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"text": "\n117849\nLong-term effect of intravitreal bevacizumab (avastin) in patients with chronic diffuse diabetic macular edema.\n\nKook, D\n\nWolf, A\n\nKreutzer, T\n\nNeubauer, A\n\nStrauss, R\n\nUlbig, M\n\nKampik, A\n\nHaritoglou, C\n\nBeiträge in Fachzeitschriften\nISI:000259329100004\n18779710.0\n10.1097/IAE.0b013e318176de48\nNone\nPurpose: To evaluate the long-term efficacy of bevacizumab for the treatment of chronic diffuse diabetic macular edema after various previous treatments. Methods: A total of 126 patients (mean age: 66 years) with chronic diffuse diabetic macular edema were consecutively incorporated in this prospective, noncomparative case series. Inclusion was performed independently from the size of edema, retinal thickness, visual acuity (VA), age, metabolic control, type of diabetes, or type of previous treatments. The patients underwent a complete eye examination including best-corrected VA with ETDRS charts, slit lamp examination, intraocular pressure measurement, stereoscopic biomicroscopy of the macula, retinal thickness measurement using optical coherence tomography (OCT), fluorescein angiography, and fundus photography. All patients were treated with repeated intravitreal injections of bevacizumab (1.25 mg). Patients were observed in intervals of 4-12 weeks for a period of up to 6-12 months. Results: All patients had received various previous treatments such as laser treatment (62% focal laser treatment, 38% panretinal laser treatment), vitrectomy (11 %), or intravitreal injection of triamcinolone (41 %). All patients completed 6 months and 59 patients (47%) completed 12 months of follow-up; within this period 48% had received at least three intravitreal injections of bevacizumab. Mean diameter of foveal avascular zone was 858 +/- 341 mu m. At baseline mean VA was 40.3 ETIDRS letters (0.82 logMAR Snellen VA) and mean central retinal thickness on OCT was 463 mu m. Throughout follow-up VA changes were not significant with a mean change of -1.6 ETDRS letters after 6 months, but significant with +5.1 ETDRS letters after 12 months. Mean central retinal thickness (OCT) decreased to 374 mu m after 6 months (P < 0.001) and to 357 mu m after 12 months (P < 0.001). Changes of retinal thickness and visual acuity did not correlate. No other factors investigated, such as age, central retinal thickness, or previous treatments, were predictive for a change of VA. Macular ischemia was not exacerbated as a result of the treatment. Conclusion: Even in cases with chronic diffuse ischemic diabetic macular edema, a long-term decrease of central retinal thickness can be observed following repeated intravitreal injections of bevacizumab. In these patients, mean decrease in retinal thickness is aligned with a gain in mean VA. Treatment with bevacizumab at an earlier stage of diabetic macular edema without ischemia may be associated with an even better functional outcome.\n\nStrauß, Rupert\n\n\n"
},
{
"text": "\n144761\nPressure Overload Creates Right Ventricular Diastolic Dysfunction in a Mouse Model: Assessment by Echocardiography.\n\nEgemnazarov, B\n\nSchmidt, A\n\nCrnkovic, S\n\nSydykov, A\n\nNagy, BM\n\nKovacs, G\n\nWeissmann, N\n\nOlschewski, H\n\nOlschewski, A\n\nKwapiszewska, G\n\nMarsh, LM\n\nBeiträge in Fachzeitschriften\nISI:000357390800010\n25840639.0\n10.1016/j.echo.2015.02.014\nNone\nNoninvasive diagnostic tools for right ventricular (RV) dysfunction measurements are increasingly being used, although their association with the pathologic mechanisms of dysfunction is poorly understood. Although investigations have focused mainly on RV systolic function, RV diastolic function remains mostly neglected. The aim of this study was to test which echocardiographic parameters best reflect RV diastolic function in mice.\n Pulmonary artery banding (PAB) was used to induce RV pressure overload in mice. Transthoracic echocardiography and invasive hemodynamic measurements were performed after 3 weeks in PAB and sham-operated mice. Subsequently, the hearts were investigated by histology and analyzed for gene expression.\n PAB-induced pressure overload (RV systolic pressure PAB 52.6 ± 11.8 mm Hg vs sham 27.0 ± 2.7 mm Hg) resulted in RV hypertrophy and remodeling, as reflected by increased Fulton index (PAB 0.37 ± 0.05 vs sham 0.25 ± 0.02, P = .001). Masson's trichrome staining revealed increased interstitial fibrosis (PAB 12.25 ± 3.12% vs sham 3.97 ± 1.58%, P = .002). This was associated with significant systolic RV dysfunction as demonstrated by reduced contractility index and diastolic dysfunction as demonstrated by end-diastolic pressure (PAB 2.66 ± 0.83 mm Hg vs sham 1.49 ± 0.50 mm Hg, P < .001) and τ (PAB 40.0 ± 16.1 msec vs sham 13.0 ± 3.5 msec, P < .001). Messenger ribonucleic acid expression of β-myosin heavy chain, atrial and brain natriuretic peptides, collagen family members was elevated, and the sarco/endoplasmic reticulum Ca(2+)-ATPase was decreased. Echocardiography revealed significant increases in RV free wall thickness and isovolumic relaxation time and a decrease in left ventricular eccentricity index, E', and tricuspid annular plane systolic excursion. Isovolumic relaxation time and E' were significantly correlated with end-diastolic pressure (rs = 0.511 and -0.451) and τ (rs = 0.739 and -0.445, respectively). Moreover, E' was negatively correlated with the degree of RV fibrosis (rs = -0.717).\n Within 3 weeks, PAB causes pressure overload-induced RV hypertrophy and remodeling with compensated systolic and diastolic dysfunction in mice. RV free wall thickness, tricuspid annular plane systolic excursion, E', E/E' ratio, and isovolumic relaxation time appear to be the most reliable echocardiographic parameters for the assessment of RV dysfunction.\n Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.\n\nCrnkovic, Slaven\n\nEgemnazarov, Bakytbek\n\nKovacs, Gabor\n\nKwapiszewska-Marsh, Grazyna\n\nMarsh, Leigh\n\nNagy, Miklos Bence\n\nOlschewski, Andrea\n\nOlschewski, Horst\n\nSchmidt, Albrecht\n\n\n"
