TY - JOUR A1 - Sherif, Mohammad A. A1 - Ince, Hüseyin A1 - Maniuc, Octavian A1 - Reiter, Therese A1 - Voelker, Wolfram A1 - Ertl, Georg A1 - Öner, Alper T1 - Two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation JF - BMC Cardiovascular Disorders N2 - Background: Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we examined the accuracy of a novel method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus. Methods: We evaluated the theoretical impact of the measurement of the annulus diameter and area using the circumcircle of a triangle method on the decision to perform the procedure and choice of the prosthesis size. Results: Sixty-three consecutive patients were scheduled for TAVI. Mean age was 82 +/- 4 years, and 25 patients (55.6 %) were female. Mean aortic annulus diameter was 20.3 +/- 2.2 mm assessed by TEE on the mid-esophageal long-axis view and 23.9 +/- 2.3 mm using CT (p < 0.001). There was a tendency for the TEE derived areas using the new method to be higher (p < 0.001). The TEE measurements were on average 42.33 mm(2) higher than the CT measurements without an evidence of a systematic over-or under-sizing (p = 1.00). Agreement between TEE and CT chosen valve sizes was good overall (kappa = 0.67 and weighted kappa = 0.71). For patients who turned out to have no AR, the two methods agreed in 84.6 % of patients. Conclusions: CT remanis the gold standard in sizing of the aortic valve annulus. Nevertheless, sizing of the aortic valve annulus using TEE derived area may be helpful. The impact of integration of this method in the algorithm of aortic annulus sizing on the outcome of patients undergoing TAVI should be examined in future studies. KW - multicenter KW - TAVI KW - impact KW - complex KW - anatomy KW - dimensions KW - regurgitation KW - root KW - sizing KW - echocardiography KW - multidetector computed-tomography KW - replacement KW - outcomes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136002 VL - 15 IS - 181 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 - THES A1 - Schober, Kilian T1 - Der Einfluss von CLEC16A auf Autophagie - ein neuer Mechanismus in der Pathogenese von Typ-1-Diabetes T1 - The influence of CLEC16A on autophagy - a new mechanism in the pathogenesis of type 1 diabetes N2 - Das Gen CLEC16A ist mit der Autoimmunerkrankung Typ-1-Diabetes assoziiert. NOD-Mäuse mit einem Clec16a-KD sind vor der Entwicklung von Diabetes geschützt, der entscheidende Wirkungsort für Clec16a sind dabei TECs. Im Rahmen zentraler Toleranz präsentieren TECs CD4+ Thymozyten Selbstantigene auf MHC II-Komplexen. Autophagie ist ein Zellprozess, der in TECs MHC II-Komplexen Selbstantigene zuführt und so für die Entwicklung zentraler Toleranz essentiell ist. Das Ortholog von CLEC16A, ema, fördert die Bildung von Autophagosomen. So wurde vermutet, dass CLEC16A ein Suszeptibilitätsgen für Typ-1-Diabetes ist, weil es Autophagie in TECs und somit deren MHC II-Beladung verändert. Die vorliegende Arbeit schaltete CLEC16A in einer humanen Zelllinie durch RNAi aus und untersuchte die autophagische Aktivität dieser Zellen. Außerdem untersuchte sie die Autophagie von TECs aus NOD-Clec16a-KD-Mäusen. Die Beurteilung erfolgte morphologisch durch Immunzytochemie bzw. -histochemie und funktionell durch Immunoblots. Es wurde gezeigt, dass der KD von CLEC16A in vitro und in vivo Autophagie funktionell beeinträchtigt. Damit liefert die vorliegende Arbeit zusammen mit den Ergebnissen der Arbeitsgruppe Kissler einen möglichen Erklärungsansatz, warum CLEC16A ein mit Typ-1-Diabetes assoziiertes Gen ist. CLEC16A fördert Autophagie in TECs, was die Selbstantigen-Beladung von MHC II-Komplexen verändert. Selbstreaktive CD4+ Thymozyten führen so zum Verlust zentraler Toleranz und der Entwicklung von Typ-1-Diabetes. Weitere Untersuchungen sind jedoch notwendig, um diese Hypothese zu bekräftigen. N2 - The gene CLEC16A is associated with type 1 diabetes. NOD mice with a Clec16a-KD are protected from diabetes. Specifically, the protection is dependent on a Clec16a-KD in TECs. TECs present self-antigens