Änderung der Aktivität der PAPS-Synthase kann vermutlich die Aktivität der DHEA Sulfotransferase maßgeblich beeinflussen. Weder die Regulation der PAPS Synthase noch deren Wirkung auf SULT2A1 wurden bisher in menschlichen Zelllinien oder beim Menschen untersucht. Hauptziel dieser Arbeit war die Analyse der Enzymexpression des DHEA/DHEAS Shuttles (mRNA und Protein von SULT2A1, PAPSS1, PAPSS2) in verschiedenen humanen Zelllinien. Ferner wurde untersucht, ob eine der Zelllinien als Modell geeignet ist, die Regulation von SULT2A1 sowie insbesondere PAPSS1 und PAPSS2 in bestimmten pathophysiologischen Situationen zu untersuchen. Hier konnte gezeigt werden, dass insbesondere die adrenale Zelllinie NCI-h295R die Enzyme des DHEA/DHEAS Shuttles sowohl als mRNA als auch als Protein exprimiert. Mittels Enzym-Assay konnte eine Konversion von DHEA zu DHEAS und verschiedenen weiteren Steroiden nachgewiesen werden. Eine Hemmung der CYP3B-abhängigen Konversion mittels Trilostane unterdrückt die Bildung von weiteren Androgenen in NCI-h295R Zellen allerdings effektiv, sodass DHEA größtenteils zu DHEAS konvertiert wurde. Hieraus ergeben sich vielfältige Möglichkeiten, z.B. den Einfluss von Zytokinen oder von endokrinen Disruptoren auf die Sulfonierung von DHEA und auf die Expression von PAPSS1/2 zu untersuchen. Insbesondere kann aufgrund der ähnlichen Expression von PAPSS1 und PAPSS2 in dieser Zelllinie untersucht werden, welche Auswirkung ein Ausschalten eines Enzyms mittels siRNA auf das jeweils andere hat. Die Sulfonierung von DHEA durch SULT2A1 geschieht im Zytoplasma bzw. im Golgi Apparat. Allerdings haben Untersuchungen an transfizierten Zelllinien gezeigt, dass PAPSS1 bzw. PAPSS2 sowohl im Plasma als auch nukleär vorliegen können, wenn beide gleichzeitig exprimiert waren. Mittels Immunzytochemie konnten diese Ergebnisse auch in der Zelllinie NCI-h295R nachgewiesen werden. Beide Enzyme sind auch hier vor allem nukleär exprimiert. Der physiologische Hintergrund dieser Lokalisierung ist nicht geklärt und erfordert weitere Erforschung. Vermutlich erfolgt die Sulfat-Aktivierung also im Nukleus. Möglicherweise stellt die Verlagerung der Enzyme in den Nukleus aber auch eine Reserve der PAPS Synthese dar, die durch Rückverlagerung ins Zytoplasma dort rasch zusätzliches PAPS zur Verfügung stellen kann. Die Expression der DHEA Sulfotransferase wurde bereits in einigen fötalen Geweben untersucht. Während in adultem Knorpel beim Menschen die Expression von PAPSS1 dominiert, wird z.B. im Knorpel von neugeborenen Hamstern vor allem PAPSS2 gebildet. Welche Isoform von PAPSS in welchen fötalen Geweben beim Menschen dominiert, wurde bislang nicht untersucht. In dieser Arbeit konnte mittels Realtime PCR eine differenzierte Expression von SULT2A1, PAPSS1 und PAPSS2 in fötalen Geweben nachgewiesen werden. In adultem und fötalem Gewebe der Nebennieren zeigte sich ein ähnliches Expressionsmuster. Während allerdings in der adulten Leber viel SULT2A1 vorhanden ist, konnte nur eine deutlich niedrigere Expression in fötalem Gewebe gezeigt werden. In fötalem Knorpel findet sich kaum SULT2A1. Dagegen wird in fötalem Knorpel deutlich mehr PAPSS1 gebildet als in adultem und fötalem Leber- bzw. Nebennieren-Gewebe. PAPSS2 ist sowohl beim Erwachsenen als auch beim Fötus hauptsächlich in der Nebenniere exprimiert. Auffällig ist eine relativ geringe Expression in der fötalen Leber. Ergänzend wird in dieser Arbeit eine Patientin mit Hyperandrogenismus vorgestellt, bei der zwei Mutationen im PAPSS2 Gen zu einem massiv erniedrigten DHEAS Spiegel geführt hatten. Eine heterozygote Mutation liegt im Bereich der APS-Kinase von PAPSS2 und führt zum Austausch einer Aminosäure an Position 48 im PAPSS2a Protein (T48R). In vitro konnte für diese Mutation eine Reduktion der Aktivität auf 6% nachgewiesen werden. Eine zweite Mutation fand sich in der ATP Sulfurylase Domäne von PAPSS2. Durch einen Nukleosid-Austausch (Thymidin statt Cytidin) entsteht ein Stop-Codon, was vermutlich an Position 329 zum Abbruch des Proteins führt (R329X). In vitro konnte für diese Mutation (R329X) keine Aktivität nachgewiesen werden. Durch das Fehlen von PAPS ist die Sulfonierung von Proteoglykanen im Knorpel gestört, was zu Skelettveränderungen führt. Vor allem aber kommt es durch das Fehlen der Inaktivierung von DHEA zu DHEAS zu einem Überangebot an DHEA. Dieses wird zu aktiven Androgenen konvertiert und verursacht klinisch einen Hyperandrogenismus. Interessant und überraschend ist, dass die PAPSS1-Aktivität im Knorpel eine gewisse Sulfonierung der Proteoglykane ermöglicht. Im Gegensatz dazu trägt PAPSS1 offensichtlich kaum zur Sulfonierung von DHEA bei, da der DHEAS Spiegel extrem niedrig ist. Möglicherweise spielt hier auch die subzelluläre Lokalisation der PAPS Synthase eine entscheidende Rolle. KW - Dehydroepiandrosteron KW - Zelllinie KW - Phosphoadenosinphosphosulfat KW - DHEA KW - PAPSS2 KW - adrenal KW - cell lines KW - DHEA-Sulfotransferase Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-102068 ER - TY - THES A1 - Michalska, Marta T1 - Molecular Imaging of atherosclerosis T1 - Molekulare Bildgebung der Atherosklerose N2 - Atherosklerose ist eine aktive und progressive Erkrankung, bei der vaskuläre Adhäsionsmoleküle wie VCAM-1 eine entscheidende Rolle durch Steuerung der Rekrutierung von Immunzellen in den frühen und fortgeschrittenen Plaques spielen. Ein zielgerichteter Einsatz von VCAM-1-Molekülen mit spezifischen Kontrastmitteln ist daher eine Möglichkeit, die VCAM-1-Expression zu kontrollieren, Plaquewachstum ab einem frühen Zeitpunkt zu visualisieren und eine frühe Prävention von Atherosklerose vor Beginn der Thrombusbildung zu etablieren. Des Weiteren bietet die nichtinvasive Magnetresonanz (MR)-Bildgebung den Vorteil der Kombination molekularer und morphologischer Daten. Sie ermöglicht, mithilfe von entwickelten VCAM-1-markierten Eisenoxidpartikeln, den spezifischen Nachweis entzündlicher Prozesse während der Atherosklerose. Diese Arbeit belegt, dass mit dem VCAM-1-Konzept eine vielversprechende Herangehensweise gefunden wurde und dass das, mit spezifischen superparamagnetischen Eisenoxid (USPIO) konjugierte VCAM-1-Peptid, gegenüber unspezifischer USPIOs ein erhöhtes Potenzial bei der Untersuchung der Atherosklerose in sich trägt. Im ersten Teil der Arbeit konnte im Mausmodell gezeigt werden, dass gerade das VCAM-1-Molekül ein sinnvoller Ansatzpunkt zur Darstellung und Bildgebung von Atherosklerose ist, da in der frühen Phase der Entzündung die vaskulären Zelladhäsionsmoleküle überexprimiert und auch kontinuierlich, während der fortschreitenden Plaquebildung, hochreguliert werden. Weiterhin beschreibt diese Arbeit die Funktionstüchtigkeit und das Vermögen des neu gestalteten USPIO Kontrastmittels mit dem zyklischen Peptid, in seiner Spezialisierung auf die VCAM-1 Erkennung. Experimentelle Studien mit ultra-Hochfeld-MRT ermöglichten weitere ex vivo und in vivo Nachweise der eingesetzten USPIO-VCAM-1-Partikel innerhalb der Region um die Aortenwurzel in frühen und fortgeschrittenen atherosklerotischen Plaques von 12 und 30 Wochen alten Apolipoprotein E-defizienten (ApoE-/-) Mäusen. Mit ihrer Kombination aus Histologie und Elektronenmikroskopie zeigt diese Studie zum ersten Mal die Verteilung von VCAM-1-markierten USPIO Partikeln nicht nur in luminalem Bereich der Plaques, sondern auch in tieferen Bereichen der medialen Muskelzellen. Dieser spezifische und sensitive Nachweis der frühen und fortgeschrittenen Stadien der Plaquebildung bringt auf molekularer Ebene neue Möglichkeiten zur Früherkennung von atherosklerotischen Plaques vor dem Entstehen von 8 Rupturen. Im Gegensatz zum USPIO-VCAM-1-Kontrastmittel scheiterten unspezifische USPIO Partikel an der Identifikation früher Plaqueformen und begrenzten die Visualisierung von Atherosklerose auf fortgeschrittene Stadien in ApoE-/- Mäusen. N2 - Atherosclerosis is an active and progressive condition where the vascular cell adhesion molecules as VCAM-1 play a vital role controlling the recruitment of immune cells within the early and advanced plaques. Therefore targeting of VCAM-1 molecules with specific contrast agent bears the possibility to monitor the VCAM-1 expression, visualize the plaque progression starting at the early alterations, and help to establish early prevention of atherosclerosis before the origin of the thrombus formation, of which late recognition leads to myocardial infarction. Furthermore noninvasive magnetic resonance imaging (MRI) offers the benefit of combining the molecular and anatomic data and would thus enable specific detection of