},
{
"text": "\n165008\nFirst Insights into the Diverse Human Archaeome: Specific Detection of Archaea in the Gastrointestinal Tract, Lung, and Nose and on Skin.\n\nKoskinen, K\n\nPausan, MR\n\nPerras, AK\n\nBeck, M\n\nBang, C\n\nMora, M\n\nSchilhabel, A\n\nSchmitz, R\n\nMoissl-Eichinger, C\n\nBeiträge in Fachzeitschriften\nISI:000418889500003\n29138298.0\n10.1128/mBio.00824-17\nPMC5686531\nHuman-associated archaea remain understudied in the field of microbiome research, although in particular methanogenic archaea were found to be regular commensals of the human gut, where they represent keystone species in metabolic processes. Knowledge on the abundance and diversity of human-associated archaea is extremely limited, and little is known about their function(s), their overall role in human health, or their association with parts of the human body other than the gastrointestinal tract and oral cavity. Currently, methodological issues impede the full assessment of the human archaeome, as bacteria-targeting protocols are unsuitable for characterization of the full spectrum of Archaea The goal of this study was to establish conservative protocols based on specifically archaea-targeting, PCR-based methods to retrieve first insights into the archaeomes of the human gastrointestinal tract, lung, nose, and skin. Detection of Archaea was highly dependent on primer selection and the sequence processing pipeline used. Our results enabled us to retrieve a novel picture of the human archaeome, as we found for the first time Methanobacterium and Woesearchaeota (DPANN superphylum) to be associated with the human gastrointestinal tract and the human lung, respectively. Similar to bacteria, human-associated archaeal communities were found to group biogeographically, forming (i) the thaumarchaeal skin landscape, (ii) the (methano)euryarchaeal gastrointestinal tract, (iii) a mixed skin-gastrointestinal tract landscape for the nose, and (iv) a woesearchaeal lung landscape. On the basis of the protocols we used, we were able to detect unexpectedly high diversity of archaea associated with different body parts.IMPORTANCE In summary, our study highlights the importance of the primers and data processing pipeline used to study the human archaeome. We were able to establish protocols that revealed the presence of previously undetected Archaea in all of the tissue samples investigated and to detect biogeographic patterns of the human archaeome in the gastrointestinal tract and on the skin and for the first time in the respiratory tract, i.e., the nose and lungs. Our results are a solid basis for further investigation of the human archaeome and, in the long term, discovery of the potential role of archaea in human health and disease.\n Copyright © 2017 Koskinen et al.\n\nKoskinen Mora, Kaisa\n\nMoissl-Eichinger, Christine\n\n\n"
},
{
"text": "\n182419\nMale Slings for Postprostatectomy Incontinence: A Systematic Review and Meta-analysis.\n\nMeisterhofer, K\n\nHerzog, S\n\nStrini, KA\n\nSebastianelli, L\n\nBauer, R\n\nDalpiaz, O\n\nBeiträge in Fachzeitschriften\nISI:000531657200004\n30718160.0\n10.1016/j.euf.2019.01.008\nNone\nMale slings are recommended by the European Association of Urology guideline for the treatment of mild to moderate postprostatectomy incontinence. However, none of them has been proved to be superior to the others, and there are no defined guidelines to preference of a given sling model.\n To evaluate and compare the efficacy and safety of the different types of male slings in the treatment of postprostatectomy incontinence.\n This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. A systematic literature search in the databases of PubMed, Embase, and Cochrane using the keywords "incontinence, "prostatectomy, and "male sling/system" was conducted in June 2018. Studies in English with at least 15 patients and a minimum follow-up of 12 mo were included. As the primary endpoint, we assessed the cure rate of the different sling types. As secondary endpoints, we assessed the improvement rate, subjective cure rate, overall complication rate, explantation rate, risk factors for failure, and effect on patients' quality of life.\n The literature search identified 833 articles. A total of 64 studies with 72 patient cohorts were eligible for inclusion. Fixed slings were implanted in 55 (76.4%) of the patient cohorts. The objective cure rate varies between 8.3% and 87% (pooled estimate 0.50, 95% confidence interval [CI] 0.45-0.56, I2=82%). Subjective cure was achieved in 33-94.4%. Adjustable slings showed objective cure rates between 17% and 92% (pooled estimate 0.61, 95% CI 0.51-0.71, I2=88%). The subjective cure rate varies between 28% and 100%. In both types of slings, pain was the most common complication, but chronic painful conditions were really rare (1.3% in fixed slings and 1.5% in adjustable slings). The most common complication after pain was urinary retention in fixed slings, and infection and consequential explantation in adjustable slings.\n Both fixed and adjustable slings are beneficial for the treatment of postprostatectomy incontinence. Although adjustable slings might lead to higher objective cure rates, they might be associated with higher complication and explantation rates. However, at present, due to significant heterogeneity of the data, this cannot be said with certainty. More randomized controlled trials with long-term follow-up and the same definition for continence are needed.\n Fixed and adjustable slings are effective treatment options in mild to moderate postprostatectomy incontinence.\n Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.\n\nDalpiaz, Orietta\n\nHerzog, Sereina Annik\n\n\n"
