Medical University of ViennaVienna

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Medical University of ViennaVienna

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Fischer H.,Medical University of ViennaVienna | Fumicz J.,Medical University of ViennaVienna | Rossiter H.,Medical University of ViennaVienna | Napirei M.,Ruhr University Bochum | And 3 more authors.
Journal of Investigative Dermatology | Year: 2017

Sebaceous glands produce sebum via holocrine secretion, a largely uncharacterized mode of programmed cell death that contributes to the homeostasis and barrier function of the skin. To determine the mechanism of DNA degradation during sebocyte cell death, we have inactivated candidate DNA-degrading enzymes by targeted gene deletions in mice. DNase1 and DNase1-like 2 were dispensable for nuclear DNA degradation in sebocytes. By contrast, epithelial cell-specific deletion of lysosomal DNase2 blocked DNA degradation in these cells. DNA breakdown during sebocyte differentiation coincided with the loss of LAMP1 and was accelerated by the abrogation of autophagy, the central cellular program of lysosome-dependent catabolism. Suppression of DNA degradation by the deletion of DNase2 resulted in aberrantly increased concentrations of residual DNA and decreased amounts of the DNA metabolite uric acid in secreted sebum. These results define holocrine secretion as a DNase2-mediated form of programmed cell death and suggest that autophagy-dependent metabolism, DNA degradation, and the molecular composition of sebum are mechanistically linked. © 2016 The Authors


Kamper M.,Medical University of ViennaVienna | Mittermayer F.,Medical University of ViennaVienna | Cabuk R.,Medical University of ViennaVienna | Gelles K.,Medical University of ViennaVienna | And 2 more authors.
Biochimie | Year: 2017

Cholesterol is an important nutrient for fetal development and transplacental transport occurs at all stages of human pregnancy. Furthermore, cholesterol is required for membrane building as well as steroid hormone synthesis. Therefore, all placental cell types require cholesterol for proper function. In human term placenta, the syncytiotrophoblast (STB) faces the maternal circulation. Uptake of maternal-derived cholesterol at the apical membrane of the STB is well understood, but the route by which cholesterol exits at the basal side for subsequent transfer across the fetal endothelial cells (FEC) or to other placental cell types remains not well characterized. Our aim was to provide evidence for basal secretion of apolipoprotein B-100 (apoB) containing lipoproteins. Furthermore, we investigated the placental localization of apolipoprotein receptors (LRP2, LDLR and LRP1) to identify cell targets of lipoprotein particles secreted in a polarized fashion by the STB. In trophoblast-derived BeWo cells grown on permeable filter supports, we demonstrate by immunoprecipitation apical as well as basolateral apoB secretion, which was significantly upregulated by estrogen-treatment for 24 or 48 h. Furthermore, we showed by immunofluorescence microscopy apoB and microsomal triglyceride transfer protein subunits localization in the STB and placental stromal cells in situ. All investigated receptors were detected by RT-qPCR and western blot in BeWo cells, but only expression of LRP2 was estrogen-inducible. In situ, the multi-ligand receptor LRP2 was expressed exclusively in the cytotrophoblast (CTB), the STB precursor cell type. LDLR and LRP1 localized to trophoblasts as well as stromal cells in situ. In summary, basal apoB secretion by BeWo cells supports the concept of basal lipoprotein particle secretion by placental STB. These lipoprotein particles may serve as cholesterol source for STB precursor cells, the CTBs, as well as all stromal cells of the chorionic villi including FECs, which were herein demonstrated to express apoB receptors, LRP2 and LDLR, respectively. © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)


Sase A.,Medical University of ViennaVienna | Aher Y.D.,Medical University of ViennaVienna | Saroja S.R.,Medical University of ViennaVienna | Ganesan M.K.,Medical University of ViennaVienna | And 9 more authors.
Neuropharmacology | Year: 2016

