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"text": "\n170738\nSaxagliptin but Not Sitagliptin Inhibits CaMKII and PKC via DPP9 Inhibition in Cardiomyocytes.\n\nKoyani, CN\n\nTrummer, C\n\nShrestha, N\n\nScheruebel, S\n\nBourgeois, B\n\nPlastira, I\n\nKickmaier, S\n\nSourij, H\n\nRainer, PP\n\nMadl, T\n\nSattler, W\n\nPelzmann, B\n\nMalle, E\n\nvon Lewinski, D\n\nBeiträge in Fachzeitschriften\nISI:000450119400001\n30487758.0\n10.3389/fphys.2018.01622\nPMC6246635\nSome oral anti-hyperglycemic drugs, including gliptins that inhibit dipeptidyl peptidase 4 (DPP4), have been linked to the increased risk of heart failure (HF) in type-2 diabetic patients. While the cardiovascular safety trial, TECOS, revealed no link between sitagliptin and the risk of HF, a substantial 27% increase in the hospitalization for HF was observed in type-2 diabetic patients treated with saxagliptin within the SAVOR-TIMI 53 trial. A previous in vitro study revealed that saxagliptin impairs the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-phospholamban (PLB)-sarcoplasmic reticulum Ca2+-ATPase 2a axis and protein kinase C (PKC) activity in cardiomyocytes leading to impaired cardiac contractility and electrophysiological function. However, the link between saxagliptin and its target proteins (CaMKII and PKC) remains to be explored. Since DPP8 and DPP9 (but not DPP4) are expressed by cardiomyocytes and saxagliptin is internalized by cardiomyocytes, we investigated whether DPP8/9 contribute to saxagliptin-mediated inhibition of CaMKII and PKC activity. Structural analysis revealed that the DPP4-saxagliptin interaction motif (S630, Y547) for the cyanopyrrolidine group is conserved in DPP8 (S755, Y669) and DPP9 (S730, Y644). Conversely, F357 that facilitates binding of the anchor lock domain of sitagliptin in the S2 extensive subsite of DPP4 is not conserved in DPP8/9. In parallel, unlike saxagliptin, sitagliptin did not affect phosphorylation of CaMKII/PLB or activity of PKC in HL-1 cardiomyocytes. These findings were recapitulated by pharmacological inhibition (TC-E-5007, a DPP8/9 antagonist) and knock-down of DPP9 (but not DPP8). In primary mouse ventricular cardiomyocytes, saxagliptin (but not sitagliptin) impaired Ca2+ transient relaxation and prolonged action potential duration (APD). These results suggest that saxagliptin-DPP9 interaction impairs the CaMKII-PLB and PKC signaling in cardiomyocytes. We reveal a novel and potential role of DPP9 in cardiac signaling. The interaction of saxagliptin with DPP9 may represent an underlying mechanism for the link between saxagliptin and HF. Elucidation of saxagliptin-DPP9 interaction and downstream events may foster a better understanding of the role of gliptins as modulators of cardiac signaling.\n\nBourgeois, Benjamin Michel Rene\n\nKickmaier, Sandra\n\nMadl, Tobias\n\nMalle, Ernst\n\nPelzmann, Brigitte\n\nPlastira, Ioanna\n\nRainer, Peter\n\nSattler, Wolfgang\n\nScherübel-Posch, Susanne\n\nShrestha, Niroj\n\nSourij, Harald\n\nTrummer, Christopher\n\nvon Lewinski, Dirk\n\n\n"
},
{
"text": "\n182744\nEarly diagnosis is associated with improved clinical outcomes in benign esophageal perforation: an individual patient data meta-analysis.\n\nVermeulen, BD\n\nvan der Leeden, B\n\nAli, JT\n\nGudbjartsson, T\n\nHermansson, M\n\nLow, DE\n\nAdler, DG\n\nBotha, AJ\n\nD'Journo, XB\n\nEroglu, A\n\nFerri, LE\n\nGubler, C\n\nHaveman, JW\n\nKaman, L\n\nKozarek, RA\n\nLaw, S\n\nLoske, G\n\nLindenmann, J\n\nPark, JH\n\nRichardson, JD\n\nSalminen, P\n\nSong, HY\n\nSøreide, JA\n\nSpaander, MCW\n\nTarascio, JN\n\nTsai, JA\n\nVanuytsel, T\n\nRosman, C\n\nSiersema, PD\n\nBenign Esophageal Perforation Collaborative Group\n\nBeiträge in Fachzeitschriften\nISI:000549678600001\n32681374.0\n10.1007/s00464-020-07806-y\nNone\nTime of diagnosis (TOD) of benign esophageal perforation is regarded as an important risk factor for clinical outcome, although convincing evidence is lacking. The aim of this study is to assess whether time between onset of perforation and diagnosis is associated with clinical outcome in patients with iatrogenic esophageal perforation (IEP) and Boerhaave's syndrome (BS).