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Department of Psychiatry and Psychotherapy
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Department of Dermatology, Venerology and Allergology
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    ABSTRACT: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Low-dose (32 µg/kg/day) and high-dose (320 µg/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-β pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. We investigated a model showing early DN without overt tubulo-interstitial fibrosis and activation of the TGF-β-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes. © 2015 S. Karger AG, Basel.
    Kidney and Blood Pressure Research 03/2015; 40(1):77-88. DOI:10.1159/000368484
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    ABSTRACT: Regulated nuclear entry of clock proteins is a conserved feature of eukaryotic circadian clocks and serves to separate the phase of mRNA activation from mRNA repression in the molecular feedback loop. In Drosophila, nuclear entry of the clock proteins, PERIOD (PER) and TIMELESS (TIM), is tightly controlled, and impairments of this process produce profound behavioral phenotypes. We report here that nuclear entry of PER-TIM in clock cells, and consequently behavioral rhythms, require a specific member of a classic nuclear import pathway, Importin α1 (IMPα1). In addition to IMPα1, rhythmic behavior and nuclear expression of PER-TIM require a specific nuclear pore protein, Nup153, and Ran-GTPase. IMPα1 can also drive rapid and efficient nuclear expression of TIM and PER in cultured cells, although the effect on PER is mediated by TIM. Mapping of interaction domains between IMPα1 and TIM/PER suggests that TIM is the primary cargo for the importin machinery. This is supported by attenuated interaction of IMPα1 with TIM carrying a mutation previously shown to prevent nuclear entry of TIM and PER. TIM is detected at the nuclear envelope, and computational modeling suggests that it contains HEAT-ARM repeats typically found in karyopherins, consistent with its role as a co-transporter for PER. These findings suggest that although PER is the major timekeeper of the clock, TIM is the primary target of nuclear import mechanisms. Thus, the circadian clock uses specific components of the importin pathway with a novel twist in that TIM serves a karyopherin-like role for PER.
    PLoS Genetics 02/2015; 11(2):e1004974. DOI:10.1371/journal.pgen.1004974
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    ABSTRACT: The purpose of this article is to evaluate the American Society of Anesthesiologists Physical Status (ASA PS) and the Charlson comorbidity index (CCI) for the prediction of postoperative mortality.The ASA PS has been suggested to be equally good as the CCI in predicting postoperative outcome. However, these scores have never been compared in a broad surgical population.We conducted a retrospective cohort study in a German tertiary care university hospital. Predictive accuracy was compared using the area under the receiver-operating characteristic curves (AUROC). In a post hoc approach, a regression model was fitted and cross-validated to estimate the association of comorbidities and intraoperative factors with mortality. This model was used to improve prediction by recalibrating the CCI for surgical patients (sCCIs) and constructing a new surgical mortality score (SMS).The data of 182,886 patients with surgical interventions were analyzed. The CCI was superior to the ASA PS in predicting postoperative mortality (AUROCCCI 0.865 vs AUROCASAPS 0.833, P < 0.001). Predictive quality further improved after recalibration of the sCCI and construction of the new SMS (AUROCSMS 0.928 vs AUROCsCCI 0.896, P < 0.001). The SMS predicted postoperative mortality especially well in patients never admitted to an intensive care unit.The newly constructed SMS provides a good estimate of patient's risk of death after surgery. It is capable of identifying those patients at especially high risk and may help reduce postoperative mortality.
    Medicine 02/2015; 94(8):e576. DOI:10.1097/MD.0000000000000576


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    Chariteplatz 1, 10117, Berlin, Germany
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    Professor Karl Max Einhäupl
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Top publications last week by downloads

Fortschritte der Neurologie · Psychiatrie 09/2011; 79(9):517-23. DOI:10.1055/s-0031-1281602
Biological Psychiatry 07/2001; 49(12):1023-39. DOI:10.1016/S0006-3223(01)01157-X

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