A series of compounds have been reported to enhance memory via the DA system and herein a heterocyclic compound was tested for working memory (WM) enhancement. 2-((benzhydrylsulfinyl)methyl)thiazole (CE-103) was synthesized in a six-step synthesis. Binding of CE-103 to the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters and dopamine reuptake inhibition was tested as well as blood brain permeation and a screen for GPCR targets. 60 male Sprague Dawley rats were divided into six groups: CE-103 treated 1-10 mg/kg body weight, trained (TDI) and yoked (YDI) and vehicle treated, trained (TVI) and yoked (YVI) rats. Daily single intraperitoneal injections for a period of 10 days were administered and rats were tested in a radial arm maze (RAM). Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT) and complexes containing the D1-3 dopamine receptor subunits were determined. CE-103 was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 14.73 μM). From day eight the compound was decreasing WM errors in the RAM significantly at both doses tested as compared to the vehicle controls. In the trained CE-103-treated group levels of the complex containing the phosphorylated dopamine transporter (pDAT) as well as D1R were decreased while levels of complexes containing D2R and D3R were significantly increased. CE-103 was shown to enhance spatial WM and DA reuptake inhibition with subsequent modulation of D1-3 receptors is proposed as a possible mechanism of action. © 2015 Published by Elsevier Ltd.


Stattermayer A.F.,Medical University of Vienna | Traussnigg S.,Medical University of Vienna | Dienes H.-P.,Medical University of ViennaVienna | Aigner E.,Paracelsus Medical University | And 11 more authors.
Journal of Hepatology | Year: 2015

Background & Aims The earliest characteristic alterations of the liver pathology in Wilson disease (WD) include steatosis, which is sometimes indistinguishable from non-alcoholic fatty liver disease (NAFLD). Steatosis in WD may reflect copper-induced mitochondrial dysfunction. A genetic polymorphism in rs738409, in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), is strongly associated with appearance of in NAFLD. This study evaluated the role of PNPLA3 and hepatic copper content for development of steatosis in patients with WD. Methods Liver biopsies obtained at diagnosis and the PNPLA3 genotype were analyzed in 98 Caucasian patients with WD (male: 52 [53.1%]; mean age: 27.6 years [CI 95%: 24.8-30.4, range: 5.8-61.5]). Steatosis was graded as percentage of lipid containing hepatocytes by an expert hepatopathologist unaware of the results of genetic testing. Results Moderate/severe steatosis (>33% of hepatocytes) was observed in 28 patients (pediatric: n = 13/26 [50.0%], adult: n = 15/72 [20.8%]; p = 0.01). Forty-six patients (46.9%; pediatric: n = 7, adult: n = 39; p = 0.022) had cirrhosis. Multivariate logistic regression identified PNPLA3 G allele (OR: 2.469, CI 95%: 1.203-5.068; p = 0.014) and pediatric age (OR: 4.348; 1.577-11.905; p = 0.004) as independent variables associated with moderate/severe steatosis. In contrast, hepatic copper content did not impact on moderate/severe steatosis (OR: 1.000, CI 95%: 1.000-1.001; p = 0.297). Conclusions Steatosis is common in WD and the PNPLA3 G allele contributes to its pathogenesis. The role of hepatic copper concentration and ATP7B mutations in steatosis development deserve further investigations. © 2015 European Association for the Study of the Liver.


Zauleck M.K.,KatharinenhospitalStuttgart | Gabriel S.,Universitatsklinikum KremsKrems a d Donau | Fischmeister M.F.,Private PracticeLinz | Hirtler L.,Medical University of ViennaVienna
Clinical Anatomy | Year: 2014

The aims of this study were to evaluate the discernibility of the LIR (lateral intercondylar ridge) and the LBR (lateral bifurcate ridge) and show their reliability in femoral tunnel placement in ACL (anterior cruciate ligament) reconstruction. Additionally, their position to the femoral axis, their course, and the ACL footprint were analyzed. For this study, 235 human femora were evaluated. Of these, 166 specimens originated from the Museum of Natural History (group A), and 69 were obtained from fixed cadavers at the Anatomic Institute (group B). The femoral footprint and the osseous landmarks were identified macroscopically and labeled in the photographs. A coordinate system was outlined, and the dimensions, position, and orientation of the femoral footprint of the ACL were measured. The LBR was found in 24.7% of the specimens in group A and in only 13.2% of the specimens in group B. The LIR was found in 97.9% and 85.3% of the specimens in groups A and B, respectively. The area of the ACL footprint was 127.21±32.54 mm2 in group A and 119.58±34.84 mm2 in group B. The shapes and angles of the osseous landmarks near the line of Blumensaat were highly variable. The LBR is an unreliable intraoperative landmark for arthroscopic ACL reconstruction due to its low incidence. Other anatomical structures, such as the LIR or the osteochondral border, may be more helpful and reliable landmarks to guide proper tunnel placement. © 2014 Wiley Periodicals, Inc.