\n We searched MEDLINE, Embase and Cochrane library through June 2018 to identify studies. Authors were invited to share individual patient data and a meta-analysis was performed (PROSPERO: CRD42018093473). Patients were subdivided in early (≤ 24 h) and late (> 24 h) TOD and compared with mixed effects multivariable analysis while adjusting age, gender, location of perforation, initial treatment and center. Primary outcome was overall mortality. Secondary outcomes were length of hospital stay, re-interventions and ICU admission.\n Our meta-analysis included IPD of 25 studies including 576 patients with IEP and 384 with BS. In IEP, early TOD was not associated with overall mortality (8% vs. 13%, OR 2.1, 95% CI 0.8-5.1), but was associated with a 23% decrease in ICU admissions (46% vs. 69%, OR 3.0, 95% CI 1.2-7.2), a 22% decrease in re-interventions (23% vs. 45%, OR 2.8, 95% CI 1.2-6.7) and a 36% decrease in length of hospital stay (14 vs. 22 days, p < 0.001), compared with late TOD. In BS, no associations between TOD and outcomes were found. When combining IEP and BS, early TOD was associated with a 6% decrease in overall mortality (10% vs. 16%, OR 2.1, 95% CI 1.1-3.9), a 19% decrease in re-interventions (26% vs. 45%, OR 1.9, 95% CI 1.1-3.2) and a 35% decrease in mean length of hospital stay (16 vs. 22 days, p = 0.001), compared with late TOD.\n This individual patient data meta-analysis confirms the general opinion that an early (≤ 24 h) compared to a late diagnosis (> 24 h) in benign esophageal perforations, particularly in IEP, is associated with improved clinical outcome.\n\nLindenmann, Jörg\n\n\n"
},
{
"text": "\n1057\nFeasibility of peripheral blood stem cell (PBSC) and peripheral blood mononuclear cell (PBMNC) separation in children with a body weight below 20 KG.\n\nUrban, C\n\nSchwinger, W\n\nBenesch, M\n\nLackner, H\n\nKerbl, R\n\nGilli, R\n\nPätzold, U\n\nBurdach, S\n\nBeiträge in Fachzeitschriften\nISI:A1997XC43000009\n9180913.0\n10.1002%2F%28SICI%291096-911X%28199708%2929%3A2%3C115%3A%3AAID-MPO9%3E3.0.CO%3B2-H\nNone\nNine children from 10 to 76 months (median 28.0), weighing 8.5 to 19.7 kg (median 13.0 kg) underwent peripheral blood stem cell separation (PBSCS) or peripheral blood mononuclear cell separation (PBMNCS), after insertion of a double-lumen central venous catheter (8-10 French). Separations were performed with a continuous flow blood separator (Fen-wall CS 3000 plus), running a specially adopted separation-program. In 7 children (5 with neuroblastoma IV, 1 with multifocal Ewing's sarcoma, and 1 with rhabdomyosarcoma IV), stem cells were mobilized by application of G-CSF at a dosage of 15-27.7 micrograms/kg body weight (median 16.25) subcutaneously following high-dose chemotherapy, according to the disease-related protocols, whereas 2 children had PBMNCS to induce graft vs. leukemia (GvL)-reaction in the HLA-identical sibling suffering from relapsed chronic myelogenous leukemia (CML: n = 1), or chronic myelomonocytic leukemia (CMML: n = 1) after allogeneic BMT. In all cases, the collecting procedure was performed after filling the cell separator with priming solution consisting of 2 U of irradiated and washed packed red cells, 250 ml human albumin, and 0.9% NaCl. In the 7 patients with solid tumors between 0.45 and 62.7 x 10(6) CD-34 positive cells/kg body weight were separated; the patient who had the lowest yield was separated twice after another mobilizing course. Three patients (2 with neuroblastoma IV and 1 with multifocal Ewing's-sarcoma) underwent a double transplantation with 1-3 portions of the collected stem cells within a 5- to 6-week interval. Two children had a rapid engraftment on both peripheral blood stem cell transplantations (PBSCTs). The third child, who had the lowest yield and was separated twice had prompt engraftment at the first PBSCT but delayed and incomplete engraftment at the second PBSCT. One patient after adoptive immunotransfer with PBMNCs for relapsed CML is now 40 months in complete cytogenetic and molecular biological remission, whereas the other patient treated for relapsed CMML did not respond to the PBMNC-transfusion. The results indicate that PBSCS and PBMNCS can be performed in children with a body weight below 20 kg.\n\nBenesch, Martin\n\nKerbl, Reinhold\n\nLackner, Herwig\n\nSchwinger, Wolfgang\n\nUrban, Ernst-Christian\n\n\n"
},
{