to CD4+ thymocytes for positive selection and central tolerance. Some TECs show constitutive levels of autophagy and in these cells, autophagy changes the TCR ligandome of self antigens, thereby modulating central tolerance. The orthologous gene of CLEC16A in Drosophila, ema, promotes the formation of autophagosomes. It was therefore hypothesized that CLEC16A is associated with type 1 diabetes, as it changes autophagy in TECs. This doctoral thesis knocked down CLEC16A in a human cell line, using RNA interference, and investigated TECs from NOD-Clec16a-KD mice. Autophagic flux was determined using immunocytochemistry/immunohistochemistry and immunoblot of the autophagic markers p62 and LC3. It was shown that a KD of CLEC16A compromises autophagic activity in vitro and in vivo. Together with further results from the lab of Stephan Kissler, a change in autophagy in TECs through CLEC16A provides a possible reason for the association with type 1 diabetes, but also other autoimmune diseases: CLEC16A enhances autophagy in TECs, which modulates MHC II self-peptide loading. Self reactive CD4+ T cells are thus not eliminated by central tolerance and contribute to the pathogenesis of type 1 diabetes. KW - Thymus KW - Autophagie KW - Diabetes mellitus KW - Typ-1-Diabetes KW - Autophagie KW - Zentrale Toleranz Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138715 ER - TY - JOUR A1 - Montes-Cobos, Elena A1 - Li, Xiao A1 - Fischer, Henrike J. A1 - Sasse, André A1 - Kügler, Sebastian A1 - Didié, Michael A1 - Toischer, Karl A1 - Fassnacht, Martin A1 - Dressel, Ralf A1 - Reichardt, Holger M. T1 - Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload JF - PLoS One N2 - Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes. KW - cells KW - balance KW - polarization KW - transgenic rats Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137575 VL - 10 IS - 11 ER - TY - JOUR A1 - Zhao, De-Wei A1 - Yu, Mang A1 - Hu, Kai A1 - Wang, Wei A1 - Yang, Lei A1 - Wang, Ben-Jie A1 - Gao, Xiao-Hong A1 - Guo, Yong-Ming A1 - Xu, Yong-Qing A1 - Wei, Yu-Shan A1 - Tian, Si-Miao A1 - Yang, Fan A1 - Wang, Nan A1 - Huang, Shi-Bo A1 - Xie, Hui A1 - Wei, Xiao-Wei A1 - Jiang, Hai-Shen A1 - Zang, Yu-Qiang A1 - Ai, Jun A1 - Chen, Yuan-Liang A1 - Lei, Guang-Hua A1 - Li, Yu-Jin A1 - Tian, Geng A1 - Li, Zong-Sheng A1 - Cao, Yong A1 - Ma, Li T1 - Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey JF - Chinese Medical Journal N2 - Background: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating disease that represents a significant financial burden for both individuals and healthcare systems. Despite its significance, however, its prevalence in the Chinese general population remains unknown. This study aimed to investigate the prevalence of NONFH and its associated risk factors in the Chinese population. Methods: A nationally representative survey of 30,030 respondents was undertaken from June 2012 to August 2013. All participants underwent a questionnaire investigation, physical examination of hip, and bilateral hip joint X-ray and/or magnetic resonance imaging examination. Blood samples were taken after overnight fasting to test serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels. We then used multivariate logistic regression analysis to investigate the associations between various metabolic, demographic, and lifestyle-related variables and NONFH. Results: NONFH was diagnosed in 218 subjects (0.725%) and the estimated NONFH cases were 8.12 million among Chinese people aged 15 years and over. The prevalence of NONFH was significantly higher in males than in females (1.02% vs. 0.51%, \(\chi^2\) = 24.997, P < 0.001). Among NONFH patients, North residents were subjected to higher prevalence of NONFH than that of South residents (0.85% vs. 0.61%, \(\chi^2\) = 5.847, P = 0.016). Our multivariate regression analysis showed that high blood levels of triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, male, urban residence, family history of osteonecrosis of the femoral head, heavy smoking, alcohol abuse and glucocorticoid