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  • 1
    In: Clinical Endocrinology, January 2014, Vol.80(1), pp.65-72
    Description: Byline: Mireille N. M. Poppel, Willibald Zeck, Daniela Ulrich, Eva-Christina Schest, Birgit Hirschmugl, Uwe Lang, Christian Wadsack, Gernot Desoye Summary Objective Chemerin is a novel adipokine implicated in inflammation and obesity. We hypothesized that foetal chemerin would be elevated in gestational diabetes mellitus (GDM) and correlate with foetal and maternal adiposity. Design Observational, longitudinal study. Subjects and measurements Foetal chemerin was measured separately in arterial and venous cord blood of 30 infants born to mothers with (n = 15) and without GDM (n = 15), in their mothers in early third trimester and at delivery and in amniotic fluid (week 32) of women with GDM. Expression of chemerin and its receptor in human foetal tissues commercially available and in placental cells was measured by quantitative PCR. Associations between foetal and maternal anthropometric and metabolic variables were assessed in multivariate regression models. Results In GDM, foetal arterial but not venous cord blood chemerin levels were elevated by about 60% (P 0ae05). Venous cord blood chemerin was higher in infants of obese women (P 0ae01). In multivariate analyses, neither amniotic fluid nor cord blood chemerin levels correlated with birth weight or ponderal index. Both arterial and venous chemerin levels were related to maternal chemerin at birth, and arterial chemerin was associated with GDM status in addition. Maternal levels were unaltered in GDM, but higher in maternal obesity. Foetal liver produces fourfold more chemerin mRNA than other foetal tissues, whereas its receptor prevails in spleen. Conclusions Based on multivariate analyses, foetal growth appears unrelated to foetal chemerin. Maternal obesity and GDM have differential effects on foetal chemerin levels. Site of major production (liver) and action (spleen) differ in human foetal tissues. Article Note: Equal contribution of both authors.
    Keywords: Obesity -- Analysis ; Gestational Diabetes -- Analysis ; Rna -- Analysis;
    ISSN: 0300-0664
    E-ISSN: 1365-2265
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  • 2
    Language: English
    In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 15 November 2014, Vol.59(10), pp.1420-8
    Description: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients. In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated. Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined. No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).
    Keywords: Hcv ; HIV ; Antiretrovirals ; Drug–Drug Interactions ; Faldaprevir ; Adenine -- Analogs & Derivatives ; Anti-HIV Agents -- Pharmacology ; Benzoxazines -- Pharmacology ; Oligopeptides -- Pharmacology ; Organophosphonates -- Pharmacology ; Protease Inhibitors -- Pharmacology ; Ritonavir -- Pharmacology ; Sulfonamides -- Pharmacology ; Thiazoles -- Pharmacology
    ISSN: 10584838
    E-ISSN: 1537-6591
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  • 3
    Language: English
    In: Psychopharmacology, 2010, Vol.208(3), pp.353-363
    Description: Rationale/objectives: There is a high prevalence of substance use disorder (SUD) in first-episode schizophrenia (SZ), but its contribution to the underlying SZ pathophysiology remains unclear. Several studies using transcranial magnetic stimulation (TMS) have observed abnormalities in human motor cortex (M1) excitability in SZ. Studies on cortical excitability comparing SZ patients with and without comorbid substance abuse are lacking. Methods: A total of 29 first-episode SZ patients participated in this study; 12 had a history of comorbid cannabis abuse (SZ-SUD) and 17 did not (SZ-NSUD). We applied TMS to right and left M1 areas to assess the resting motor threshold (RMT), short-interval cortical inhibition (SICI), intracortical facilitation (ICF), and the contralateral cortical silent period (CSP). Results: In SICI and ICF conditions, right M1 stimulation led to significantly higher motor evoked potential ratios in SZ-SUD compared to SZ-NSUD. This suggests lower cortical inhibition and increased ICF in first-episode SZ with previous cannabis abuse. There were no group differences in RMT and CSP duration. Neither were there any significant correlations between psychopathology (as indexed by Positive and Negative Syndrome Scale), disease characteristics, the extent of cannabis abuse, and TMS parameters (SICI, ICF, and CSP). Conclusions: Comorbid cannabis abuse may potentiate the reduced intracortical inhibition and enhanced ICF observed in first-episode SZ patients in some previous studies. This finding suggests an increased alteration of GABA sub(A) and NMDA receptor activity in cannabis-abusing first-episode patients as compared to schizophrenia patients with no history of substance abuse. This may constitute a distinct vulnerability factor in this special population.