},
{
"text": "\n183298\nIntranasal Lipid Particulate Drug Delivery Systems: An Update on Clinical Challenges and Biodistribution Studies of Cerebroactive Drugs in Alzheimer's disease.\n\nArora, D\n\nBhatt, S\n\nKumar, M\n\nVattikonda, HDC\n\nTaneja, Y\n\nJain, V\n\nJoshi, V\n\nGali, CC\n\nBeiträge in Fachzeitschriften\nISI:000562737300007\n32228421.0\n10.2174/1381612826666200331085854\nNone\nAlzheimer's is the primary cause of death in the various countries that affect wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for the systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN's). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities.\n 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer's disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs.\n Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data.\n From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes.\n Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored.\n Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.\n\n\n"
},
{
"text": "\n155940\nEvaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial.\n\nNashan, B\n\nSchemmer, P\n\nBraun, F\n\nDworak, M\n\nWimmer, P\n\nSchlitt, H\n\nBeiträge in Fachzeitschriften\nISI:000352105100001\n25873064.0\n10.1186/s13063-015-0626-0\nPMC4384314\nIntroduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients.\n Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis.\n This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus.\n NCT01551212 .\n\nSchemmer, Peter\n\n\n"
},
{
"text": "\n174951\nChondrocyte Culture Parameters for Matrix-Assisted Autologous Chondrocyte Implantation Affect Catabolism and Inflammation in a Rabbit Model.\n\nSauerschnig, M\n\nBerninger, MT\n\nKaltenhauser, T\n\nPlecko, M\n\nWexel, G\n\nSchönfelder, M\n\nWienerroither, V\n\nImhoff, AB\n\nSchöttle, PB\n\nRosado Balmayor, E\n\nSalzmann, GM\n\nBeiträge in Fachzeitschriften\nISI:000464980400005\n30934789.0\n10.3390/ijms20071545\nPMC6479589\nCartilage defects represent an increasing pathology among active individuals that affects the ability to contribute to sports and daily life. Cell therapy, such as autologous chondrocyte implantation (ACI), is a widespread option to treat larger cartilage defects still lacking standardization of in vitro cell culture parameters. We hypothesize that mRNA expression of cytokines and proteases before and after ACI is influenced by in vitro parameters: cell-passage, cell-density and membrane-holding time. Knee joint articular chondrocytes, harvested from rabbits (n = 60), were cultured/processed under varying conditions: after three different cell-passages (P1, P3, and P5), cells were seeded on 3D collagen matrices (approximately 25 mm³) at three different densities (2 × 10⁵/matrix, 1 × 10⁶/matrix, and 3 × 10⁶/matrix) combined with two different membrane-holding times (5 h and two weeks) prior autologous transplantation. Those combinations resulted in 18 different in vivo experimental groups. Two defects/knee/animal were created in the trochlear groove (defect dimension: ∅ 4 mm × 2 mm). Four identical cell-seeded matrices (CSM) were assembled and grouped in two pairs: One pair giving pre-operative in vitro data (CSM-i), the other pair was implanted in vivo and harvested 12 weeks post-implantation (CSM-e). CSMs were analyzed for TNF-α, IL-1β, MMP-1, and MMP-3 via qPCR. CSM-i showed higher expression of IL-1β, MMP-1, and MMP-3 compared to CSM-e. TNF-α expression was higher in CSM-e. Linearity between CSM-i and CSM-e values was found, except for TNF-α. IL-1β expression was higher in CSM-i at higher passage and longer membrane-holding time. IL-1β expression decreased with prolonged membrane-holding time in CSM-e. For TNF-α, the reverse was true. Lower cell-passages and lower membrane-holding time resulted in stronger TNF-α expression. Prolonged membrane-holding time resulted in increased MMP levels among CSM-i and CSM-e. Cellular density was of no significant effect. We demonstrated cytokine and MMP expression levels to be directly influenced by in vitro culture settings in ACI. Linearity of expression-patterns between CSM-i and CSM-e may predict ACI regeneration outcome in vivo. Cytokine/protease interaction within the regenerate tissue could be guided via adjusting in vitro culture parameters, of which membrane-holding time resulted the most relevant one.\n\nPlecko, Michael\n\nWienerroither, Valerie\n\n\n"
},
{