intake, overweight, and obesity were all significantly associated with an increased risk of NONFH. Conclusions: Our findings highlight that NONFH is a significant public health challenge in China and underscore the need for policy measures on the national level. Furthermore, NONFH shares a number of risk factors with atherosclerosis. KW - nontraumatic osteonecrosis of the femoral head KW - risk factors KW - idiopathic osteonecrosis KW - early-stage osteonecrosis KW - implantation KW - bone KW - marrow KW - follow-up KW - intake KW - avascular necrosis KW - occupational-status KW - cigarette smoking KW - alcohol KW - prevalence Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138482 VL - 128 IS - 21 ER - TY - THES A1 - Gabor, Sabine T1 - Präklinische Evaluation von Aldosteronsynthaseinhibitoren als PET-Tracer für die Differentialdiagnostik des primären Hyperaldosteronismus mit besonderem Fokus auf Cyanofluorphenylpyridinen und deren Derivate T1 - Preclinical evaluation of aldosterone synthase inhibitors as PET tracers for the differential diagnosis of primary hyperaldosteronism with special focus on cyanofluorophenylpyrindines and derivates N2 - Zusammenfassend lässt sich festhalten, dass in dieser Arbeit 15 neu entwickelte Substanzen zur selektiven und hochaffinen Blockade der Aldosteronsynthase untersucht werden konnten. Es wurden mehrere neue aufeinander aufbauende Testsysteme etabliert, um die neuen Substanzen auf ihre Selektivität und Affinität gegenüber der Aldosteronsynthase zu untersuchen. Eine Testung der Inhibition der humanen Aldosteronsynthase und der 11β-Hydroxylase zuerst in getrennten Zellkulturansätzen, die die humanen Enzyme stabil exprimieren, und anschließend in der NCI-h295 Zelllinie, die beide Enzyme und zusätzlich die meisten anderen Enzyme der Steroidbiosynthese stabil exprimieren, ist eine gute Voraussetzung, um selektive und hochaffine Aldosteronsynthaseinhibitoren zu finden. Hier konnten sechs Inhibitoren ausgewählt werden, die hochaffin und selektiv an die Aldosteronsynthase binden und diese inhibieren. Die weitere Testung der [18F] markierten Substanzen zeigte für eine Substanz eine hochaffine und selektive Bindung an humanes adrenales Gewebe und keine unspezifische Bindung an andere humane Gewebe. Hier liegt die Voraussetzung vor, den Tracer weiteren in vivo Studien zuzuführen, um am humanisierten Mausmodell zu untersuchen, ob eine Bindung in vivo entsprechend den vielversprechenden Ergebnissen in vitro abläuft. Auch die ex vivo Studie an Nebennieren einer gegenüber der CYP11B2 humanisierten Maus bekräftigte diese Ergebnisse. Mit Hilfe dieser Untersuchungsmethoden lassen sich in Zukunft noch weiter entwickelte Substanzen umfangreich auf ihre Selektivität, Spezifität und Affinität testen. Dies dient als Grundlage für weitere Untersuchungen zur Entwicklung eines PET-Tracers für die Differentialdiagnostik bei primärem Hyperaldosteronismus. Eine Erkrankung, die häufiger ist als vermutet, und bei der die Differentialdiagnostik die entscheidende Voraussetzung für die Einleitung einer Therapie ist, die sich entweder operativ oder medikamentös darstellt. Bisherige differentialdiagnostische Vorgehensweisen beim primären Hyperaldosteronismus bieten aktuell keine zufriedenstellenden Ergebnisse; dies kann sich mit der Einführung eines neuen PET Tracers ändern. N2 - In this thesis 15 newly developed aldosterone synthase inhibitors were investigated for the selectivity and affinity for the human aldosterone synthase over the human 11β-hydroxylase. Different test systems were evaluated for this aim. Testing all inhibitors for the inhibition of aldosterone synthase in a cell line expressing the human aldosterone synthase and 11β-hydroxylase, respectively, and in the NCI-h295 cell line expressing both enzymes and most other enzymes of the steroidogenesis is a suitable tool to identify potent aldosterone synthase inhibitors. 