VCAM-1 targeted iron oxide contrast agent within inflammatory process of atherosclerosis. This thesis exactly presents the VCAM-1 concept as a suitable molecular approach and the potential of specific ultrasmall superparamagnetic iron oxide (USPIO) conjugated to the VCAM-1 binding peptide over unspecific non-targeted USPIO particles for evaluation of atherosclerosis. This work firstly demonstrated that selection of VCAM-1 molecules offers a good and potential strategy for imaging of atherosclerosis, as these vascular cell adhesion molecules are highly expressed in the early phase of inflammation and also continuously up-regulated within the advanced plaques. Secondly, this thesis showed the proof of principle and capability of the newly designed USPIO contrast agent conjugated to the specific cyclic peptide for VCAM-1 recognition. The experimental studies including ultra-high field MRI enabled further ex vivo and in vivo detection of applied USPIO-VCAM-1 particles within the aortic root region of early and advanced atherosclerotic plaques of 12 and 30 week old apolipoprotein E deficient (ApoE-/-) mice. Using a combination of histology and electron microscopy, this study for the first time pointed to distribution of targeted USPIO-VCAM-1 particles within plaque cells expressing VCAM-1 not only in luminal regions but also in deeper medial smooth muscle cell areas. Hence functionalized USPIO particles targeting VCAM-1 molecules allow specific and sensitive detection of early and advanced plaques at the molecular level, giving the new possibilities for early recognition of atherosclerotic plaques before the appearance of advanced and prone to rupture lesions. In contrast to the functionalized USPIO-VCAM-1, utilized non-targeted USPIO particles did not succeed in early plaque 6 identification limiting visualization of atherosclerosis to advanced forms in atherosclerotic ApoE-/- mice. KW - VCAM KW - Arteriosklerose KW - Superparamagnetische Eisenoxid Kontrastmittel KW - vaskuläre Adhäsionsmoleküle KW - Atherosklerose KW - superparamagnetische Eisenoxid Kontrastmittel KW - vascular cell adhesion molecules KW - atherosclerosis KW - iron oxide contrast agent KW - Kontrastmittel Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-73243 ER - TY - JOUR A1 - Elias, Johannes A1 - Heuschmann, Peter U. A1 - Schmitt, Corinna A1 - Eckhardt, Frithjof A1 - Boehm, Hartmut A1 - Maier, Sebastian A1 - Kolb-Mäurer, Annette A1 - Riedmiller, Hubertus A1 - Müllges, Wolfgang A1 - Weisser, Christoph A1 - Wunder, Christian A1 - Frosch, Matthias A1 - Vogel, Ulrich T1 - Prevalence dependent calibration of a predictive model for nasal carriage of methicillin-resistant Staphylococcus aureus JF - BMC Infectious Diseases N2 - Background Published models predicting nasal colonization with Methicillin-resistant Staphylococcus aureus among hospital admissions predominantly focus on separation of carriers from non-carriers and are frequently evaluated using measures of discrimination. In contrast, accurate estimation of carriage probability, which may inform decisions regarding treatment and infection control, is rarely assessed. Furthermore, no published models adjust for MRSA prevalence. Methods Using logistic regression, a scoring system (values from 0 to 200) predicting nasal carriage of MRSA was created using a derivation cohort of 3091 individuals admitted to a European tertiary referral center between July 2007 and March 2008. The expected positive predictive value of a rapid diagnostic test (GeneOhm, Becton & Dickinson Co.) was modeled using non-linear regression according to score. Models were validated on a second cohort from the same hospital consisting of 2043 patients admitted between August 2008 and January 2012. Our suggested correction score for prevalence was proportional to the log-transformed odds ratio between cohorts. Calibration before and after correction, i.e. accurate classification into arbitrary strata, was assessed with the Hosmer-Lemeshow-Test. Results Treating culture as reference, the rapid diagnostic test had positive predictive values of 64.8% and 54.0% in derivation and internal validation corhorts with prevalences of 2.3% and 1.7%, respectively. In addition to low prevalence, low positive predictive values were due to high proportion (> 66%) of mecA-negative Staphylococcus aureus among false positive results. Age, nursing home residence, admission through the medical emergency department, and ICD-10-GM admission diagnoses starting with “A” or “J” were associated with MRSA carriage and were thus included in the scoring system, which showed good calibration in predicting probability of carriage and the rapid diagnostic test’s expected positive predictive value. Calibration for both probability of carriage and expected positive predictive value in the internal validation cohort was improved by applying the correction score. Conclusions Given a set of patient parameters, the presented models accurately predict a) probability of nasal carriage of MRSA and b) a rapid diagnostic test’s expected positive predictive value. While the former can inform decisions regarding empiric antibiotic treatment and infection control, the latter can influence choice of screening method. KW - Methicillin-resistant staphylococcus aureus KW - Infection control KW - Clinical prediction rule KW - Predictive value of tests KW - False positive reactions KW - Calibration Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96091 UR - http://www.biomedcentral.com/1471-2334/13/111 ER - TY - JOUR A1 - Haring, Bernhard A1 - Pettinger, Mary A1 - Bea, Jennifer W. A1 - Wactawski-Wende, Jean A1 - Carnahan, Ryan M. A1 - Ockene, Judith K. A1 - Wyler von Ballmoos, Moritz A1 - Wallace, Robert B. A1 - Wassertheil-Smoller, Sylvia T1 - Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative JF - BMC Geriatrics N2 - Background Laxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated. Methods This prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3-year follow-up visit on everyone. Data on self-reported falls (≥2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI. Results Age-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate-adjusted hazard ratios for any laxative use were 1.06 (95% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95% CI, 0.85-1.22) for hip fractures and 1.01 (95% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake. Conclusion These findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use. KW - laxative KW - use KW - fall KW - fracture KW - bone mineral density KW - aging Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-95960 UR - http://www.biomedcentral.com/1471-2318/13/38 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Gunreben, Ignaz A1 - Heuschmann, Peter Ulrich A1 - Kleinschnitz, Christoph T1 - Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study JF - Cerebrovascular Diseases N2 - Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26% vs. 97 ± 24%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk. KW - biomarker KW - factor XI KW - factor XII KW - ischemic stroke KW - chronic cerebrovascular disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199076 SN - 1015-9770 SN - 1421-9786 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 38 IS - 5 ER - TY - JOUR A1 - Schneider, Andreas A1 - Gutjahr-Lengsfeld, Lena A1 - Ritz, Eberhard A1 - Scharnagl, Hubert A1 - Gelbrich, Götz A1 - Pilz, Stefan A1 - Macdougall, Iain C. A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients JF - Nephron Clinical Practice N2 - Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness. KW - dialysis KW - erythropoietin KW - diabetes KW - epidemiology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196511 SN - 1660-2110 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 128 IS - 1-2 ER - TY - THES A1 - Hartmann, Sonja T1 - Relevance of antibodies targeting the beta1-adrenergic receptor for renal function T1 - Relevanz von Antikörpern gegen den beta1-adrenergen Rezeptor für die Nierenfunktion N2 - Functionally active (conformational) autoantibodies directed against the β1-adrenergic receptor (β1-AR) are supposed to have a pathogenic relevance in human heart failure, particularly in idiopathic dilated cardiomyopathy (DCM). Prevalence of anti-β1-autoantibodies (anti-β1-aabs) in the healthy population is almost negligible, whereas it amounts to up to 30% in heart failure patients with idiopathic DCM. As β1-ARs are not restricted to the heart and are also highly expressed in particular segments of the nephron, it is conceivable that such