    Keywords: Schizophrenia ; Substance abuse ; Cortical inhibition ; Transcranial magnetic stimulation (TMS) ; Cannabinoids ; Electrophysiology
    ISSN: 0033-3158
    E-ISSN: 1432-2072
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  • 4
    In: Journal of Clinical Pharmacology, 2015, Vol.55(4), pp.467-477
    Description: : The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC0–24 h), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC0–24 h), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC0–120 h), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC0–∞), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms.
    Keywords: Clinical Research (Cre) ; Clinical Trials (Ctr) ; Drug Interactions ; Infectious Diseases (Inf) ; Pharmacokinetics and Drug Metabolism ; Cytochrome P-450 Enzyme Inhibitors -- Pharmacology ; Cytochrome P-450 Enzyme System -- Metabolism ; Oligopeptides -- Pharmacology ; Protease Inhibitors -- Pharmacology ; Thiazoles -- Pharmacology;
    ISSN: 0091-2700
    E-ISSN: 15524604
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  • 5
    Language: English
    In: Physiological genomics, 21 November 2011, Vol.43(22), pp.1255-62
    Description: Maternal lipoproteins have been studied extensively in human pregnancies, but little is known about the role of fetal lipoproteins. The vascularized human placenta interfaces between the mother and fetus to transfer nutrients for sustaining pregnancy. Unlike that of adults, fetal high-density lipoprotein (HDL), which is in contact with placental vessels, is characterized by a high proportion of apolipoprotein E (apoE). We hypothesize this unique composition of fetal HDL affects key functions of the growing fetal tissues. The aim was to identify genes regulated by apoE-HDL by incubating human placental endothelial cells (HPEC) with either fetal HDL or apoE-rich reconstituted HDL particles (apoE-rHDL). HPEC were exposed to 15 μg/ml fetal HDL, 15 μg/ml apoE-rHDL, or medium for 16 h, respectively. Microarray analysis determined genes regulated by fetal HDL and apoE. Characterization of HDL particles revealed a different hydrodynamic radius for apoE-rHDL (13.70 nm) compared with fetal HDL (18.11 nm). Stepwise gene clustering after microarray experiments identified 79 differentially expressed genes (P 〈 0.05) when cells were exposed to HDL compared with controls. Among them 16 genes were downregulated, whereas five genes were upregulated by twofold, respectively. When HPEC were incubated with apoE-rHDL 18-fold more genes (1,417, 12% of transcripts) were regulated (P 〈 0.05) in contrast to HDL. Thereof, 172 genes were downregulated and 376 genes upregulated (twofold). In the common subset of 38 genes regulated by both HDL particles, genes involved in cholesterol biosynthesis and cell protection prevailed. Strikingly, results suggest that HDL has the capability of regulating metallothioneins, which may have an effect on oxidative stress in HPEC.