6 inhibitors were selected showing an affine and selective binding and inhibition of the aldosterone synthase. By further investigation of the radiolabeled [18F] tracers one compound showed high and specific binding to human adrenocortical tissue and no unspecific binding to other human tissues. This is the requirement to proceed to in vivo studies using a humanized mouse model investigating the binding of the tracers in vivo. The ex vivo experiments using the adrenals towards the aldosterone synthase humanised mice confirmed the results seen in vitro. With the help of these testing systems more compounds can be investigated for the selectivity, affinity and specifity towards the inhibition of the aldosterone synthase in future. This is the requirement for the evaluation of a PET tracer for the subtype differentiation of primary hyperaldosteronism. KW - Aldosteronsynthaseinhibitor KW - primärer Hyperaldosteronismus KW - PET-Tracer Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137096 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 - THES A1 - Lang, Mirjam T1 - Diffusionsmessung mittels Rebreathing T1 - Diffusion measurement by rebreathing N2 - Für die Messung der Diffusionskapazität der Lunge für Kohlenmonoxid (Transferfak-tor) stehen verschiedene Verfahren zur Verfügung. Die Messwerte für den Transferfak-tor unterscheiden sich nicht nur je nach dem angewandten Verfahren, sondern auch in Abhängigkeit von der technischen Ausrüstung und den Eigenheiten der Methodik. Ziel dieser Arbeit war es, ein neu eingeführtes Rebreath-Gerät, das die Diffusionskapazität nach der von Stam (Stam et al. 1998) entwickelten Methode misst, in der klinischen Praxis zu testen. Die Messwerte sollten mit den Messungen nach dem Steady-State-Verfahren, das sich im Lungenfunktionslabor der Medizinischen Klinik und Poliklinik I der Universität Würzburg bewährt hatte, in Beziehung gesetzt werden. Durch adäquate Korrektur der Rebreath-Messwerte sollte eine möglichst gute Übereinstimmung der kor-respondierenden Messwerte erzielt werden. Bei den untersuchten Patientenkollektiven handelte es sich um lungengesunde Proban-den und um Patienten mit obstruktiven bzw. restriktiven Lungenerkrankungen. Bei allen Kollektiven wurden Diffusionskapazitätsmessungen nach beiden Verfahren durchge-führt und parallel dazu auch spirometrische und bodyplethysmografische Untersuchun-gen vorgenommen. Die Auswertung der Messdaten umfasste zunächst eine univariate Analyse zur Ermittlung von diagnostischen und demografischen Einflussgrößen (Prä-diktoren) auf die Messwerte der beiden Verfahren und auf die Bodyplethysmographie. Anschließend wurden schrittweise mittels multipler linearer Regression aus den ver-schiedenen Einflussgrößen primäre Prädiktoren für die Messungen mit den beiden Ver-fahren ermittelt. Schließlich wurde eine Schätzformel abgeleitet, die unter der Berück-sichtigung der wichtigsten Prädiktoren die optimale Näherung der Rebreath-Messwerte an die korrespondierenden Steady-State-Messwerte erlaubte. Mit beiden Verfahren wurden für die Patienten niedrigere Werte der Diffusionskapazi-tät ermittelt als für gesunde Probanden, mit den niedrigsten Werten bei Patienten mit restriktiver Lungenerkrankung. Für obstruktiv Erkrankte fanden sich die höchsten Alve-olarvolumina und entsprechend die niedrigsten Werte für den Krogh-Faktor. Mit beiden Verfahren konnte eine Abhängigkeit der Messwerte für den Transferfaktor von Ge-schlecht und Alter festgestellt werden. Als primärer Prädiktor galt allerdings in beiden Fällen die Diagnose. Bemerkenswert ist der starke Einfluss des BMI auf einige der ge-messenen Parameter (TLCOkorr, Krogh-Faktor, DLCO%), was eine stärkere Berück-sichtigung des BMI als prädiktiven Faktor nahe legt. Die Korrelation zwischen den Messwerten aus den beiden Verfahren war mäßig. Das Steady-State-Gerät maß den Transferfaktor signifikant und wesentlich höher als das Rebreath-Gerät. Die schwächste Korrelation fand sich unter allen untersuchten Parame-tern für die Prozentwerte vom Soll TLCO% und DLCO%. Die Abweichung der korres-pondierenden Messwerte unterschied sich zudem je nach Diagnose, Alter und Höhe des Messwerts. Die Spirometrie und Bodyplethysmografie zeigte die zu erwartenden