autoantibodies might also affect kidney function to some extent through the activation of renal β1-ARs. In the kidney, β1-ARs are highly abundant in the juxtaglomerular apparatus, the distal convoluted tubules, the collecting duct, and the renal arteries. However, the functional significance of β1-ARs at these particular sites along the nephron is poorly understood, as are the effects of conformational stimulating anti-β1-aabs on renal β1-ARs. From the available literature, it is well known that the β1-adrenergic system is involved in, e.g., the regulation of renin-secretion from juxtaglomerular cells. In addition, the β1-adrenergic system is thought to be involved in the regulation of the urine pH via type B-intercalated cells in the collecting duct. In contrast, the regulation of salt- and fluid-secretion in the medullary collecting duct appears to occur independently from the SNS. As a consequence, the present work aimed to unravel the potential pathophysiological links between renal function, alterations in the cardiovascular system, and circulating agonist-like anti- β1-abs. We analyzed possible renal effects of anti-β1-abs in a human-analogous rat model. After immunization with a GST-fusion protein containing the second extracellular loop (β1-ECII) of the human β1-AR, Lewis-rats develop functionally active, stimulating, conformational anti-β1-ECII-abs. Within the first 6 months, anti-β1-ECII-ab-positive animals develop a hypertensive phenotype, which after 9 months evolves into a DCM phenotype. In n=40 GST/ β1-ECII-immunized Lewis rats and n=40 age-matched, 0.9% NaCl-injected control animals, we sequentially (i.e. at months 1, 2, 3, 6, 9, 12, 15, and 18 after start of immunization) analyzed the changes in renal function on a molecular, functional, and structural level. We could show that the presence of stimulating anti-β1-ECII-abs – even though having detrimental effects on the heart – has only a minor impact on kidney function and structure. Within the first 3 months after induction of anti-β1-ECII-abs, the levels and activity of renin were significantly increased in immunized compared to corresponding control animals, which was confirmed by experiments on isolated perfused kidneys, in which anti-β1-ECII-abs were able to directly induce the liberation of renin. However, within several weeks the initial anti-β1-ECII-ab-mediated RAAS activation was counter-regulated by auto-regulatory mechanisms activated in the kidney. Similarly, glomerular filtration rate (GFR) and renal blood flow (RBF) were initially decreased in the presence of the stimulating anti-β1-ECII-abs, but returned to control values within 3 months after immunization of the animals. Although expression of several pro-fibrotic markers was significantly up-regulated in anti-β1-ECII-ab-positive rats, no significant differences were noted on a histomorphological level with regard to the occurrence of renal fibrosis, glomerular damage, tubular damage, and perivascular fibrosis. Only a mild decrease in glomerular filtration function was observed in the kidneys of anti-β1-ECII-ab-positive animals from immunization-month 12 on, apparent by increased levels of urinary protein. Even though anti-β1-ECII-abs were able to induce mild changes in renal function, their effects were not strong enough to critically damage the kidneys in our rat-model. Differences between immunized anti-β1-ECII-ab-positive and corresponding control rats at later time-points (that is, from immunization-month 12 on) are most likely secondary to the progressive heart failure phenotype that immunized animals develop in the course of the experiment. The present study is the first to focus on the effects of stimulating anti-β1-ECII-abs on the kidney, and on the prevalence of these effects for the heart (referred to as cardio-renal crosstalk). Although our results were obtained in a rat model, they might contribute to better understand the situation in anti-β1-AR-aab-positive human patients. Following the results of our experiments, treatment of such patients should focus on direct and specific neutralization/elimination of stimulating anti-β1-ECII-aab or at least comprise therapeutic strategies that counteract the anti-β1-ECII-aab-effects on the heart by standard treatment for heart failure (i.e. ACE inhibitors, AT1-receptor blockers, and β-blockers) according to current guidelines. N2 - Funktionell aktive, konformationelle Autoantikörper, die gegen den β1-adrenergen Rezeptor (β1-AR) gerichtet sind, sind vermutlich pathologisch relevant bei Herzinsuffizienz, insbesondere bei der idiopathischen Dilativen Kardiomyopathie (DCM). Die Prävalenz solcher Antikörper ist in der gesunden Population vernachlässigbar, wohingegen sie bei der idiopathischen DCM 30% erreicht. Da β1-AR nicht nur im Herzen, sondern auch in der Niere stark exprimiert werden, ist naheliegend, dass solche Antikörper über eine Stimulation renaler β1-AR auch die Nierenfunktion beeinflussen können. In der Niere werden β1-AR überwiegend im juxtaglomerulären Apparat, im distalen Tubulus, in den Sammelrohren und in den renalen Arterien exprimiert. Die Bedeutung der in diesen Bereichen hohen Expression von β1-AR für die Nierenfunktion ist noch nicht vollständig geklärt, ebenso wie die renalen Effekte von stimulierenden β1-AR-Antikörpern. Aus der Literatur ist bekannt, dass das β1-adrenerge System unter anderem an der Renin-Sekretion der juxtaglomerulären Zellen beteiligt ist. Außerdem wird vermutet, dass das β1-adrenerge System in die Regulation des pH-Wertes des Urins über die Typ B-interkalierenden Zellen des Sammelrohrs eingreift, wohingegen die Regulation der Salz- und Wasserexkretion im medullären Sammelrohr wahrscheinlich unabhängig vom sympathischen Nervensystem abläuft. Die vorliegende Arbeit zielt darauf ab, die potentiellen pathophysiologischen Zusammenhänge zwischen renaler Funktion, Änderungen innerhalb des kardiovaskulären Systems und zirkulierenden, agonist-ähnlichen anti-β1-Autoantikörpern darzustellen. Wir haben die möglichen renalen Effekte der anti-β1-AK in einem human-ähnlichen Ratten-Modell untersucht. Nach Immunisierung mit einem GST-Fusionsprotein, welches den zweiten extrazellulären Loop des β1-AR beinhaltet, entwickeln Lewis-Ratten funktionell aktive, stimulierende Antikörper gegen β1-ECII. Anti-β1-ECII-AK-positive Tiere entwickeln nach ca. 6 Monaten einen hypertensiven Phänotyp, welcher nach 9 Monaten in einen DCM Phänotyp übergeht. Wir haben Änderungen der renalen Funktion auf molekularer, funktioneller, und struktureller Ebene in n=40 GST/ β1-ECII-immunisierten Lewis-Ratten und n=40 altersgleichen 0.9% NaCl-injizierten Kontrolltieren sequenziell (d.h. 1, 2, 3, 6, 9, 12, 15 und 18 Monate nach Beginn der Immunisierung) analysiert. Wir konnten zeigen, dass die stimulierenden anti-β1-ECII-Antikörper – obwohl sie eine schädigende Wirkung auf das Herz haben – die Nierenfunktion und -Struktur nur gering beeinflussen. In den ersten Monaten nach Induktion der anti-β1-ECII-AK stieg die Reninkonzentration und -aktivität in den immunisierten Tieren im Vergleich zu den entsprechenden Kontrollen signifikant an. Dieses Ergebnis konnte im Model der isolierten perfundierten Niere bestätigen werden, in dem anti-β1-ECII-AK eine direkte Freisetzung von Renin induzierten. Diese frühe AK-vermittelte Aktivierung des RAAS wurde jedoch innerhalb weniger Wochen durch autoregulatorische Mechanismen der Niere aufgehoben. Ebenso waren anfangs die glomeruläre Filtrationsrate und der renale Blutfluss in anti-β1-ECII-AK-positiven Ratten vermindert, kehrten jedoch nach 3 Monaten zu den Werten der Kontrolltiere zurück. Obwohl die Expression mehrerer pro-fibrotischer Marker signifikant erhöht war, konnten keine signifikanten Veränderungen auf histomorphologischer Ebene hinsichtlich des Auftretens renaler Fibrose, glomerulärer und tubulärer Schädigung, oder perivaskulärer Fibrose festgestellt werden. Lediglich die glomeruläre Filtrationsfunktion war ab dem 12. Immunisierungsmonat zunehmend beeinträchtigt, was sich an einer progredienten Proteinurie zeigte. Obwohl anti-β1-ECII-AK durchaus einen gewissen Effekt auf die Nierenfunktion haben, ist ihr Einfluss nicht stark genug um die Niere kritisch zu schädigen. Unterschiede zwischen immunisierten und Kontrolltieren, welche zu späteren Zeitpunkten (d.h. ab dem 12. Immunisierungsmonat) auftreten, sind wahrscheinlich sekundäre Effekte der progredienten Herzinsuffizienz, die die immunisierten Tiere im Verlauf des Experiments entwickeln. Unsere Studie ist die Erste, die sich mit den Effekten von stimulierenden anti-β1-AK auf