"text": "\n63131\nExpression and cellular localisation of chloride intracellular channel 3 in human placenta and fetal membranes.\n\nMoney, TT\n\nKing, RG\n\nWong, MH\n\nStevenson, JL\n\nKalionis, B\n\nErwich, JJ\n\nHuisman, MA\n\nTimmer, A\n\nHiden, U\n\nDesoye, G\n\nGude, NM\n\nBeiträge in Fachzeitschriften\nISI:000246449700009\n17027078.0\n10.1016/j.placenta.2006.08.002\nNone\nChloride channels regulate the movement of a major cellular anion and are involved in fundamental processes that are critical for cell viability. Regulation of intracellular chloride is achieved by multiple classes of channel proteins. One class of putative channels are the chloride intracellular channel (CLIC) family. Evidence suggests that several CLICs are expressed in human placenta, although their roles in this tissue are not certain. Northern blot analysis has shown that CLIC3 is highly expressed in placenta relative to other human tissues; however, its cellular distribution is not known. This study used microarray expression profiling to clarify which CLICs are expressed in human placenta and RT-PCR, Western blot and immunohistochemistry to determine the expression pattern of CLIC3 in human placenta and fetal membranes. Placentas and fetal membranes were obtained from term pregnancies after delivery and placental tissue was obtained from first trimester following either chorionic villous sampling or elective pregnancy termination. Trophoblast cells were isolated from first trimester and term placentas and placental endothelial cells were isolated from term placentas. Microarray expression profiling identified high expression of mRNA for CLICs 1, 3 and 4 in the isolated first trimester and term trophoblast cells. High mRNA expression in the isolated endothelial cells was also found for CLICs 1 and 4, but not CLIC3. Low expression was found for CLIC5 in all three types of isolated cells. RT-PCR confirmed that CLIC3 mRNA was expressed in trophoblast cells at both gestational ages, but was not present in endothelial cells. CLIC3 mRNA was also identified in whole placental extracts at both gestational ages and in term amnion and choriodecidua. Immunohistochemistry using a chicken anti-human CLIC3 antibody localised strong CLIC3-specific staining to the syncytiotrophoblast and villous cytotrophoblast cells in both first trimester and term placentas, and weaker staining in extravillous trophoblast cells in first trimester. In fetal membranes at term strong CLIC3-specific staining was localised to chorionic trophoblast cells, with weaker staining in amniotic epithelial and decidual cells. It was previously shown that chloride uptake was increased into cells that had been transfected with CLIC3. CLIC3 may facilitate chloride ion movement and the regulation of cellular processes associated with the movement of chloride in the placental and fetal membrane cells in which it is expressed.\n\nDesoye, Gernot\n\nHiden, Ursula\n\n\n"
},
{
"text": "\n67022\nA controlled trial of recombinant human erythropoietin after bone marrow transplantation.\n\nLink, H\n\nBoogaerts, MA\n\nFauser, AA\n\nSlavin, S\n\nReiffers, J\n\nGorin, NC\n\nCarella, AM\n\nMandelli, F\n\nBurdach, S\n\nFerrant, A\n\nLinkesch, W\n\nTura S\n\nBacigalupo A, Schindel, F\n\nHeinrichs, H\n\nBeiträge in Fachzeitschriften\nISI:A1994PR22100009\n7949088.0\nNone\nNone\nRecombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels > or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.\n\n\n"
},
{
"text": "\n75645\nEvidence for a direct stimulatory effect of prostacyclin on renin release in man.\n\nPatrono, C\n\nPugliese, F\n\nCiabattoni, G\n\nPatrignani, P\n\nMaseri, A\n\nChierchia, S\n\nPeskar, BA\n\nCinotti, GA\n\nSimonetti, BM\n\nPierucci, A\n\nBeiträge in Fachzeitschriften\nISI:A1982NA38100027\n7033292.0\n10.1172/JCI110435\nPMC371187\nTHE OBJECTIVES OF THIS INVESTIGATION WERE: (a) to characterize the time and dose dependence of the effects of prostacyclin (PGI(2)) on renin release in healthy men; (b) to define whether PGI(2)-induced renin release is secondary to hemodynamic changes; (c) to determine the plasma and urine concentrations of 6-keto-PGF(1alpha) (the stable breakdown product of PGI(2)) associated with renin release induced by exogenous or pharmacologically enhanced endogenous PGI(2). Intravenous PGI(2) or 6-keto-PGF(1alpha) infusions at nominal rates of 2.5, 5.0, 10.0, and 20.0 ng/kg per min were performed in each of six normal human subjects; in three of them, PGI(2) infusion was repeated after beta-adrenergic blockade and cyclooxygenase inhibition. PGI(2), but not 6-keto-PGF(1alpha), caused a time- and dose-dependent increase of plasma renin activity, which reached statistical significance at 5.0 ng/kg per min and was still significantly elevated 30 min after discontinuing the infusion. Although combined propranolol and indomethacin treatment significantly enhanced the hypotensive effects of infused PGI(2), it did not modify the dose-related pattern of PGI(2)-induced renin release.Plasma 6-keto-PGF(1alpha) levels rose from undetectable levels (<7.5 pg/ml) in a stepwise fashion during increasingly higher infusion rates of PGI(2) or 6-keto-PGF(1alpha). The threshold concentration of plasma 6-keto-PGF(1alpha) associated with a statistically significant stimulation of renin release was approximately 200 pg/ml. Upon discontinuing PGI(2) or 6-keto-PGF(1alpha) infusion, the disappearance of 6-keto-PGF(1alpha) from blood showed an identical biphasic behavior, the initial phase having an apparent t((1/2)) of 3.2 min. The intravenous infusion of furosemide, which is known to stimulate renin release via a cyclooxygenase-dependent mechanism, caused a three-to fourfold increase of urinary 6-keto-PGF(1alpha) excretion rate, concomitant with the elevation of plasma renin activity levels, in six healthy women. 6-Keto-PGF(1alpha) remained undetectable in peripheral venous plasma throughout the study.WE CONCLUDE THAT IN HUMAN SUBJECTS: (a) PGI(2)-induced renin release occurs with a dose and time dependence similar to its reported platelet effects; (b) PGI(2)-induced renin release is not mediated by adrenergic stimuli or cyclooxygenase-dependent mechanisms secondary to hemodynamic changes; (c) furosemide-induced renin release is associated with increased renal PGI(2) formation; and (d) PGI(2) appears to act as a local modulator rather than a circulating hormone in controlling juxtaglomerular function.\n\nPeskar, Bernhard\n\n\n"