    Keywords: Gene Expression Regulation ; Apolipoproteins E -- Genetics ; Endothelial Cells -- Metabolism ; Lipoproteins, HDL -- Genetics ; Placenta -- Metabolism
    ISSN: 10948341
    E-ISSN: 1531-2267
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  • 6
    Language: English
    In: Clinical Research in Cardiology, 2016, Vol.105(4), pp.349-355
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00392-015-0927-z Byline: Eva-Luise Hobl (1), Birgit Reiter (2), Christian Schoergenhofer (1), Michael Schwameis (1), Ulla Derhaschnig (1), Irene Marthe Lang (3), Thomas Stimpfl (2), Bernd Jilma (1) Keywords: Drug interactions; Morphine; Platelet function tests; Prasugrel; Vasodilator-stimulated phosphoprotein Abstract: Background Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. Objectives To clarify whether more potent P2Y.sub.12-inhibitors may provide an effective alternative, we examined drug--drug interactions between morphine and prasugrel. Methods Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. Results Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C .sub.max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. Conclusions Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C .sub.max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. Clinical Trial Registration: NCT01369186, EUDRA-CT : 2010-023761-22. Author Affiliation: (1) Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria (2) Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria (3) Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria Article History: Registration Date: 15/10/2015 Received Date: 26/08/2015 Accepted Date: 15/10/2015 Online Date: 22/10/2015 Article note: T. Stimpfl and B. Jilma contributed equally.
    Keywords: Drug interactions ; Morphine ; Platelet function tests ; Prasugrel ; Vasodilator-stimulated phosphoprotein
    ISSN: 1861-0684
    E-ISSN: 1861-0692
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  • 7
    Language: English
    In: Sci Rep, 2017, Vol.7(1), pp.12628-12628
    Description: Increased Lipoprotein associated phospholipase A (LpPLA) has been associated with inflammatory pathologies, including Type 2 Diabetes. Studies on LpPLA and Gestational Diabetes Mellitus (GDM) are rare, and have focused mostly on maternal outcome. In the present study, we investigated whether LpPLA activity on foetal lipoproteins is altered by maternal GDM and/or obesity (a major risk factor for GDM), thereby contributing to changes in lipoprotein functionality. We identified HDL as the major carrier of LpPLA activity in the foetus, which is in contrast to adults. We observed marked expression of LpPLA in placental macrophages (Hofbauer cells; HBCs) and found that LpPLA activity in these cells was increased by insulin, leptin, and pro-inflammatory cytokines. These regulators were also increased in plasma of children born from GDM pregnancies. Our results suggest that insulin, leptin, and pro-inflammatory cytokines are positive regulators of LpPLA activity in the foeto-placental unit. Of particular interest, functional assays using a specific LpPLA inhibitor suggest that high-density lipoprotein (HDL)-associated LpPLA exerts anti-oxidative, athero-protective functions on placental endothelium and foetus. Our results therefore raise the possibility that foetal HDL-associated LpPLA might act as an anti-inflammatory enzyme improving vascular barrier function.
    Keywords: Biology;
    ISSN: 2045-2322
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  • 8
    Language: English
    In: Cellular Physiology and Biochemistry, June 2012, Vol.29(5-6), pp.809-818
    Description: Background: Cardiac action potential repolarisation is determined by K+ currents including IKs. IKs channels are heteromeric channels composed of KCNQ1 and KCNE E-subunits. Mutations in KCNQ1 are associated with sinus bradycardia, familial atrial fibrillation (fAF) and/or short QT syndrome as a result of gain-of-function, and long QT syndrome (LQTS) due to loss-of-function in the ventricles. Here, we report that the missense mutation R231C located in S4 voltage sensor domain is associated with a combined clinical phenotype of sinus bradycardia, fAF and LQTS. We aim to understand the molecular basis of the complex clinical phenotype. Methods: We expressed and functionally analyzed the respective channels kinetics in Xenopus laevis oocytes. The molecular nature of the residue R231 was studied by homology modeling and molecular dynamics simulation. Results: As a result, the mutation reduced voltage sensitivity of channels, possibly due to neutralization of the positive charge of the arginine side chain substituted by cysteine. Modeling suggested that the charge carrying side chain of R231 is positioned suitably to transfer transmembrane voltages into conformational energy. Further, the mutation altered the functional interactions with KCNE subunits. Conclusion: The mutation acted in a E-subunit dependent manner, suggesting IKs function altered by the presence of different KCNE subunits in sinus node, atria and ventricles as the molecular basis of sinus bradycardia, fAF and LQTS in mutation carriers.