Maneek-Keber M.,National Institute of ChemistryLjubljana | Frank-Bertoncelj M.,University Medical Center LjubljanaLjubljana | Hafner-Bratkovie I.,National Institute of ChemistryLjubljana | Smole A.,National Institute of ChemistryLjubljana | And 9 more authors.
Science Signaling | Year: 2015

Oxidative stress produced in response to infection or sterile injury activates the innate immune response. We found that extracellular vesicles (EVs) isolated from the plasma of patients with rheumatoid arthritis or secreted from cells subjected to oxidative stress contained oxidized phospholipids that stimulated cells expressing Toll-like receptor 4 (TLR4) in a manner dependent on its co-receptor MD-2. EVs from healthy subjects or reconstituted synthetic EVs subjected to limited oxidation gained the ability to stimulate TLR4-expressing cells, whereas prolonged oxidation abrogated this property. Furthermore, we found that 15-lipoxygenase generated hydro(pero)xylated phospholipids that stimulated TLR4-expressing cells. Molecular modeling suggested that the mechanism of activation of TLR4 by oxidized phospholipids in EVs was structurally similar to that of the TLR4 ligand lipopolysaccharide (LPS). This was supported by experiments showing that EV-mediated stimulation of cells required MD-2, that mutations that block LPS binding to TLR4 abrogated the stimulatory effect of EVs, and that EVs induced TLR4 dimerization. On the other hand, analysis of gene expression profiles showed that genes encoding factors that resolve inflammation were more abundantly expressed in responses to EVs than in response to LPS. Together, these data suggest that EVs act as an oxidative stress-induced endogenous danger signal that underlies the pervasive role of TLR4 in inflammatory diseases.


Gremmel T.,Dana-Farber Cancer Institute | Gremmel T.,Medical University of ViennaVienna | Michelson A.D.,Dana-Farber Cancer Institute | Frelinger A.L.,Dana-Farber Cancer Institute
Platelets | Year: 2016

Pathways of platelet activation that are not targeted by current antithrombotic therapy may be crucial for the development of ischemic events in patients undergoing coronary angiography. We therefore investigated whether in vivo and thrombin receptor activating peptide (TRAP)-stimulated platelet activation and monocyte-platelet aggregate (MPA) levels can serve as independent risk markers for adverse outcomes in aspirin-treated patients presenting for cardiac catheterization. In vivo and TRAP-stimulated platelet surface P-selectin, activated glycoprotein IIb/IIIa (GPIIb/IIIa) and MPA levels were determined in 682 consecutive patients undergoing cardiac catheterization and in 47 healthy controls. Two-year follow-up data were obtained from 562 patients. In vivo platelet surface P-selectin, activated GPIIb/IIIa and MPA levels were significantly higher in patients with angiographically-proven coronary artery disease than in healthy controls (all p≤0.02). Patients with an acute coronary syndrome (ACS; n=125) had significantly higher levels of in vivo MPA than patients without ACS (n=437; p=0.01). In the overall study population (n=562) the surface expression of P-selectin and activated GPIIb/IIIa, and the levels of MPA in vivo and in response to TRAP were similar in patients without and with subsequent ischemic events (all p>0.05). Similar results were obtained when only patients with angiographically-proven coronary artery disease (n=459), stent implantation (n=205) or ACS (n=125) were analyzed. Receiver-operating characteristic curve analyses did not reveal cut-off values for P-selectin, activated GPIIb/IIIa, and MPA levels for the prediction of ischemic events. In conclusion, in vivo and TRAP-stimulated platelet activation and MPA levels did not predict adverse ischemic outcomes in aspirin-treated patients presenting for cardiac catheterization. © 2015 Taylor & Francis, LLC.