die Niere und ihre Zusammenhänge mit der antikörper-induzierten Herzinsuffizienz (dem sogenannten kardio-renalen „Crosstalk“) befasst. Obwohl unsere Ergebnisse in einem Tiermodell erzielt wurden, könnten sie von großem Nutzen sein, um die Krankheitsentwicklung von anti-β1-Autoantikörper-positiven Patienten besser zu verstehen. Unseren Ergebnissen zufolge sollte die Behandlung von Autoimmun-DCM auf eine möglichst direkte und spezifische Neutralisierung/Eliminierung von anti-β1-Autoantikörpern abzielen und gleichzeitig alle kardio- und renal-protektiven Elemente der Standard-Therapie der Herzinsuffizienz (d.h. Gabe von ACE-Hemmern, AT1-Rezeptor-Inhibitoren und β-Blockern) einschließen. KW - Nierenfunktion KW - Beta-1-Rezeptor KW - kidney KW - Antikörper KW - beta1-adrenergic receptor KW - antibodies Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-106285 ER - TY - JOUR A1 - Wagner, Martin A1 - Krämer, Johannes A1 - Blohm, Elisabeth A1 - Vergho, Dorothee A1 - Weidemann, Frank A1 - Breunig, Frank A1 - Wanner, Christoph T1 - Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease N2 - Background: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD. Methods: In 96 patients (53% female; age 40 ± 12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL. Results: Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD −6.2, for RRT −11.8, for pain −9.1, p < 0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL. Conclusion: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD. KW - Quality of life KW - SF-36 KW - Chronic kidney disease KW - Fabry disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111159 UR - http://www.biomedcentral.com/1471-2369/15/188 ER - TY - JOUR A1 - Locatelli, Francesco A1 - Spasovski, Goce A1 - Dimkovic, Nada A1 - Wanner, Christoph A1 - Dellanna, Frank A1 - Pontoriero, Giuseppe T1 - The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study JF - Nephrology Dialysis Transplantation N2 - BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3% for colestilan and 54.0 and 80.6% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS: Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer. KW - chronic kidney disease KW - colestilan KW - hyperphosphataemia KW - placebo KW - sevelamer Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121114 VL - 29 IS - 5 ER - TY - JOUR A1 - Ladwig, Karl-Heinz A1 - Lederbogen, Florian A1 - Albus, Christian A1 - Angermann, Christiane A1 - Borggrefe, Martin A1 - Fischer, Denise A1 - Fritzsche, Kurt A1 - Haass, Markus A1 - Jordan, Jochen A1 - Jünger, Jana A1 - Kindermann, Ingrid A1 - Köllner, Volker A1 - Kuhn, Bernhard A1 - Scherer, Martin A1 - Seyfarth, Melchior A1 - Völler, Heinz A1 - Waller, Christiane A1 - Herrmann-Lingen, Christoph T1 - Position paper on the importance of psychosocial factors in cardiology: Update 2013 T1 - Positionspapier zur Bedeutung psychosozialer Faktoren in der Kardiologie: Update 2013 JF - GMS German Medical Science N2 - Background: The rapid progress of psychosomatic research in cardiology and also the increasing impact of psychosocial issues in the clinical daily routine have prompted the Clinical Commission of the German Heart Society (DGK) to agree to an update of the first state of the art paper on this issue which was originally released in 2008. Methods: The circle of experts was increased, general aspects were implemented and the state of the art was updated. Particular emphasis was dedicated to coronary heart diseases (CHD), heart rhythm diseases and heart failure because to date the evidence-based clinical knowledge is most advanced in these particular areas. Differences between men and women and over the life span were considered in the recommendations as were influences of cognitive capability and the interactive and synergistic impact of classical somatic risk factors on the affective comorbidity in heart disease patients. Results: A IA recommendation (recommendation grade I and evidence grade A) was given for the need to consider psychosocial risk factors in the estimation of coronary risks as etiological and prognostic risk factors. Furthermore, for the recommendation to routinely integrate psychosocial patient management into the care of heart surgery patients because in these patients, comorbid affective disorders (e.g. depression, anxiety and post-traumatic stress disorder) are highly prevalent and often have a malignant prognosis. A IB recommendation was given for the treatment of psychosocial risk factors aiming to prevent the onset of CHD, particularly if the psychosocial risk factor is harmful in itself (e.g. depression) or constrains the treatment of the somatic risk factors. Patients with acute and chronic CHD should be offered anti-depressive medication if these patients suffer from medium to severe states of depression and in this case medication with selective reuptake inhibitors should be given. In the long-term course of treatment with implanted cardioverter defibrillators (ICDs) a subjective health technology assessment is warranted. In particular, the likelihood of affective comorbidities and the onset of psychological crises should be carefully considered. Conclusions: The present state of the art paper presents an update of current empirical evidence in psychocardiology. The paper provides evidence-based recommendations for the integration of psychosocial factors into cardiological practice and highlights areas of high priority. The evidence for estimating the efficiency for psychotherapeutic and psychopharmacological interventions has increased substantially since the first release of the policy document but is, however, still weak. There remains an urgent need to establish curricula for physician competence in psychodiagnosis, communication and referral to ensure that current psychocardiac knowledge is translated into the daily routine. N2 - Hintergrund: Die rasche Weiterentwicklung der psychokardiologischen Forschung, aber auch die wachsende Verankerung psychosozialer Fragestellungen im klinischen Alltag haben die Klinische Kommission der DGK bewogen, einer Aktualisierung und Weiterentwicklung des 2008 erstmals publizierten Positionspapiers zur Bedeutung psychosozialer Faktoren in der Kardiologie zuzustimmen. Methoden: Der Kreis der Autoren wurde vergrößert, allgemeine Aspekte eingefügt und das Wissen in allen Abschnitten auf den heutigen Stand gebracht. Schwerpunkte der Empfehlungen sind die koronare Herzerkrankung, Herzrhythmusstörungen und die Herzinsuffizienz, da hier der Stand der empirischen Evidenz und des klinisches Wissens zu psychosozialen Fragestellungen am weitesten entwickelt ist. Berücksichtigt wurden bei den Empfehlungen Besonderheiten von Frauen und Männern, Unterschiede bzgl. der Lebensspanne, Einflüsse auf die kognitive Leistungsfähigkeit und die interaktive synergistische Bedeutung klassischer Risikofaktoren bei affektiver Komorbidität. Ergebnisse: Eine I-A-Empfehlung (Empfehlungsgrad I, Evidenzgrad A) wurde vergeben für die Aufforderung, psychosoziale Risikofaktoren bei der Einschätzung des KHK-Risikos zu berücksichtigen, die als unabhängige ätiologische und prognostische Risikofaktoren für das Auftreten der koronaren Herzerkrankung (KHK) und für Komplikationen im Behandlungsverlauf der KHK bedeutsam sind. Ferner für die Empfehlung, Patienten mit Herzoperationen von einem interdisziplinären Team zu betreuten, in dem die Möglichkeit besteht, auf psychosoziale Aspekte einzugehen, da bei diesen Patienten komorbide psychische Störungen wie Depressivität, Angst und posttraumatische Belastungsstörung häufig und prognostisch ungünstig sind. Eine I-B-Empfehlung wurde vergeben für die Behandlung psychosozialer Risikofaktoren mit dem Ziel einer Primärprävention der KHK, wenn das Risikomerkmal an sich Krankheitswert hat (z. B. Depression) oder die Behandlung klassischer Risikofaktoren erschwert ist. Eine antidepressive Pharmakotherapie soll Patienten nach akutem Koronarsyndrom sowie in der Phase der chronischen KHK angeboten werden, die an einer mindestens mittelschweren rezidivierenden depressiven Störung leiden. Dabei sollen vorzugsweise Substanzen aus der Gruppe der selektiven Serotoninwiederaufnahmehemmer (SSRI) zum Einsatz kommen. Bei der langfristigen ärztlichen Begleitung von ICD-Patienten sollen die psychosozialen Folgen der ICD-Technologie beachtet und insbesondere relevante Affektstörungen sowie Krisen bei ICD-Patienten erkannt und fachgerecht behandelt werden. Schlussfolgerungen: Das Positionspapier formuliert konkrete Anwendungsfelder mit hoher Priorität für die Einbeziehung psychosozialer Faktoren in