},
{
"text": "\n103462\nIcatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.\n\nCicardi, M\n\nBanerji, A\n\nBracho, F\n\nMalbrán, A\n\nRosenkranz, B\n\nRiedl, M\n\nBork, K\n\nLumry, W\n\nAberer, W\n\nBier, H\n\nBas, M\n\nGreve, J\n\nHoffmann, TK\n\nFarkas, H\n\nReshef, A\n\nRitchie, B\n\nYang, W\n\nGrabbe, J\n\nKivity, S\n\nKreuz, W\n\nLevy, RJ\n\nLuger, T\n\nObtulowicz, K\n\nSchmid-Grendelmeier, P\n\nBull, C\n\nSitkauskiene, B\n\nSmith, WB\n\nToubi, E\n\nWerner, S\n\nAnné, S\n\nBjörkander, J\n\nBouillet, L\n\nCillari, E\n\nHurewitz, D\n\nJacobson, KW\n\nKatelaris, CH\n\nMaurer, M\n\nMerk, H\n\nBernstein, JA\n\nFeighery, C\n\nFloccard, B\n\nGleich, G\n\nHébert, J\n\nKaatz, M\n\nKeith, P\n\nKirkpatrick, CH\n\nLangton, D\n\nMartin, L\n\nPichler, C\n\nResnick, D\n\nWombolt, D\n\nFernández Romero, DS\n\nZanichelli, A\n\nArcoleo, F\n\nKnolle, J\n\nKravec, I\n\nDong, L\n\nZimmermann, J\n\nRosen, K\n\nFan, WT\n\nBeiträge in Fachzeitschriften\nISI:000280552700007\n20818888.0\n10.1056/NEJMoa0906393\nPMC4662377\nHereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.\n In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.\n A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.\n In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)\n\nAberer, Werner\n\n\n"
},
{
"text": "\n171072\nThe accuracy of digital templating in uncemented total hip arthroplasty.\n\nHolzer, LA\n\nScholler, G\n\nWagner, S\n\nFriesenbichler, J\n\nMaurer-Ertl, W\n\nLeithner, A\n\nBeiträge in Fachzeitschriften\nISI:000458199700015\n30523444.0\n10.1007/s00402-018-3080-0\nPMC6373540\nPreoperative planning is an essential part of total hip arthroplasty (THA). It facilitates the surgical procedure, helps to provide the correct implant size and aims at restoring biomechanical conditions. In recent times, surgeons rely more and more on digital templating techniques. Although the conversion to picture archiving and communication system had many positive effects, there are still problems that have to be taken into consideration.\n The core objective was to evaluate the impact of the planners' experience on the accuracy of predicting component size in digital preoperative templating of THA. In addition, the influence of overweight and obesity (according to WHO-criteria), patient's sex and component design on the accuracy of preoperative planning have been analysed.\n The retrospective study included 632 consecutive patients who had primary uncemented THA. Digital templating was done using "syngo-EndoMap" software by Siemens Medical Solutions AG. Mann-Whitney U test and Kruskal-Wallis test have been used for statistical analysis. The accuracy of predicting component size has been evaluated by comparing preoperative planned sizes with implanted sizes as documented by the surgeons. The planner's experience was tested by comparing the reliability of preoperative planning done by senior surgeons or residents. The influence of BMI on predicting component size has been tested by comparing the accuracy of digital templating between different groups of BMI according to WHO-criteria. The same procedure has been done for evaluating the impact of patient´s sex and component design.\n The implant size was predicted exactly in 42% for the femoral and in 37% for the acetabular component. 87% of the femoral components and 78% of the acetabular cups were accurate within one size. Digital templating of femoral implant size was significantly more reliable when done by a senior surgeon. No difference was found for the acetabular component sizes. The BMI also had an impact on estimating the correct femoral implant size. In overweight patients, planning was significantly more inaccurate than normal weight people. Differences were seen in obese patients. However, these were not significant. Accuracy of acetabular components was not affected. The design of the prostheses and the patient's sex had no influence on predicting component size.\n Inexperience and overweight are factors that correlate with inaccuracy of preoperative digital templating in femoral components, whereas acetabular components seem to be independent of these factors.\n\nFriesenbichler, Jörg\n\nHolzer, Lukas\n\nLeithner, Andreas\n\nMaurer-Ertl, Werner\n\n\n"
},
{