Nolz R.,Medical University of Vienna | Schwartz E.,Medical University of ViennaVienna | Langs G.,Medical University of ViennaVienna | Loewe C.,Medical University of Vienna | And 4 more authors.
European Journal of Vascular and Endovascular Surgery | Year: 2015

Objectives The aim was to compare multidirectional stent graft movement in patients with and without a type 2 endoleak. Methods This was a retrospective case control study of patients being followed up after elective endovascular aneurysm repair of abdominal aortic aneurysms. The post-procedural and final follow up multislice computed tomography (MSCT) of 69 patients with and 74 without a type 2 endoleak were analyzed. Three dimensional (3D) surface models of the stent graft, delimited by landmarks using custom built software, were derived from these MSCT data. The stent graft was segmented in different zones, and the proportion of the total stent graft surface moving >9 mm between the post-procedural and the final follow up MSCT was calculated, given in percentages, and compared between groups. Changes of infrarenal neck, renal artery to stent graft distance, and freedom from stent graft related endoleaks were evaluated. Results Overall surface movement was higher in the no endoleak (18.8%, IQR 0.1-45.1%) than in the type 2 endoleak group (5.3%, IQR 0-29.7%; p = .06). Furthermore, significantly higher surface movement in the no endoleak group was found in the proximal anchoring zone (p = .04) and the distal left limb (p = .01), which was the modular limb in 81.1% (p < .01). Neck diameter increase (1.0 mm, IQR 0-3.0 mm; p < .01) and renal artery to stent graft distance difference (0 mm, IQR 0-3.3 mm; p < .01) were significantly higher in the no endoleak group. Five patients in the no endoleak and one patient in the type 2 endoleak group suffered from a stent graft related endoleak (p = .27). Conclusions The presence of a type 2 endoleak is associated with decreased surface movement of the proximal anchoring zone and the distal modular limb of bifurcated stent grafts. © 2015 European Society for Vascular Surgery.


Helbich M.,University Utrecht | Leitner M.,Louisiana State University | Kapusta N.D.,Medical University of ViennaVienna
British Journal of Psychiatry | Year: 2015

Background: Little is known about the effects of lithium intake through drinking water on suicide. This intake originates either from natural rock and soil elution and/or accumulation of lithium-based pharmaceuticals in ground water. Aims: To examine the interplay between natural lithium in drinking water, prescribed lithium-based pharmaceuticals and suicide in Austria. Method: Spatial Bayesian regressions for males, females and pooled suicide mortality rates were estimated. Results: Although the expected inverse association between lithium levels in drinking water and suicide mortality was confirmed for males and for total suicide rates, the relationship for females was not significant. The models do not indicate that lithium from prescriptions, assumed to accumulate in drinking water, is related to suicide risk patterns either as an individual effect or as a moderator of lithium levels in drinking water. Gender-specific differences in risk factors and local risk hot spots are confirmed. Conclusions: The findings do not support the hypotheses that lithium prescriptions have measureable protective effects on suicide or that they interact with lithium in drinking water. © The Royal College of Psychiatrists 2015.


PubMed | Medical University of ViennaVienna and Medical University of Vienna
Type: | Journal: Frontiers in neuroanatomy | Year: 2016

Diffusion tensor imaging (DTI) and tractography offer the unique possibility to visualize the developing white matter macroanatomy of the human fetal brain in vivo and in utero and are currently under investigation for their potential use in the diagnosis of developmental pathologies of the human central nervous system. However, in order to establish in utero DTI as a clinical imaging tool, an independent comparison between macroscopic imaging and microscopic histology data in the same subject is needed. The present study aimed to cross-validate normal as well as abnormal in utero tractography results of commissural and internal capsule fibers in human fetal brains using postmortem histological structure tensor (ST) analysis. In utero tractography findings from two structurally unremarkable and five abnormal fetal brains were compared to the results of postmortem ST analysis applied to digitalized whole hemisphere sections of the same subjects. An approach to perform ST-based deterministic tractography in histological sections was implemented to overcome limitations in correlating in utero tractography to postmortem histology data. ST analysis and histology-based tractography of fetal brain sections enabled the direct assessment of the anisotropic organization and main fiber orientation of fetal telencephalic layers on a micro- and macroscopic scale, and validated in utero tractography results of corpus callosum and internal capsule fiber tracts. Cross-validation of abnormal in utero tractography results could be achieved in four subjects with agenesis of the corpus callosum (ACC) and in two cases with malformations of internal capsule fibers. In addition, potential limitations of current DTI-based in utero tractography could be demonstrated in several brain regions. Combining the three-dimensional nature of DTI-based in utero tractography with the microscopic resolution provided by histological ST analysis may ultimately facilitate a more complete morphologic characterization of axon guidance disorders at prenatal stages of human brain development.

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