die kardiologische Praxis, die eine leitlinienkonforme Evidenz aufweisen. Trotz deutlicher Fortschritte seit der Erstveröffentlichung des Positionspapiers existieren weiterhin Forschungsdefizite für die Bewertung der Wirksamkeit psychotherapeutischer und psychopharmakologischer Konzepte bei kardialen Patienten. Curricula für die Vermittlung von (psycho-)diagnostischer, kommunikativer und differenzialdiagnostischer Kompetenz müssen rasch entwickelt werden, um eine Transmission des aktuellen Wissensstands in die Alltagspraxis zu ermöglichen. KW - depression KW - anxiety KW - post-traumatic stress disorder KW - psychotherapy KW - psychopharmacology KW - Depression KW - Psychopharmakologie KW - Psychotherapie KW - posttraumatische Belastungsstörung KW - Angst Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121196 VL - 12 ER - TY - JOUR A1 - Schick, Martin A. A1 - Baar, Wolfgang A1 - Flemming, Sven A1 - Schlegel, Nicolas A1 - Wollborn, Jakob A1 - Held, Christopher A1 - Schneider, Reinhard A1 - Brock, Robert W. A1 - Roewer, Norbert A1 - Wunder, Christian T1 - Sepsis-induced acute kidney injury by standardized colon ascendens stent peritonitis in rats - a simple, reproducible animal model JF - Intensive Care Medicine Experimental N2 - Background Up to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring. Methods Anaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days. Results All sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days. Conclusions The presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI. KW - CASP KW - animal model KW - acute kidney injury KW - sepsis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126111 VL - 2 IS - 34 ER - TY - JOUR A1 - Frey, Anna A1 - Popp, Sandy A1 - Post, Antonia A1 - Langer, Simon A1 - Lehmann, Marc A1 - Hofmann, Ulrich A1 - Siren, Anna-Leena A1 - Hommers, Leif A1 - Schmitt, Angelika A1 - Strekalova, Tatyana A1 - Ertl, Georg A1 - Lesch, Klaus-Peter A1 - Frantz, Stefan T1 - Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain JF - Frontiers in Behavioral Neuroscience N2 - Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression. KW - chronic heart failure KW - myocardial infarction KW - anxiety KW - depression KW - mice Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118234 SN - 1662-5153 VL - 8 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Gunreben, Ignaz A1 - Nieswandt, Bernhard A1 - Stoll, Guido A1 - Heuschmann, Peter Ulrich A1 - Kleinschnitz, Christoph T1 - Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study JF - PLoS ONE N2 - Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case–control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46%) had significantly higher VWF levels than HV (113±36%, P<0.001), but lower levels than AIS/TIA patients (200±95%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation. KW - cerebrovascular diseases KW - sex addiction KW - biomarkers KW - ischemic stroke KW - blood KW - stroke KW - platelets KW - demography Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119588 SN - 1932-6203 VL - 9 IS - 6 ER - TY - JOUR A1 - Steinbrunn, Torsten A1 - Chatterjee, Manik A1 - Bargou, Ralf C. A1 - Stühmer, Thorsten T1 - Efficient Transient Transfection of Human Multiple Myeloma Cells by Electroporation - An Appraisal JF - PLoS ONE N2 - Cell lines represent the everyday workhorses for in vitro research on multiple myeloma (MM) and are regularly employed in all aspects of molecular and pharmacological investigations. Although loss-of-function studies using RNA interference in MM cell lines depend on successful knockdown, no well-established and widely applied protocol for efficient transient transfection has so far emerged. Here, we provide an appraisal of electroporation as a means to introduce either short-hairpin RNA expression vectors or synthesised siRNAs into MM cells. We found that electroporation using siRNAs was much more efficient than previously anticipated on the basis of transfection efficiencies deduced from EGFP-expression off protein expression vectors. Such knowledge can even confidently be exploited in "hard-to-transfect" MM cell lines to generate large numbers of transient knockdown phenotype MM cells. In addition, special attention was given to developing a protocol that provides easy implementation, good reproducibility and manageable experimental costs. KW - cell cultures KW - green fluorescent protein KW - oligonucleotides KW - multiple myeloma KW - plasmid construction KW - transfection KW - small interfering RNAs KW - electroporation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119616 VL - 9 IS - 6 ER - TY - JOUR A1 - Frantz, Stefan A1 - Monaco, Claudia A1 - Arslan, Fatih T1 - Danger Signals in Cardiovascular Disease JF - Mediators of Inflammation N2 - No abstract available. KW - cardiovascular disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120110 SN - 1466-1861 VL - 2014 IS - 395278 ER - TY - JOUR A1 - Zinman, Bernard A1 - Inzucchi, Silvio E. A1 - Lachin, John M. A1 - Wanner, Christoph A1 - Ferrari, Roberto A1 - Fitchett, David A1 - Bluhmki, Erich A1 - Hantel, Stefan A1 - Kempthorne-Rawson, Joan A1 - Newman, Jennifer A1 - Johansen, Odd Erik A1 - Woerle, Hans-Juergen A1 - Broedl, Uli C. T1 - Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME (TM)) JF - Cardiovascular Diabetology N2 - Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME (TM) trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes. Methods: Patients who were drug naive (HbA(1c) >= 7.0% and <= 9.0%), or on background glucose-lowering therapy (HbA(1c) >= 7.0% and <= 10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until >= 691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided a of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved. Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 +/- 9 years, BMI 30.6 +/- 5.3 kg/m(2), HbA1c 8.1 +/- 0.8%, and eGFR 74 +/- 21 ml/min/1.73 m(2). The study is expected to report in 2015. Discussion: EMPA REG OUTCOME (TM) will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection. KW - glycemic control KW - blood pressure KW - macrovascular KW - doule blind KW - chronic kidney disease KW - type-1 diabetes mellitus KW - safety KW - metformin KW - add-on KW - albuminuria KW - sulfonylurea KW - efficacy KW - canagliflozin KW - microvascular KW - SGLT2 inhibitor KW - type 2 diabetes KW - body weight KW - empagliflozin Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116036 SN - 1475-2840 VL - 13 IS - 102 ER - TY - JOUR A1 - Devine, Eric A1 - Krieter, Detlef H. A1 - Rüth, Marieke A1 - Jankovski, Joachim A1 - Lemke, Horst-Dieter T1 - Binding Affinity and Capacity for the Uremic Toxin Indoxyl Sulfate JF - Toxins N2 - Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma binding affinity and capacity were tested: (i), increasing the sodium chloride (NaCl) concentration to achieve a higher ionic strength; (ii), increasing the temperature; and (iii), dilution. The effects on the dissociation constant K-D and the protein bound fraction of the prototypical uremic toxin indoxyl sulfate (IS) in plasma of healthy and uremic individuals were studied. Binding of IS corresponded to one site binding in normal plasma. K-D increased linearly with the NaCl concentration between 0.15 (K-D = 13.2 +/- 3.7 mu M) and 0.75 M (K-D = 56.2 +/- 2.0 mu M). Plasma dilution further reduced the protein bound toxin fraction by lowering the protein binding capacity of the plasma. Higher temperatures also decreased the protein bound fraction of IS in human plasma. Increasing the NaCl concentration was effective to weaken the binding of IS also in uremic plasma: the protein bound fraction decreased from 89% +/- 3% to 81% +/- 3% at 0.15 and 0.75 M NaCl, respectively. Dilution and increasing the ionic strength and temperature enhance the free fraction of IS allowing better removal of the substance during dialysis. Applied during clinical dialysis, this may have beneficial effects on the long-term outcome of maintenance dialysis patients. KW - protein binding KW - hemodialysis KW - human serum albumin KW - dialyzer membrane KW - P-cresyl sulfate KW - removal KW - dialysate KW - progression KW - clearance KW - kidney disease; KW - protein-bound solutes KW - chronic kidney-disease KW - ionic strength KW - uremic toxin Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117486 VL - 6 IS - 2 ER - TY - JOUR A1 - Fruchart, Jean-Charles A1 - Davignon, Jean A1 - Hermans, Michael P. A1 - Al-Rubeaan, Khalid A1 - Amarenco, Pierre A1 - Assmann, Gerd A1 - Barter, Philip A1 - Betteridge, John A1 - Bruckert, Eric A1 - Cuevas, Ada