"text": "\n178990\nCharacterization of <i>GDF2</i> Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.\n\nHodgson, J\n\nSwietlik, EM\n\nSalmon, RM\n\nHadinnapola, C\n\nNikolic, I\n\nWharton, J\n\nGuo, J\n\nLiley, J\n\nHaimel, M\n\nBleda, M\n\nSouthgate, L\n\nMachado, RD\n\nMartin, JM\n\nTreacy, CM\n\nYates, K\n\nDaugherty, LC\n\nShamardina, O\n\nWhitehorn, D\n\nHolden, S\n\nBogaard, HJ\n\nChurch, C\n\nCoghlan, G\n\nCondliffe, R\n\nCorris, PA\n\nDanesino, C\n\nEyries, M\n\nGall, H\n\nGhio, S\n\nGhofrani, HA\n\nGibbs, JSR\n\nGirerd, B\n\nHouweling, AC\n\nHoward, L\n\nHumbert, M\n\nKiely, DG\n\nKovacs, G\n\nLawrie, A\n\nMacKenzie Ross, RV\n\nMoledina, S\n\nMontani, D\n\nOlschewski, A\n\nOlschewski, H\n\nOuwehand, WH\n\nPeacock, AJ\n\nPepke-Zaba, J\n\nProkopenko, I\n\nRhodes, CJ\n\nScelsi, L\n\nSeeger, W\n\nSoubrier, F\n\nSuntharalingam, J\n\nToshner, MR\n\nTrembath, RC\n\nNoordegraaf, AV\n\nWort, SJ\n\nWilkins, MR\n\nYu, PB\n\nLi, W\n\nGräf, S\n\nUpton, PD\n\nMorrell, NW\n\nBeiträge in Fachzeitschriften\nISI:000518194000015\n31661308.0\n10.1164/rccm.201906-1141OC\nPMC7047445\nRationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.\n\nKovacs, Gabor\n\nOlschewski, Andrea\n\nOlschewski, Horst\n\n\n"
},
{
"text": "\n187282\nImpact of smoking behavior on survival following allogeneic hematopoietic stem cell transplantation - smoking cessation matters.\n\nScheidl, S\n\nAvian, A\n\nFlick, H\n\nGaal, S\n\nGreinix, H\n\nOlschewski, H\n\nBeiträge in Fachzeitschriften\nNone\n33837775.0\n10.1093/ntr/ntab070\nNone\nThere are only few data on the impact of smoking and smoking cessation on outcome of patients treated with allogeneic hematopoietic stem cell transplantation, a well established therapy for hematologic malignancies.\n In a retrospective cohort study design we examined impact of smoking and smoking cessation on survival among 309 eligible consecutive adults who underwent allogeneic hematopoietic stem cell transplantation using reduced-intensity (n=179) or myeloablative (n=130) conditioning between 1999 and 2018.\n Smoking and was independently associated with increased mortality with a five-year overall survival of 25% in current smokers vs. 53% in never smokers vs. 48% in past smokers. Never smokers lived significantly longer (HR: 2.00, 95%CI: 1.19-3.35, p=0.008) and had a better event-free survival (HR: 2.11, 95%CI: 1.27-3.49, p=0.004) than current smokers. In the long run never smokers also lived significantly longer than past smokers (HR: 1.45, 95%CI: 1.16-1.81, p = 0.001). Patients who quit smoking prior to allogeneic hematopoietic stem cell transplantation showed a tendency towards increased survival compared to those continued smoking (HR: 1.53, 95%CI: 0.95-2.45, p = 0.078). In relation to life-time cigarette dose smokers with low-dose (1-10 pack-years) cigarette consumption lived significantly longer (HR: 1.60, 95%CI: 1.03-2.50, p=0.037) and had a better event-free survival (HR: 1.66, 95%CI: 1.07-2.58, p=0.025) than patients with high-dose (≥ 10 pack-years) cigarette consumption.\n In allogeneic hematopoietic stem cell transplantation for hematologic malignancies, smoking history per se, life-time cigarette dose, and continued smoking, were significantly associated with increased all-cause mortality and reduced event-free survival.\n Continued and past smoking represent established risk factors for malignant and non-malignant diseases, however, they are also a strong risk factor for a poor outcome after allogeneic hematopoietic stem cell transplantation for hematologic diseases. Our study shows that the hazard ratio for death after such a transplantation is doubled if patients continue smoking and even if they have quit smoking, their risk remains significantly elevated. This suggests that the smoking history provides important predictive factors for outcome of allogeneic hematopoietic stem cell transplantation and that smoking cessation should be implemented in the treatment of hematologic diseases as early as possible.\n © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.\n\nAvian, Alexander\n\nFlick, Holger\n\nGreinix, Hildegard\n\nOlschewski, Horst\n\nScheidl, Stefan\n\n\n"
},
{
"text": "\n1975\nPhysiology and pathophysiology of organic acids in cerebrospinal fluid.\n\nHoffmann, GF\n\nMeier-Augenstein, W\n\nStöckler, S\n\nSurtees, R\n\nRating, D\n\nNyhan, WL\n\nBeiträge in Fachzeitschriften\nISI:A1993LT28800005\n8412012.0\n10.1007/BF00711898\nNone\nConcentrations of organic acids in cerebrospinal fluid (CSF) appear to be directly dependent upon their rate of production in the brain. There is evidence that the net release of short-chain monocarboxylic acids from the brain is a major route for removing these products of cerebral metabolism. Concentrations of organic acids in blood and CSF are largely independent of each other. Quantitative reference values for the concentrations of organic acids in CSF and plasma as well as ratios of individual organic acids between CSF and plasma were determined in 35 pairs of samples from paediatric patients. Over 25 organic acids were quantifiable in all or in the majority of CSF and/or plasma specimens (limit of detection 1 mumol/L). There were substantial differences in the CSF/plasma ratios between subgroups of organic acids. Metabolites related to fatty-acid oxidation were present in CSF in substantially less amounts than in plasma. Organic acids related to carbohydrate and energy metabolism and to amino acid degradation were present in CSF in the same amounts as or slightly smaller amounts than in plasma. Finally, some organic acids were found in substantially higher amounts in CSF than in plasma, e.g. glycolate, glycerate, 2, -dihydroxybutyrate, citrate and isocitrate. Studies of organic acids in CSF and plasma samples are presented from patients with 'cerebral' lactic acidosis, disorders of propionate and methylmalonate metabolism, glutaryl-CoA dehydrogenase deficiency and L-2-hydroxy-glutaric aciduria. It became apparent that derangements of organic acids in the CSF may occur independently