geschlechts-, al-ters- und diagnosespezifischen Charakteristika, wobei nahezu alle bodyplethysmografi-schen Parameter primär mit der Diagnose und nur sekundär mit demografischen Fakto-ren korrelierten. Die Einsekundenkapazität FEV1 erwies sich als ein wichtiger Prädiktor für die Steady-State-Diffusionskapazität und als geeignet, um die Rebreath-Messwerte der Zielsetzung entsprechend zu korrigieren. Sowohl für die Absolut- als auch für Rela-tivwerte der Diffusionskapazität konnte eine Schätzformel abgeleitet werden, welche die optimale Näherung der Rebreath-Werte an die entsprechenden Steady-State-Werte ermöglichte. Die bessere Näherung gelang für die Absolutwerte des Transferfaktors. N2 - Several methods have been developed to estimate the pulmonary diffusing capacity for carbon monoxide ( transfer factor). The measurements for the transfer factor differ not only depending on the applied method, but also on the technical equipment and the peculiarities of the methodology. The aim of this study was to test in clinical practice a newly introduced rebreath device that measures the diffusion capacity after rebreathing method developed by Stam (Stam et al. 1998). The measured values should be set in relationship with the measurements according to the steady-state method, which had been proven in pulmonary function laboratory of the Department of Internal Medicine I, University of Würzburg. Measurements were perfomed with healty volunteers and outpatients with obstructive and restrictive lung disease. All patients were measured by the rebreathing method, by the the steady state method and by the bodyplethysmographie. The evaluation of the measurement data initially comprised a univariate analysis of diagnostic and demographic influences (predictors) on the measurement values of both methods and of the bodyplethysmographie. Then by stepwise multiple regression analysis of the various influencing factors primary predictors for the measurements with both methods were determined. Finally, an estimation formula has been derived that allowed the optimal approximation of the values by the rebreathing method and the steady state method, taking account of the most important predictors. With both methods, diffusion capacity in patients was smaller than in healthy patients, with the lowest values in the patients with restrictive lung disease. Also with both methods a dependence of the measured values for the transfer factor of gender and age was found. Although the primary predictor in both cases was the diagnosis. Noteworthy is the strong influence of BMI on some of the measured parameters (TLCOkorr, Krogh-Faktor, DLCO%), suggesting a stronger consideration of BMI as a predictor. The correlation between the measured values of both methods was moderately. The steady state device measured the transfer factor significantly and substantially higher than the rebreathing appliance. Among all investigated parameters the weakest correlation was found for the percentage values from the setpoint TLCO% and DLCO%. The deviation of the corresponding measured values also differed by diagnosis, age and height of the measured value. The bodyplethysmographie showed the expected gender-, age-, and diagnosis specific characteristics. Almost all bodyplethysmographic parameters correlated primarily with the diagnosis, and only secondarily with demographic factors. The FEV1 was found to be an important predictor for the steady-state diffusion capacity and as appropriate, to correct the rebreath- values accordingly to the objective. Both the absolute and relative values of diffusion capacity an estimation formula was derived, which enabled the optimum approximation of the rebreath values to the respective steady-state values. The better approximation succeeded for the absolute values of the transfer factor. KW - Rebreathing KW - Rebreathing KW - Rückatmungsmethode Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132750 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 - 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 -