A1 - Farnier, Michel A1 - Ferrannini, Ele A1 - Fioretto, Paola A1 - Genest, Jacques A1 - Ginsberg, Henry N. A1 - Gotto Jr., Antonio M. A1 - Hu, Dayi A1 - Kadowaki, Takashi A1 - Kodama, Tatsuhiko A1 - Krempf, Michel A1 - Matsuzawa, Yuji A1 - Núñez-Cortés, Jesús Millán A1 - Monfil, Calos Calvo A1 - Ogawa, Hisao A1 - Plutzky, Jorge A1 - Rader, Daniel J. A1 - Sadikot, Shaukat A1 - Santos, Raul D. A1 - Shlyakhto, Evgeny A1 - Sritara, Piyamitr A1 - Sy, Rody A1 - Tall, Alan A1 - Tan, Chee Eng A1 - Tokgözoğlu, Lale A1 - Toth, Peter P. A1 - Valensi, Paul A1 - Wanner, Christoph A1 - Zambon, Albertro A1 - Zhu, Junren A1 - Zimmet, Paul T1 - Residual macrovascular risk in 2013: what have we learned? JF - Cardiovascual Diabetology N2 - Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R(3)i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R(3)i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R(3)i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptor alpha agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R(3)i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk. KW - phospholipid fatty acids KW - term fenofibrate therapy KW - cardiovascular munster procam KW - residual cardiovascular risk KW - atherogenic dyslipidaemia KW - type 2 diabetes KW - therapeutic options KW - high denisty lipoprotein KW - randomized controlled-trial KW - coronary artery disease KW - type-2 diabetes mellitus KW - triglyceride-rich lipoproteins KW - alpha/delta agonist GFT505 KW - placebo-controlled trial Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117546 SN - 1475-2840 VL - 13 IS - 26 ER - TY - JOUR A1 - Verrua, Elisa A1 - Ferrante, Emanuele A1 - Filopanti, Marcello A1 - Malchiodi, Elena A1 - Sala, Elisa A1 - Giavoli, Claudia A1 - Arosio, Maura A1 - Lania, Andrea Gerardo A1 - Ronchi, Christina Lucia A1 - Mantovani, Giovanna A1 - Beck-Peccoz, Paolo A1 - Spada, Anna T1 - Reevaluation of Acromegalic Patients in Long-Term Remission according to Newly Proposed Consensus Criteria for Control of Disease JF - International Journal of Endocrinology N2 - Acromegaly guidelines updated in 2010 revisited criteria of disease control: if applied, it is likely that a percentage of patients previously considered as cured might present postglucose GH nadir levels not adequately suppressed, with potential implications on management. This study explored GH secretion, as well as hormonal, clinical, neuroradiological, metabolic, and comorbid profile in a cohort of 40 acromegalic patients considered cured on the basis of the previous guidelines after a mean follow-up period of 17.2 years from remission, in order to assess the impact of the current criteria. At the last follow-up visit, in the presence of normal IGF-I concentrations, postglucose GH nadir was over 0.4 mu g/L in 11 patients (Group A) and below 0.4 mu g/L in 29 patients (Group B); moreover, Group A showed higher basal GH levels than Group B, whereas a significant decline of both GH and postglucose GH nadir levels during the follow-up was observed in Group B only. No differences in other evaluated parameters were found. These results seem to suggest that acromegalic patients considered cured on the basis of previous guidelines do not need a more intensive monitoring than patients who met the current criteria of disease control, supporting instead that the cut-off of 0.4 mcg/L might be too low for the currently used GH assay. KW - IGF-I KW - glucose tolerance test KW - growth hormone deficiency KW - body mass index KW - oral glucose KW - GH response KW - mortality KW - immunoassays KW - statement KW - diagnosis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117790 SN - 1687-8345 ER - TY - JOUR A1 - Mitchell, Anna L. A1 - Macarthur, Katie D. R. A1 - Gan, Earn H. A1 - Baggott, Lucy E. A1 - Wolff, Anette S. B. A1 - Skinningsrud, Beate A1 - Platt, Hazel A1 - Short, Andrea A1 - Lobell, Anna A1 - Kampe, Olle A1 - Bensing, Sophie A1 - Betterle, Corrado A1 - Kasperlik-Zaluska, Anna A1 - Zurawek, Magdalena A1 - Fichna, Marta A1 - Kockum, Ingrid A1 - Eriksson, Gabriel Nordling A1 - Ekwall, Olov A1 - Wahlberg, Jeanette A1 - Dahlqvist, Per A1 - Hulting, Anna-Lena A1 - Penna-Martinez, Marissa A1 - Meyer, Gesine A1 - Kahles, Heinrich A1 - Badenhoop, Klaus A1 - Hahner, Stephanie A1 - Quinkler, Marcus A1 - Falorni, Alberto A1 - Phipps-Green, Amanda A1 - Merriman, Tony R. A1 - Ollier, William A1 - Cordell, Heather J. A1 - Undlien, Dag A1 - Czarnocka, Barbara A1 - Husebye, Eystein A1 - Pearce, Simon H. S. T1 - Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts JF - PLOS ONE N2 - Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis. KW - Graves disease KW - identical twins KW - hashimotos-thyroiditis KW - population KW - gene KW - polymorphism KW - susceptibility KW - prevalence KW - haplotype KW - rheumatoid arthritis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117105 VL - 9 IS - 3 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Störk, Stefan A1 - Herrmann, Sebastian A1 - Kramer, Bastian A1 - Cikes, Maja A1 - Gaudron, Philipp Daniel A1 - Knop, Stefan A1 - Ertl, Georg A1 - Bijnens, Bart A1 - Weidemann, Frank T1 - Predictive Value of Assessing Diastolic Strain Rate on Survival in Cardiac Amyloidosis Patients with Preserved Ejection Fraction JF - PLOS ONE N2 - Objectives: Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSRdias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%). Background: Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LSsys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSRdias also related to outcome in these patients. Methods: Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LSsys and LSRdias were obtained in six LV segments from apical 4-chamber views. Results: Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5–35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6±2 vs. 8±3 mm), global LSRdias and basal-septal LSRdias were significantly lower in non-survivors than in survivors (all p<0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LSsys, global LSRdias, basal-septal LSRdias and E/LSRdias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.17–3.26, P = 0.010), global LSRdias (HR = 7.30, 95% CI 2.08–25.65, P = 0.002), and E/LSRdias (HR = 2.98, 95% CI 1.54–5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSRdias was optimal at a cutoff value of 0.85 S−1 (sensitivity 68%, specificity 67%). Global LSRdias <0.85 S−1 predicted a 4-fold increased mortality in CA patients with preserved LVEF. Conclusions: STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF. KW - diagnostic medicine KW - echocardiography KW - prognosis KW - calcium imaging KW - ejection fraction KW - death rates KW - amyloidosis KW - deformation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118024 SN - 1932-6203 VL - 9 IS - 12 ER - TY - JOUR A1 - Haring, Bernhard A1 - Gronroos, Noelle A1 - Nettleton, Jennifer A. A1 - Wyler von Ballmoos, Moritz C. A1 - Selvin, Elizabeth A1 - Alsonso, Alvaro T1 - Dietary Protein Intake and Coronary Heart Disease in a Large Community Based Cohort: Results from the Atherosclerosis Risk in Communities (ARIC) Study N2 - Background Prospective data examining the relationship between dietary protein intake and incident coronary heart disease (CHD) are inconclusive. Most evidence is derived from homogenous populations such as health professionals. Large community-based analyses in more diverse samples are lacking. Methods We studied the association of protein type and major dietary protein sources and risk for incident CHD in 12,066 middle-aged adults (aged 45–64 at baseline, 1987–1989) from four U.S. communities enrolled in the Atherosclerosis Risk in Communities (ARIC) Study who were free of diabetes mellitus and cardiovascular disease at baseline. Dietary protein intake was assessed at baseline and after 6 years of follow-up by food frequency questionnaire. Our primary outcome was adjudicated coronary heart disease events or deaths with following up through December 31, 2010. Cox proportional hazard models with multivariable adjustment were used for statistical analyses. Results During a median follow-up of 22 years, there were 1,147 CHD events. In multivariable analyses total, animal and vegetable protein were not associated with an increased risk for CHD before or after adjustment. In food group analyses of major dietary protein sources, protein intake from red and processed meat, dairy products, fish, nuts, eggs, and legumes were not significantly associated with CHD risk. The hazard ratios [with 95% confidence intervals] for risk of CHD across quintiles