of the systemic metabolism. Quantitative organic acid analysis in CSF will yield new information on the pathophysiology in the central nervous system (CNS) of these disorders and may prove necessary for successful monitoring of treatment of organoacidopathies, which present mainly with neurological disease. For example, in glutaryl-CoA dehydrogenase deficiency the urinary excretion of glutarate appears to be an inadequate parameter for monitoring the effect of dietary therapy, without plasma and CSF determinations. In L-2-hydroxyglutaric aciduria the elevation of L-2-hydroxyglutarate was found to be greater in CSF than in plasma. In addition, some other organic acids, glycolate, glycerate, 2, -dihydroxybutyrate, citrate and isocitrate, were also elevated in the CSF of the patients out of proportion to normal levels in plasma and urine. High concentrations of an unknown compound, which was tentatively identified as 2, -dihydroxyglutarate, were found in the CSF of patients with L-2-hydroxyglutaric aciduria.(ABSTRACT TRUNCATED AT 400 WORDS)\n\n\n"
},
{
"text": "\n78477\nManagement of acute gastroenteritis in Europe and the impact of the new recommendations: a multicenter study. The Working Group on acute Diarrhoea of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition.\n\nSzajewska, H\n\nHoekstra, JH\n\nSandhu, B (Study group with Hauer,AC)\n\nBeiträge in Fachzeitschriften\nISI:000086762500011\n10817282.0\n10.1097/00005176-200005000-00011\nNone\nBACKGROUND: The European Society for Paediatric Gasteroenterology, Hepatology and Nutrition (ESPGHAN) issued two sets of recommendations for the treatment of infants with acute gastroenteritis (1992, 1997). The purpose of this multicentre study performed in 29 European countries was to determine how closely current treatment compares with the ESPGHAN recommendations. METHODS: The outline of the study was based on a questionnaire that addressed the management of a 6-month-old infant with acute gastroenteritis complicated by mild to moderate dehydration. National coordinators circulated the questionnaire to randomly selected primary care physicians and to hospital-based paediatricians. RESULTS: A total of 2997 questionnaires were returned, of which 1768 were from Western Europe (WE) and 1229 from Central and Eastern Europe (CEE). Eighty-four percent of responding physicians said they would follow the ESPGHAN recommendation to use oral rehydration solution (ORS) for rehydration, with 66% using an ORS containing 60 mmol/l sodium ORS. Only 16% (WE 15%, CEE 19%) would follow the guidelines and use rapid oral rehydration over 3 to 4 hours. Forty-five percent would rehydrate infants in a 3- to 6-hour period (WE 35%, CEE 60%), and 17% (WE 23%, CEE 9%) would extend the rehydration period to 12 to 24 hours. ESPGHAN recommendation of rapid reintroduction of normal feeding after 3 to 4 hours of oral rehydration would be followed by only 21% of responding physicians, and only 43% (WE 46%, CEE 38%) would start feeding with full-strength formula. However, the guideline about continuation of breast-feeding is widely followed (total 77%; WE 78%, CEE 75%). Thirty-six percent (WE 45%, CEE 23%) use a lactose-containing formula after successful oral rehydration. Contrary to the ESPGHAN guideline 35% (WE 30%, CEE 42%) would use a lactose-free formula and 19% (WE 12%, CEE 28%) a lactose and cow's milk protein-free formula. Only 37% (WE 30%, CEE 46%) of responding physicians would follow the recommendation to use ORS to replace ongoing losses from watery diarrhoea. CONCLUSIONS: The results of the survey suggest that with the exception of recommending ORS for rehydration and continuation of breast-feeding during diarrhoea, a minority of responding European physicians follow the ESPGHAN guidelines for optimal management of children with acute gastroenteritis.\n\nHauer, Almuthe\n\n\n"
},
{
"text": "\n160414\nClinical predictors of patient related delay in the VIENNA ST-elevation myocardial infarction network and impact on long-term mortality.\n\nJäger, B\n\nFarhan, S\n\nRohla, M\n\nChrist, G\n\nPodczeck-Schweighofer, A\n\nSchreiber, W\n\nLaggner, AN\n\nWeidinger, F\n\nStefenelli, T\n\nDelle-Karth, G\n\nKaff, A\n\nMaurer, G\n\nHuber, K\n\nVienna STEMI Registry Group\n\nBeiträge in Fachzeitschriften\nISI:000399753200007\n26888787.0\n10.1177/2048872616633882\nNone\nWhile contributors to system delay in ST-elevation myocardial infarction (STEMI) are well described, predictors of patient-related delays are less clear. The aim of this study was to identify predictors that cause delayed diagnosis of STEMI in a metropolitan system of care (VIENNA STEMI network) and to investigate a possible association with long-term mortality.\n The study population investigated consisted of 2366 patients treated for acute STEMI in the Vienna STEMI registry from 2003-2009. Multivariable regression modelling was performed for (a) onset of pain to first medical contact (FMC) as a categorical variable (pain-to-FMC⩽60 min versus >60 min: 'early presenters' versus 'late presenters'); and for (b) onset of pain-to-FMC (min) as a continuous variable.