"text": "\n153406\nCharacterization of the binding pattern of human aquaporin-4 autoantibodies in patients with neuromyelitis optica spectrum disorders.\n\nTuller, F\n\nHolzer, H\n\nSchanda, K\n\nAboulenein-Djamshidian, F\n\nHöftberger, R\n\nKhalil, M\n\nSeifert-Held, T\n\nLeutmezer, F\n\nBerger, T\n\nReindl, M\n\nBeiträge in Fachzeitschriften\nISI:000378864900001\n27371173.0\n10.1186/s12974-016-0642-3\nPMC4930584\nThe discovery of a highly specific antibody against the aquaporin-4 (AQP4) water channel (AQP4-IgG) unified the spectrum of neuromyelitis optica spectrum disorders (NMOSD), which are considered to be antibody-mediated autoimmune diseases. The AQP4 water channel is located on astrocytic end-feet processes and consists of six transmembrane helical domains forming three extracellular loops A, C, and E in which defined amino acids were already proven to be critical for AQP4-IgG binding. However, the clinical relevance of these findings is unclear. Therefore, we have characterized the epitope specificity of AQP4-IgG-positive NMOSD patients.\n We established a cell-based flow cytometry assay for the quantitative detection of AQP4-IgG-positive serum samples. Human embryonic kidney (HEK) cells were transiently transfected with an EmGFP-tagged AQP4-M23, AQP4-M1, or six AQP4-M23 extracellular loop mutants including two mutations in loop A (serial AA substitution, insertion of a myc-tag), two in loop C (N153Q, insertion of a myc-tag), and two in loop E (H230G, insertion of a myc-tag). Fourty-seven baseline and 49 follow-up serum samples and six paired cerebrospinal fluid (CSF) baseline samples of 47 AQP4-IgG-positive Austrian NMOSD patients were then tested for their binding capability to AQP4-M1 and AQP4-M23 isoforms and these six extracellular loop mutants.\n Overall, we could identify two broad patterns of antibody recognition based on differential sensitivity to mutations in extracellular loop A. Pattern A was characterized by reduced binding to the two mutations in loop A, whereas pattern B had only partial or no reduced binding to these mutations. These two patterns were not associated with significant differences in demographic and clinical parameters or serum titers in this retrospective study. Interestingly, we found a change of AQP4-IgG epitope recognition pattern in seven of 20 NMOSD patients with available follow-up samples. Moreover, we found different binding patterns in five of six paired CSF versus serum samples, with a predominance of pattern A in CSF.\n Our study demonstrates that AQP4-IgG in sera of NMOSD patients show distinct patterns of antibody recognition. The clinical and diagnostic relevance of these findings have to be addressed in prospective studies.\n\nKhalil, Michael\n\nSeifert-Held, Thomas\n\n\n"
},
{
"text": "\n159218\nPilot study of mobile phone technology in allergic rhinitis in European countries: the MASK-rhinitis study.\n\nBousquet, J\n\nCaimmi, DP\n\nBedbrook, A\n\nBewick, M\n\nHellings, PW\n\nDevillier, P\n\nArnavielhe, S\n\nBachert, C\n\nBergmann, KC\n\nCanonica, GW\n\nChavannes, NH\n\nCruz, AA\n\nDahl, R\n\nDemoly, P\n\nDe Vries, G\n\nMathieu-Dupas, E\n\nFinkwagner, A\n\nFonseca, J\n\nGuldemond, N\n\nHaahtela, T\n\nHellqvist-Dahl, B\n\nJust, J\n\nKeil, T\n\nKlimek, L\n\nKowalski, ML\n\nKuitunen, M\n\nKuna, P\n\nKvedariene, V\n\nLaune, D\n\nPereira, AM\n\nCarreiro-Martins, P\n\nMelén, E\n\nMorais-Almeida, M\n\nMullol, J\n\nMuraro, A\n\nMurray, R\n\nNogueira-Silva, L\n\nPapadopoulos, NG\n\nPassalacqua, G\n\nPortejoie, F\n\nPrice, D\n\nRyan, D\n\nSamolinski, B\n\nSheikh, A\n\nSiroux, V\n\nSpranger, O\n\nTodo Bom, A\n\nTomazic, PV\n\nValero, A\n\nValovirta, E\n\nValiulis, A\n\nVandenPlas, O\n\nvan der Meulen, S\n\nvan Eerd, M\n\nWickman, M\n\nZuberbier, T\n\nBeiträge in Fachzeitschriften\nISI:000402834300004\n28072463.0\n10.1111/all.13125\nNone\nThe use of Apps running on smartphones and tablets profoundly affects medicine. The MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) App (Allergy Diary) assesses allergic rhinitis symptoms, disease control and impact on patients' lives. It is freely available in 20 countries (iOS and Android platforms).\n To assess in a pilot study whether (i) Allergy Diary users were able to properly provide baseline characteristics (ii) simple phenotypic characteristics based upon data captured by the Allergy Diary could be identified and (iii) information gathered by this study could suggest novel research questions.\n The Allergy Diary users were classified into six groups according to the baseline data that they entered into the App: (i) asymptomatic; (ii) nasal symptoms excluding rhinorrhea; (iii) rhinorrhea; (iv) rhinorrhea plus 1-2 nasal/ocular symptoms; (v) rhinorrhea plus ≥3 nasal/ocular symptoms; and (vi) rhinorrhea plus all nasal/ocular symptoms.