of protein from poultry were 1.00 [ref], 0.83 [0.70–0.99], 0.93 [0.75–1.15], 0.88 [0.73–1.06], 0.79 [0.64–0.98], P for trend = 0.16). Replacement analyses evaluating the association of substituting one source of dietary protein for another or of decreasing protein intake at the expense of carbohydrates or total fats did not show any statistically significant association with CHD risk. Conclusion Based on a large community cohort we found no overall relationship between protein type and major dietary protein sources and risk for CHD. KW - meat KW - coronary heart disease KW - poultry KW - sports and exercise medicine KW - carbohydrates KW - blood pressure KW - cardiology KW - diabetes mellitus Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113570 N1 - "All data underlying the findings in our study are freely available in a public repository governed by the ‘Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC)’ under the auspices of the National Heart, Lung and Blood Institute (NHLBI). The repository can be accessed online (https://biolincc.nhlbi.nih.gov/studies/aric/?q = aric)." ER - TY - JOUR A1 - Ronchi, Cristina L. A1 - Sbiera, Silviu A1 - Volante, Marco A1 - Steinhauer, Sonja A1 - Scott-Wild, Vanessa A1 - Altieri, Barbara A1 - Kroiss, Matthias A1 - Bala, Margarita A1 - Papotti, Mauro A1 - Deutschbein, Timo A1 - Terzolo, Massimo A1 - Fassnacht, Martin A1 - Allolio, Bruno T1 - CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma N2 - Background Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins. Objective To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC. Material and Methods CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples). Results CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0–1) in 72% of non-adrenal normal tissues, but high (H-score 2–3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01). Conclusion CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment. KW - CYP2W1 KW - cancer treatment KW - adrenal glands KW - carcinomas KW - drug therapy KW - hormones KW - immune response KW - immunohistochemistry techniques KW - surgical oncology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113096 ER - TY - JOUR A1 - Bala, Margarita A1 - Ronchi, Cristina L. A1 - Pichl, Josef A1 - Wild, Vanessa A1 - Kircher, Stefan A1 - Allolio, Bruno A1 - Hahner, Stefanie T1 - Suspected metastatic adrenocortical carcinoma revealing as pulmonary Kaposi sarcoma in adrenal Cushing’s syndrome N2 - Background Kaposi sarcoma (KS) is a malignant disease most commonly diagnosed in the setting of a human immunodeficiency virus (HIV) infection and in patients receiving immunosuppressive treatment. Pulmonary KS has never been reported in association with endogenous Cushing’s syndrome (CS). Case presentation A 60-year-old woman presented with symptoms and signs of CS. Adrenal CS was confirmed by standard biochemical evaluation. Imaging revealed a right adrenal lesion (diameter 3.5 cm) and multiple pulmonary nodules, suggesting a cortisol-secreting adrenal carcinoma with pulmonary metastases. The patient underwent right adrenalectomy with a pathohistological diagnosis of an adrenal adenoma. Subsequent thoracoscopic wedge resection of one lung lesion revealed pulmonary KS with positive immunostaining for human herpes virus 8 (HHV-8). HIV-serology was negative. Hydrocortisone replacement was initiated for secondary adrenal insufficiency after surgery. Post-operative follow up imaging showed complete remission of all KS-related pulmonary nodules solely after resolution of hypercortisolism. Conclusion KS may occur in the setting of endogenous CS and may go into remission after cure of hypercortisolism without further specific treatment. KW - Cushing’s syndrome KW - Kaposi sarcoma KW - Immunosuppression KW - Hypercortisolism Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110553 ER - TY - JOUR A1 - Haring, Bernhard A1 - Wyler von Ballmoos, Moritz C. A1 - Appel, Lawrence J. A1 - Sacks, Frank M. T1 - Healthy Dietary Interventions and Lipoprotein (a) Plasma Levels: Results from the Omni Heart Trial N2 - Background: Increased lipoprotein(a) [Lp(a)] levels are associated with atherosclerotic cardiovascular disease. Studies of dietary interventions on changes in Lp(a) are sparse. We aimed to compare the effects of three healthy dietary interventions differing in macronutrient content on Lp(a) concentration. Methods: Secondary analysis of a randomized, 3-period crossover feeding study including 155 (89 blacks; 66 whites) individuals. Participants were given DASHtype healthy diets rich in carbohydrates [Carb], in protein [Prot] or in unsaturated fat [Unsat Fat] for 6 weeks each. Plasma Lp(a) concentration was assessed at baseline and after each diet. Results: Compared to baseline, all interventional diets increased mean Lp(a) by 2 to 5 mg/dl. Unsat Fat increased Lp(a) less than Prot with a difference of 1.0 mg/dl (95% CI, -0.5, 2.5; p=0.196) in whites and 3.7 mg/dl (95% CI, 2.4, 5.0; p<0.001) in blacks (p-value between races=0.008); Unsat Fat increased Lp(a) less than Carb with a difference of 20.6 mg/dl, 95% CI, -2.1, 0.9; p=0.441) in whites and 21.5 mg/dl (95% CI, -0.2, -2.8; p=0.021) in blacks (p-value between races=0.354). Prot increased Lp(a) more than Carb with a difference of 0.4 mg/dl (95% CI, -1.1, 1.9; p=0.597) in whites and 2.2 mg/dl (95%CI, 0.9, 3.5; p=0.001) in blacks (p-value between races=0.082). Conclusion: Diets high in unsaturated fat increased Lp(a) levels less than diets rich in carbohydrate or protein with greater changes in blacks than whites. Our results suggest that substitutions with dietary mono- and polyunsaturated fatty acids in healthy diets may be preferable over protein or carbohydrates with regards to Lp(a). KW - diet KW - carbohydrates KW - blood plasma KW - heart KW - food consumption KW - cholesterol KW - fatty acids KW - plasma proteins Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111005 ER - TY - JOUR A1 - Mostovaya, Ira M. A1 - Grooteman, Muriel P.C. A1 - Basile, Carlo A1 - Davenport, Andrew A1 - de Roij van Zuijdewijn, Camiel L.M. A1 - Wanner, Christoph A1 - Nubé, Menso J. A1 - Blankestijn, Peter J. T1 - High convection volume in online post-dilution haemodiafiltration: relevance, safety and costs JF - Clinical Kidney Journal N2 - Increasing evidence suggests that treatment with online post-dilution haemodiafiltration (HDF) improves clinical outcome in patients with end-stage kidney disease, if compared with haemodialysis (HD). Although the primary analyses of three large randomized controlled trials (RCTs) showed inconclusive results, post hoc analyses of these and previous observational studies comparing online post-dilution HDF with HD showed that the risk of overall and cardiovascular mortality is lowest in patients who are treated with high-volume HDF. As such, the magnitude of the convection volume seems crucial and can be considered as the ‘dose’ of HDF. In this narrative review, the relevance of high convection volume in online post-dilution HDF is discussed. In addition, we briefly touch upon some safety and cost issues. KW - convection volume KW - costs KW - hemodiafiltration KW - mortality KW - safety Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149814 VL - 8 IS - 4 ER - TY - JOUR A1 - Preising, Christina A1 - Schneider, Reinhard A1 - Bucher, Michael A1 - Gekle, Michael A1 - Sauvant, Christoph T1 - Regulation of expression of renal organic anion transporters OAT1 and OAT3 in a model of ischemia/reperfusion injury JF - Cellular Physiology and Biochemistry N2 - Background: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI) is mediated by COX metabolites and this suppression might be critically involved in renal damage. Methods: (i) Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R) was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6) and hOAT3 (SCL22A8) were cloned into a reporter plasmid, transfected into HEK cells and (ii) transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. Results: By using inhibitors of PKA (H89) and PLC (U73122), antagonists of E prostanoid receptor type 2 (AH6809) and type 4 (L161,982), we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist) or TCS2510 (EP4 agonist) to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125) and COX2 (SC560) were also applied. Conclusion: Our data show (a) that COX1 metabolites are involved in the regulation of renal organic anion transport(ers) after I/R via the EP4 receptor and (b) that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c) hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well. KW - opossum kidney cells KW - prostaglandin e2 KW - reperfusion KW - transport experiments KW - translation KW - reporter gen assay KW - cloning of putative human promoter sequence KW - regulation of expression KW - OAT1 KW - OAT3 KW - OK cells KW - ischemic acute kidney injury model KW - HEK cells KW - ischemia KW - down regulation KW - nitric oxide KW - cellular physiology KW - cortical OAT1 KW - blood flow Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144504 VL - 37 IS - 1 ER - TY - JOUR A1 - Iyengar, Sudha K. A1 - Sedor, John R. A1 - Freedman, Barry I. A1 - Kao, W. H. Linda A1 - Kretzler, Matthias A1 - Keller, Benjamin J. A1 - Abboud, Hanna E. A1 - Adler, Sharon G. A1 - Best, Lyle G. A1 - Bowden, Donald W. A1 - Burlock, Allison A1 - Chen, Yii-Der Ida A1 - Cole, Shelley A. A1 - Comeau, Mary E. A1 - Curtis, Jeffrey M. A1 - Divers, Jasmin A1 - Drechsler, Christiane A1 - Duggirala, Ravi A1 - Elston, Robert C. A1 - Guo, Xiuqing A1 - Huang, Huateng A1 - Hoffmann, Michael Marcus A1 - Howard, Barbara V. A1 - Ipp, Eli A1 - Kimmel, Paul L. A1 - Klag, Michael J. A1 - Knowler, William C. A1 - Kohn, Orly F. A1 - Leak, Tennille S. A1 - Leehey, David J. A1 - Li, Man A1 - Malhotra, Alka A1 - März, Winfried A1 - Nair, Viji A1 - Nelson, Robert G. A1 - Nicholas, Susanne B. A1 - O’Brien, Stephen J. A1 - Pahl, Madeleine V. A1 - Parekh, Rulan S. A1 - Pezzolesi, Marcus G. A1 - Rasooly, Rebekah S. A1 - Rotimi, Charles N. A1 - Rotter, Jerome I. A1 - Schelling, Jeffrey R. A1 - Seldin, Michael F. A1 - Shah, Vallabh O. A1 - Smiles, Adam M. A1 - Smith, Michael W. A1 - Taylor, Kent D. A1 - Thameem, Farook A1 - Thornley-Brown, Denyse P. A1 - Truitt, Barbara J. A1 - Wanner, Christoph A1 - Weil, E. Jennifer A1 - Winkler, Cheryl A. A1 - Zager, Philip G. A1 - Igo, Jr, Robert P. A1 - Hanson, Robert L. A1 - Langefeld, Carl D. T1 - Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND) JF - PLoS Genetics N2 - Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10\(^{−9}\)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10\(^{−8}\)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD. KW - diabetic kidney disease KW - genome-wide association study KW - Family Investigation of Nephropathy and Diabetes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180545 VL - 11 IS - 8 ER - TY - JOUR A1 - Paschke, Ralf A1 - Lincke, Thomas A1 - Müller, Stefan P. A1 - Kreissl, Michael C. A1 - Dralle, Henning A1 - Fassnacht, Martin T1 - The Treatment of Well-Differentiated Thyroid Carcinoma JF - Deutsches Ärzteblatt International N2 - Background: Recent decades have seen a rise in the incidence of well-differentiated (mainly papillary) thyroid carcinoma around the world. In Germany, the age-adjusted incidence of well-differentiated thyroid carcinoma in 2010 was 3.5 per 100 000 men and 8.7 per 100 000 women per year. Method: This review is based on randomized, controlled trials and multicenter trials on the treatment of well-differentiated thyroid carcinoma that were retrieved by a selective literature search, as well as on three updated guidelines issued in the past two years. Results: The recommended extent of surgical resection depends on whether the tumor is classified as low-risk or high-risk, so that papillary microcar cinomas, which carry a highly favorable prognosis, will not be overtreated. More than 90% of localized, well-differentiated thyroid carcinomas can be cured with a combination of surgery and radioactive iodine therapy. Radio active iodine therapy is also effective in the treatment of well-differentiated thyroid carcinomas with distant metastases, yielding a 10-year survival rate of 90%, as long as there is good iodine uptake and the tumor goes into remission after treatment; otherwise, the 10-year survival rate is only 10%. In the past two years, better treatment options have become available for radioactive-iodine-resistant thyroid carcinoma. Phase 3 studies of two different tyrosine kinase inhibitors have shown that either one can markedly prolong progression-free survival, but not overall survival. Their more common clinically significant side effects are hand-foot syndrome, hypertension, diarrhea, proteinuria, and weight loss. Conclusion: Slow tumor growth, good resectability, and susceptibility to radioactive iodine therapy lend a favorable prognosis to most cases of well-differentiated thyroid carcinoma. The treatment should be risk-adjusted and interdisciplinary, in accordance with the current treatment guidelines. Even metastatic thyroid carcinoma has a favorable prognosis as long as there is good iodine uptake. The newly available medical treatment options for radioactive-iodine-resistant disease need to be further studied. KW - BRAF(V600E) mutation KW - distant metastases KW - papillary KW - guidelines KW - surgery KW - dissection KW - management KW - association KW - cancer KW - radioiodine therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151636 VL - 112 SP - 452 EP - 458 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Schuhmann, Michael K. A1 - Gunreben, Ignaz A1 - Kleinschnitz, Christoph T1 - Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study JF - International Journal of Molecular Science N2 - Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital Würzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies. KW - chronic cerebrovascular disease KW - lymphocytes KW - leukocytes KW - immune cells KW - biomarker KW - monocytes KW - regulatory T cells KW - ischemic stroke KW - thromboinflammation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126319 VL - 16 IS - 10 ER - TY - JOUR A1 - Baur, Johannes A1 - Schedelbeck, Ulla A1 - Pulzer, Alina A1 - Bluemel, Christina A1 - Wild, Vanessa A1 - Fassnacht, Martin A1 - Steger, U. T1 - A case report of a solitary pancreatic metastasis of an adrenocortical carcinoma JF - BMC Surgery N2 - Background Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin. Case presentation Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred. Conclusion Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer. KW - surgical treatment KW - adrenocortical KW - carcinoma metastases to pancreas Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126130 VL - 15 IS - 93 ER - TY - JOUR A1 - Schick, Martin Alexander A1 - Baar, Wolfgang A1 - Bruno, Raphael Romano A1 - Wollborn, Jakob A1 - Held, Christopher A1 - Schneider, Reinhard A1 - Flemming, Sven A1 - Schlegel, Nicolas A1 - Roewer, Norbert A1 - Neuhaus, Winfried A1 - Wunder, Christian T1 - Balanced hydroxyethylstarch (HES 130/0.4) impairs kidney function in-vivo without inflammation JF - PLoS One N2 - Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6% HES (VOL) 130/0.4 over 6h. After 24h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1–4.0% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion KW - colloids KW - kidneys KW - histopathology KW - blood KW - creatinine KW - sepsis KW - urine KW - inflammation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126068 VL - 10 IS - 9 ER - TY - JOUR A1 - Gassenmaier, Tobias A1 - Petritsch, Bernhard A1 - Kunz, Andreas S. A1 - Gkaniatsas, Spyridon A1 - Gaudron, Philipp D. A1 - Weidemann, Frank A1 - Nordbeck, Peter A1 - Beer, Meinrad T1 - Long term evolution of MRI characteristics in a case of atypical left lateral wall hypertrophic cardiomyopathy JF - World Journal of Cardiology N2 - We are reporting a long-time magnetic resonance imaging (MRI) follow-up in a rare case of cardiac left lateral wall hypertrophy. Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder and a significant cause of sudden cardiac death. Cardiac magnetic resonance (CMR) imaging can be a valuable tool for assessment of detailed information on size, localization, and tissue characteristics of hypertrophied myocardium. However, there is still little knowledge of long-term evolution of HCM as visualized by magnetic resonance imaging. Recently, our group reported a case of left lateral wall HCM as a rare variant of the more common forms, such as septal HCM, or apical HCM. As we now retrieved an old cardiac MRI acquired in this patient more than 20 years ago, we are able to provide the thrilling experience of an ultra-long MRI follow-up presentation in this rare case of left lateral wall hypertrophy. Furthermore, this case outlines the tremendous improvements in imaging quality within the last two decades of CMR imaging. KW - cardiac magnetic resonance imaging KW - hypertrophic cardiomyopathy KW - follow-up KW - atypical KW - left lateral wall Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124934 VL - 7 IS - 6 ER -