    Keywords: Original Paper ; Kcne ; Heart ; Arrhythmia ; Oocyte ; Kv7.1 ; Kvlqt1 ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
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  • 9
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 October 2014, Vol.193(7), pp.3355-65
    Description: Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. However, the pathophysiology of GvHD remains poorly understood. In this study, we analyzed the induction of Th17 cells by monocytes of patients with GvHD in vitro, demonstrating that monocytes isolated from patients with acute skin and intestinal GvHD stage I-IV and chronic GvHD induce significantly increased levels of Th17 cells compared with patients without GvHD. S100 proteins are known to act as innate amplifier of inflammation. We therefore investigated the presence of S100 proteins in the stool, serum, and bowel tissue of patients with GvHD and the influence of S100 proteins on the induction of Th17 cells. Elevated levels of S100 proteins could be detected in patients with acute GvHD, demonstrating the release of these phagocyte-specific proteins during GvHD. Furthermore, stimulation of monocytes with S100 proteins was found to promote Th17 development, emphasizing the role of S100 proteins in Th17-triggered inflammation. Altogether, our results indicate that induction of Th17 cells by activated monocytes and the stimulatory effects of proinflammatory S100 proteins might play a relevant role in the pathogenesis of acute GvHD. Regarding our data, S100 proteins might be novel markers for the diagnosis and follow-up of GvHD.
    Keywords: Graft Vs Host Disease -- Immunology ; Monocytes -- Immunology ; S100 Proteins -- Immunology ; Th17 Cells -- Immunology
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 10
    In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, June 2017, Vol.174(4), pp.390-398
    Description: Byline: Ana de Sena Cortabitarte, Franziska Degenhardt, Jana Strohmaier, Maren Lang, Birgit Weiss, Ralph Roeth, Ina Giegling, Stefanie Heilmann-Heimbach, Andrea Hofmann, Dan Rujescu, Christine Fischer, Marcella Rietschel, Markus M. Nothen, Gudrun A. Rappold, Simone Berkel The postsynaptic scaffolding protein SHANK3 is essential for the normal function of glutamatergic synapses in the brain. Emerging evidence suggests that impaired plasticity of glutamatergic synapses contributes to the pathology of schizophrenia (SCZ). To investigate whether variants in the SHANK3 gene contribute to the etiology of SCZ, we sequenced SHANK3 in 500 affected individuals (cohort C1). In total, we identified 48 variants and compared them to European controls from the 1000 Genomes Project and the Exome Variant Server. Five variants showed significant differences in frequencies between patients and controls. We were able to follow three of them up in an independent cohort (C2) comprising 993 SCZ patients and 932 German controls. We could not confirm an association for three of these variants (rs140201628, rs1557620, and rs61729471). Two rare variants with predicted functional relevance were identified in further SCZ individuals of cohort C1: c.3032G〉T (p.G1011V) and c.*27C〉T. The latter variant was found in one additional SCZ individual and the p.G1011V variant was identified in two additional SCZ individuals from cohort C2. The p.G1011V variant was the most interesting variant in our study; together with previous studies this variant has been identified in 4 out of 1,524 SCZ patients and in 4 out of 2,147 individuals with autism spectrum disorder (ASD), but not in 2468 European Sanger-sequenced controls. Therefore, we consider this variant a promising candidate variant for follow-up studies in larger samples and functional investigations. [c] 2017 Wiley Periodicals, Inc. Article Note: Ana de Sena Cortabitarte and Franziska Degenhardt contributed equally. Conflicts of interest: The authors have no conflict of interests to declare. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article. CAPTION(S): Supporting Information S1.
    Keywords: Schizophrenia ; Autism ; Intellectual Disability ; Shank
    ISSN: 1552-4841
    E-ISSN: 1552-485X
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