\n By 1 June 2016, 3260 users had registered with the Allergy Diary and 2710 had completed the baseline questionnaire. Troublesome symptoms were found mainly in the users with the most symptoms. Around 50% of users with troublesome rhinitis and/or ocular symptoms suffered work impairment. Sleep was impaired by troublesome symptoms and nasal obstruction.\n This is the first App (iOS and Android) to have tested for allergic rhinitis and conjunctivitis. A simple questionnaire administered by cell phones enables the identification of phenotypic differences between a priori defined rhinitis groups. The results suggest novel concepts and research questions in allergic rhinitis that may not be identified using classical methods.\n © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n168274\nTemporal changes of the endothelin system in human cytotrophoblasts during the first trimester of pregnancy.\n\nMajali-Martinez, A\n\nBarth, S\n\nLang, U\n\nDesoye, G\n\nCervar-Zivkovic, M\n\nBeiträge in Fachzeitschriften\nISI:000436446700021\n29947544.0\n10.33549/physiolres.933828\nNone\nThe first trimester of pregnancy is characterized by continuous proliferation, invasion and differentiation of cytotrophoblasts. These processes are precisely controlled both, in space and time by molecules such as endothelin-1 (ET-1). ET-1 is expressed in human first trimester trophoblast and is known to stimulate cytotrophoblast proliferation through endothelin A and B receptor subtypes (ET(A) and ET(B)), and cytotrophoblast invasion through ET(B). However, temporal changes of the ET system during the first trimester of pregnancy have not been previously studied. This study tested the hypothesis that ET-1 release, ET(A) and ET(B) expression are increased towards the end of the first trimester of pregnancy (weeks 10-12 vs. weeks 6-9), resulting in increased cytotrophoblast proliferation and invasion. Tissue samples were obtained from 17 surgical pregnancy interruptions (week 6-9: n=9; week 10-12: n=8). After cytotrophoblast isolation, the invasive and proliferative phenotypes were immune-separated by an alpha(6)-integrin antibody. Both proliferative and invasive cytotrophoblasts were cultured separately on plastic or Matrigel for 24 h. ET-1 release into the culture medium of both cytotrophoblast subtypes was measured by radioimmunoassay. ET(A) and ET(B) mRNA expression was measured by RT-PCR, and the ET-1 effect on cytotrophoblast proliferation and invasion was determined using proliferation and invasion assays, respectively. ET-1 release increased from early to late first trimester of pregnancy in both proliferative (1.8-4.5 fold) and invasive cytotrophoblasts (9.3-28 fold), especially when cultured on Matrigel. This was paralleled by less ET(B) mRNA on invasive cytotrophoblasts independent of the time period in first trimester, whereas ET(A) expression was similar on proliferative an invasive cytotrophoblasts. Proliferation and invasion of cytotrophoblasts under control conditions decreased from early to late first trimester. ET-1 stimulated both processes at both periods with the most pronounced effect (7-fold) on invasion in late first trimester. The ET-1/ET-receptor system changes between weeks 6-9 and 10-12 in pregnancy. Our data suggest an autocrine and endocrine ET-1 effect, which is stronger in late than in early first trimester of pregnancy paralleled by different stimulatory effects on trophoblast invasion and proliferation. In general, this suggests time as an additional effector of the critical processes governing placental development in the first trimester of human pregnancy.\n\nBarth, Sonja\n\nCervar-Zivkovic, Mila\n\nDesoye, Gernot\n\nMajali Martinez, Alejandro\n\n\n"
},
{