\n After multivariable adjustment, female sex (odds ratio (OR) 1.348; 95% confidence interval (CI) 1.013-1.792; p=0.04) and diabetes mellitus (OR 1.355; 95% CI 1.001-1.835; p=0.05) were independently associated with late presentation in STEMI patients, whereas cardiogenic shock (OR 0.582; 95% CI 0.368-0.921; p=0.021) was a predictor of early diagnosis. When onset of pain-to-FMC was treated as a continuous variable, female sex ( p=0.003), anterior infarction ( p=0.004) and diabetes mellitus ( p=0.035) were independently associated with longer delay, while hyperlipidaemia ( p=0.002) and cardiogenic shock ( p=0.017) were strong predictors of short pain-to-FMC times. Three-year-all cause mortality was 9.6% and 11.3% ( p=0.289) for early and late presenters, respectively. After adjustment for clinical factors (sex, age, diabetes, current smoking, hypertension, hyperlipidaemia, cardiogenic shock and location of myocardial infarction) only a trend for increased risk of all-cause death was observed for longer pain-to-FMC times in a cox regression model (hazard ratio (HR) 1.012; 95% CI 0.999-1.025 for every 10 min of delay; p=0.061). Interestingly, early presentation within one hour of symptom onset was not associated with three-year mortality survival (HR 1.031; 95% CI 0.676-1.573; p=0.886).\n In this all-comers study of STEMI patients in the VIENNA STEMI network, cardiogenic shock was the strongest predictor of short patient-related delays, whereas a history of diabetes and female sex were independent associated with late diagnosis in STEMI. After adjustment for clinical confounders, patient related delay did not significantly impact on long-term all-cause mortality.\n\n\n"
},
{
"text": "\n161228\nnorUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis.\n\nFickert, P\n\nHirschfield, GM\n\nDenk, G\n\nMarschall, HU\n\nAltorjay, I\n\nFärkkilä, M\n\nSchramm, C\n\nSpengler, U\n\nChapman, R\n\nBergquist, A\n\nSchrumpf, E\n\nNevens, F\n\nTrivedi, P\n\nReiter, FP\n\nTornai, I\n\nHalilbasic, E\n\nGreinwald, R\n\nPröls, M\n\nManns, MP\n\nTrauner, M\n\nEuropean PSC norUDCA Study Group\n\nBeiträge in Fachzeitschriften\nISI:000407883500018\n28529147.0\n10.1016/j.jhep.2017.05.009\nNone\nPrimary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1, 00mg/d or 1, 00mg/d) compared with placebo in patients with PSC.\n One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit.\n norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1, 00, and 1, 00mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1, 00mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups.\n norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.\n Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.\n\nFickert, Peter\n\n\n"
},
{
"text": "\n163845\nDisturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.\n\nZadora, J\n\nSingh, M\n\nHerse, F\n\nPrzybyl, L\n\nHaase, N\n\nGolic, M\n\nYung, HW\n\nHuppertz, B\n\nCartwright, JE\n\nWhitley, G\n\nJohnsen, GM\n\nLevi, G\n\nIsbruch, A\n\nSchulz, H\n\nLuft, FC\n\nMüller, DN\n\nStaff, AC\n\nHurst, LD\n\nDechend, R\n\nIzsvák, Z\n\nBeiträge in Fachzeitschriften\nISI:000414615600012\n28904069.0\n10.1161/CIRCULATIONAHA.117.028110\nPMC5671803\nPreeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in preeclampsia. Our study aims to investigate whether disturbed imprinting contributes to preeclampsia.\n We first aimed to confirm that preeclampsia is a disease of the placenta by generating and analyzing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with preeclampsia. Next, we identified differentially expressed genes in preeclamptic placentas and intersected them with the list of human imprinted genes. We used bioinformatics/statistical analyses to confirm association between imprinting and preeclampsia and to predict biological processes affected in preeclampsia. Validation included epigenetic and cellular assays. In terms of human specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis.\n We found disturbed placental imprinting in preeclampsia and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with preeclampsia. As a result of loss of imprinting, DLX5 was upregulated in 69% of preeclamptic placentas. Levels of DLX5 correlated with classic preeclampsia markers. DLX5 is expressed in human but not in murine trophoblast. The DLX5high phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of preeclamptic placentas. Pan-mammalian comparative analysis identified DLX5 as part of the human-specific regulatory network of trophoblast differentiation.\n Our analysis provides evidence of a true association among disturbed imprinting, gene expression, and preeclampsia. As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in preeclampsia research. Human-specific regulatory circuitry of DLX5 might help explain certain aspects of preeclampsia.\n © 2017 The Authors.\n\nHuppertz, Berthold\n\n\n"
},
{
"text": "\n168549\nPrimary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the <i>PNPLA3</i> variant I148M.\n\nRausch, V\n\nPeccerella, T\n\nLackner, C\n\nYagmur, E\n\nSeitz, HK\n\nLongerich, T\n\nMueller, S\n\nBeiträge in Fachzeitschriften\nNone\n28050235.0\n10.4254/wjh.v8.i35.1547\nPMC5165268\nTo investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.\n Caucasian heavy drinkers (n = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients.\n The PNPLA3 rs738409 genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005) and less with steatosis (r = 0.264, P < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r = 0.828, P < 0.005), ballooning (r = 0.516, P < 0.005), steatohepatitis (r = 0.319, P < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% vs 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3 G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers.\n In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers.\n\nLackner, Karoline\n\n\n"
}
]
}