"text": "\n187027\nProfiling of circulating tumor DNA and tumor tissue for treatment selection in patients with advanced and refractory carcinoma: a prospective, two-stage phase II Individualized Cancer Treatment trial.\n\nRiedl, JM\n\nHasenleithner, SO\n\nPregartner, G\n\nScheipner, L\n\nPosch, F\n\nGroller, K\n\nKashofer, K\n\nJahn, SW\n\nBauernhofer, T\n\nPichler, M\n\nStöger, H\n\nBerghold, A\n\nHoefler, G\n\nSpeicher, MR\n\nHeitzer, E\n\nGerger, A\n\nBeiträge in Fachzeitschriften\nISI:000625061000001\n33717225.0\n10.1177/1758835920987658\nPMC7923987\nMolecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma.\n A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm.\n Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8-71.0] compared with 81.5 days (IQR 68.5-117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6-0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option.\n Our study employed a histotype-agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes.EU Clinical Trials Registry (https://www.clinicaltrialsregister.eu): EudraCT: 2014-005341-44.\n © The Author(s), 2021.\n\nBauernhofer, Thomas\n\nBerghold, Andrea\n\nGerger, Armin\n\nGroller, Karin\n\nHasenleithner, Samantha\n\nHeitzer, Ellen\n\nHöfler, Gerald\n\nJahn, Stephan\n\nKashofer, Karl\n\nPichler, Martin\n\nPosch, Florian\n\nPregartner, Gudrun\n\nRiedl, Jakob\n\nScheipner, Lukas\n\nSpeicher, Michael\n\nStoeger, Herbert\n\n\n"
},
{
"text": "\n1131\nGenetic abnormalities in mammary ductal intraepithelial neoplasia-flat type (clinging ductal carcinoma in situ): a simulator of normal mammary epithelium.\n\nMoinfar, F\n\nMan, YG\n\nBratthauer, GL\n\nRatschek, M\n\nTavassoli, FA\n\nBeiträge in Fachzeitschriften\nISI:000086592200013\n10813719.0\n10.1002%2F%28SICI%291097-0142%2820000501%2988%3A9%3C2072%3A%3AAID-CNCR13%3E3.0.CO%3B2-H\nNone\nBACKGROUND: Mammary ductal intraepithelial neoplasia (DIN)-flat type ("clinging ductal carcinoma in situ [DCIS]") generally is a subtle epithelial alteration characterized by one or a few layer(s) of atypical cells replacing the native epithelium. The "low power" appearance of DIN-flat type can be misinterpreted easily as "normal" because of the frequent absence of multilayered proliferation and often subtle cytologic atypia. Because it presents as an often unrecognized lesion or in association with tubular carcinoma, to the authors' knowledge the clinical and biologic significance of this lesion has not been well established. METHODS. Using polymerase chain reaction, the authors examined DNA extracts from microdissected areas of 22 cases with extensive "clinging DCIS, including 13 cases associated with infiltrating ductal carcinoma as well as 5 cases associated with more conventional types of DCIS. Eight polymorphic DNA markers with a high rate of loss of heterozygosity (LOH) in classic types of DCIS were selected to identify possible genetic alterations on chromosomes 2p, 3p, 11q, 16q, and 17q. Two cases also were used for the assessment of clonality by means of X chromosome inactivation (methylation pattern of the human androgen receptor [HUMARA] gene). RESULTS. LOH was detected in 17 of 22 lesions (77%), and monoclonality was established in the 2 cases analyzed. The most common genetic alterations were at chromosomes 11q21-23.2, 16q23.1-24.2, and 3p14.2 with LOH in 50%, 45%, and 41%, respectively, of informative cases. The DIN-flat type showed the same genetic alterations (LOH) identified in adjacent in situ and infiltrating ductal carcinoma. In contrast to the DIN-flat type, the perfectly normal mammary epithelium was associated very infrequently (1 of 16 cases; 6%) with LOH. CONCLUSIONS. The DIN-flat type represents one of the earliest, morphologically recognizable, neoplastic alterations of the breast. Recognition of the DIN-flat type is important not only for the early detection of intraductal neoplasia but also to prevent misinterpretation and utilization of this lesion as a normal control in studies. This distinctive lesion could be crucial as an explanation for at least part of the > 20% reported incidence rate of breast carcinoma recurrence observed despite ostensibly "negative" margins of breast biopsies.\n\nMoinfar, Farid\n\nRatschek, Manfred\n\n\n"
},
{
"text": "\n2218\nRecombinant human erythropoietin for the correction of cancer associated anemia with and without concomitant cytotoxic chemotherapy.\n\nLudwig, H\n\nSundal, E\n\nPecherstorfer, M\n\nLeitgeb, C\n\nBauernhofer, T\n\nBeinhauer, A\n\nSamonigg, H\n\nKappeler, AW\n\nFritz, E\n\nBeiträge in Fachzeitschriften\nISI:A1995TF10400020\n8635038.0\n10.1002/1097-0142(19951201)76:11<2319::AID-CNCR2820761121>3.0.CO;2-U\nNone\nBACKGROUND. Chronic anemia is a common complication in patients with cancer, especially in those with advanced disease or who are under intensive chemotherapy. Because homologous blood transfusions involve some hazards, the safety and efficacy of recombinant human erythropoietin (r-HuEPO) in the treatment of anemic patients with cancer with and without concomitant chemotherapy were studied. METHODS. One-hundred two cancer patients with hemoglobin less than 11 g/dl, ferritin greater than 30 micrograms/l, and creatinine < 220 mumol/l were enrolled in the study, 94 were eligible for efficacy evaluation. Sixty-eight patients received chemotherapy (CT group) and 26 had no cytotoxic cancer treatment (NT group). Recombinant human erythropoietin was administered subcutaneously at a dose of 150 U/kg three times per week for 6 weeks; in nonresponders the dose was doubled for the subsequent 6 weeks. Response was defined as the achievement of a hemoglobin increase of 2g/dl. Clinical and laboratory parameters, including serum erythropoietin (EPO) levels, performance status, and quality of life, were investigated at baseline and monitored at regular intervals thereafter. RESULTS. Response was achieved by 52% and 62% of CT and NT patients, respectively. The highest response rates were observed in patients with lung cancer or with a histology of squamous cell carcinoma (both 80%). In responding patients, the symptoms of anemia subsided. They no longer needed blood transfusions after 4 weeks of therapy; and both their performance status and quality of life improved significantly. The NT patients achieved slightly more favorable results on lower weekly doses: 450 U/kg/week in NT versus 570 U/kg/week in CT patients. Serum EPO levels were higher in nonresponders at baseline and further increased during the course of treatment. Recombinant human erythropoietin was well tolerated by all patients. CONCLUSION. This multicenter study in a large patient collective shows that r-HuEPO treatment represents a safe and effective means to increase the red cell mass and eliminate the need for blood transfusions in approximately 50% of the patients with chronic anemia of cancer. Responding patients not only have increased levels of hemoglobin, but their performance status also improves significantly, and they enjoy a significantly enhanced quality of life.\n\nBauernhofer, Thomas\n\nSamonigg, Hellmut\n\n\n"
},
{
"text": "\n4014\nIgG antibodies typical for extrinsic allergic alveolitis--an inter-laboratory quality assessment.\n\nAberer, W\n\nWoltsche, M\n\nWoltsche-Kahr, I\n\nKränke, B\n\nBeiträge in Fachzeitschriften\nISI:000172418800008\n11726311.0\nNone\nNone\nBACKGROUND: Determination of specific IgG antibodies is important for the diagnosis of extrinsic allergic alveolitis (EAA). Various evaluations have however shown, that current methodology lacks sufficient standardization in that the employment of different sources of extracts and techniques makes a comparison of data from one laboratory to another almost impossible. OBJECTIVE: The aim of this study is to establish an external quality control system and to analyse, what the explanations for the different outcomes from various laboratories might be. METHODS: In the past 4 years 5 sera from patients suffering from EAA or healthy controls were sent every 6 months to 11 different allergy laboratories in Austria. The determination of specific IgG antibodies against antigens that are typical for this disease were requested. Results were gained with the method routinely used in the respective laboratory, and then sent back to the reference center for statistical evaluation. Precipitating techniques were used in 8 laboratories during the first mailings, but were gradually exchanged by automated ELISA systems being employed in 8 laboratories in the last mailing. RESULTS: 1127 values were determined in 105 expectedly positive sera and 1003 in 94 negative samples. Of the 562 values obtained with precipitation techniques in positive sera, only 52.0% were reported to be positive, and the results varied considerably among laboratories and antigens. In contrast, 93.3% were positive with commercially available ELISA techniques, with 92.3% for the EnzyDex System and even 95.5% for the UniCAP System. Regarding the specificity however, 93.0% of the expected negative results were correct negative using precipitation methods, whereas merely 75.2% were negative with the EnzyDex System and only 22.5% using the UniCAP System. Moreover 35.8% of the results using this latter method were false-positive. CONCLUSIONS: The traditional precipitation techniques proved not only technically difficult to perform, but also unreliable, difficult to reproduce, insensitive and impractical in daily laboratory work. They suffer from that many draw backs, that their use in daily routine cannot be recommended any more. Automated ELISA systems seem to fulfill the criteria for a routine technique concerning handling, automation, and quality criteria like sensitivity quite well, but not for specificity. Both techniques urgently need external standardization in order to make the results comparable among the different systems and methods; the danger of potentially false-positive results, pretending sensitizations that might be clinically irrelevant in several cases, is high.\n\nAberer, Werner\n\nKränke, Birger\n\n\n"
},
{
"text": "\n5092\nInhalation therapy with nitric oxide in pulmonary hypertension: Comparison of preterm infants versus newborn infants.\n\nSchmölzer, G\n\nUrlesberger, B\n\nReiterer, F\n\nHaim, M\n\nKutschera, J\n\nResch, B\n\nMüller, W\n\nBeiträge in Fachzeitschriften\nISI:000186014800003\n14520586.0\n10.1055/s-2003-42668\nNone\nBackground: Inhaled nitric oxide (iNO) is used as a vasodilator in pulmonary hypertension (PH) of the newborn infant. Patients and Methods: Retrospective analysis of patients, who were treated at our department with iNO in the period from 1994-001. Response was defined as an increase of the paO(2)/FiO(2) Ratio greater than or equal to 20% and/or a decrease of the oxygenation index (OI) greater than or equal to 20 % after 2 h (early response), and consecutively after. 24 h (late response). The patients were divided into a) primary persistent pulmonary hypertension of the newborn (PPHN), or b) pulmonary hypertension secondary to meconium aspiration syndrome (MAS), sepsis or congenital diaphragmatic hernia (CDH). Results: Between 1994 and 2001 we treated 47 patients with iNO at our neonatal intensive care unit. We included 16 (35%) preterm infants (GA 34, [25-37] weeks, GG 2061 [680-3410]g) (Median/Range) and 31 (65%) newborn (GA40 [38-42] weeks, GG 3510 [2550-4560]g). 18 (38%) patients suffered from primary PPHN, 29 (62%) from secondary PPHN (14 MAS [30%], 8 sepsis [17%], 4 CDH [8%]). 8 (50%) preterm and 20 (64%) term infants showed a positive NO response after 2 h, again 8 (50 %) preterm, and 20 (64%) term infants showed a positive NO response after 24h. There was neither a significant difference between term and preterm infants at 2 h, nor at 24 h. Between 2 h and 24 h 10 patients changed in their response to iNO. 5 (18 %) patients with early response showed a significant degradation after 24h, whereas 5 (26%) of the patients without early response showed a significant improvement of the oxygenation alter 24h. Alltogether 13 (72%) patients with PPHN, 8 (57%) with MAS, 2 (50%) with CDH, 4 (50%) with sepsis showed a positive iNO response after 24h. In regard to the oxygenation parameters at start of iNO-therapy, the patients with early response did not differ from the patient without response (median 01: 20, versus 21, , median paO(2)/FiO(2) Ratio: 59, versus 55, mmHg at the start of the iNO therapy). Conclusion: In regard to iNO response, there was no significant difference between term and preterm infants. Due to the changing response, a positive iNO-response after 2 h had no predictive value for the further prognosis of the oxygenation situation under iNO therapy.\n\nMüller, Wilhelm\n\nReiterer, Friedrich\n\nResch, Bernhard\n\nUrlesberger, Berndt\n\n\n"
},
{
"text": "\n108419\nVariable parathyroid hormone(1-84)/carboxylterminal PTH ratios detected by 4 novel parathyroid hormone assays.\n\nKoller, H\n\nZitt, E\n\nStaudacher, G\n\nNeyer, U\n\nMayer, G\n\nRosenkranz, AR\n\nBeiträge in Fachzeitschriften\nISI:000221169400005\n15182128.0\nNone\nNone\nPTH(1-84)/C-PTH ratio cannot be equally used as a predictor of bone turnover when different PTH assays are used. Depending on those assays, differences in total PTH values mathematically lead to varying amounts of C-PTH fragments resulting in variable, even contradictory PTH(1-84)/C-PTH ratios. Aim: Parathyroid hormone (PTH) measurement is important in the evaluation of bone disease in patients with chronic renal failure. Large carboxyl-terminal PTH fragments (C-PTH) cross-react with second-generation PTH assays, lead to an overestimation of biologically active PTH, and are evaluated by a combination of second- and third-generation PTH assays. The aim of our study was to examine whether the use of 4 different PTH assays of putatively same specificity leads to comparable results detecting C-PTH fragments. Subjects and methods: In 70 chronic dialysis patients, total PTH and PTH(1-84) were measured in parallel by 4 novel PTH assays (Nichols Advantage Intact PTH and Bio-Intact PTH Chemiluminescence Assay, Nichols Institute Diagnostics, USA, DUO Total and CAP PTH IRMA, Scantibodies Laboratory, USA). The C-PTH concentration was quantitated by subtracting PTH(1-84) from total PTH. Consecutively, the PTH(1-84)/ C-PTH ratio was calculated. Results: Nichols Intact PTH and DUO Total PTH assays were highly correlated (r = 0.985), as well as Nichols Bio-Intact and DUO CAP assays (r = 0.984). However, total PTH values measured by the Nichols assay were 30% higher (median (range): 185 (9.9-2, 32) versus 130 (2.3-1, 71.1) pg/ml, p < 0.01). PTH(1-84) values, measured by the Nichols Bio-Intact PTH assay were 8% higher compared to the Scantibodies CAP assay (median (range): 79.6 (7.5-1, 60.9) versus 73.7 (4.4-918.9) pg/ml, p = NS). Thirty-six patients had a ratio < 1 measured by the Nichols assays, whereas only 8 patients showed the same ratio when measured by the Scantibodies assays. In 28 patients (40%), contradictory PTH(1-84)/C-PTH ratios were found, showing a ratio < 1 when measure the Nichols assays, but > 1 when the Scantibodies assays were used. Conclusion: In conclusion, our results suggest that the PTH(1-84)/C-PTH ratio cannot be equally used as a predictor of bone turnover when different PTH assays are used. Depending on those assays, differences in total PTH values mathematically lead to varying amounts of C-PTH fragments resulting in variable, even contradictory PTH(1-84)/C-PTH ratios.\n\nRosenkranz, Alexander\n\n\n"
},
{
"text": "\n139208\n18F]FDG imaging of head and neck tumours: comparison of hybrid PET and morphological methods.\n\nDresel, S\n\nGrammerstorff, J\n\nSchwenzer, K\n\nBrinkbäumer, K\n\nSchmid, R\n\nPfluger, T\n\nHahn, K\n\nBeiträge in Fachzeitschriften\nISI:000184644800009\n12739070.0\n10.1007/s00259-003-1181-6\nNone\nThe aim of this study was to evaluate fluorine-18 fluorodeoxyglucose ([(18)F]FDG) imaging of head and neck tumours using a second- or third-generation hybrid PET device. Results were compared with the findings of spiral computed tomography (CT) and magnetic resonance imaging (MRI), and, as regards lymph node metastasis, the ultrasound findings. A total of 116 patients with head and neck tumours (83 males and 33 females aged 27-88 years) were examined using a hybrid PET scanner after injection of 185-350 MBq of [(18)F]FDG (Picker Prism 2000 XP-PCD, Marconi Axis gamma-PET(2) AZ). Hybrid PET examinations were performed in list mode using an axial filter. Reconstruction of data was performed iteratively. Ninety-six patients underwent CT using a multislice technique (Siemens Somatom Plus 4, Marconi MX 8000), 18 patients underwent MRI and 100 patients were examined by ultrasound. All findings were verified by histology, which was considered the gold standard, or, in the event of negative histology, by follow-up. Correct diagnosis of the primary or recurrent lesion was made in 73 of 85 patients using the hybrid PET scanner, in 50 of 76 patients on CT and in 7 of 10 patients on MRI. Hybrid PET successfully visualised metastatic disease in cervical lymph nodes in 28 of 34 patients, while 23 of 31 were correctly diagnosed with CT, 3 of 4 with MRI and 30 of 33 with ultrasound. False positive results regarding lymph node metastasis were seen in three patients with hybrid PET, in 14 patients with CT and in 13 patients with ultrasound. MRI yielded no false positive results concerning lymph node metastasis. In one patient, unrecognised metastatic lesions were seen on hybrid PET elsewhere in the body (lung: n=1; bone: n=1). Additional malignant lesions at sites other than the head and neck tumour were found in three patients (one patient with lung cancer, one patient with pelvic metastasis due to a carcinoma of the prostate and one patient with pulmonary metastasis due to breast cancer). It is concluded that [(18)F]FDG PET with hybrid PET scanners is superior to CT and MRI in the diagnosis of primary or recurrent lesions as well as in the assessment of lymph node involvement, whereas it is inferior to ultrasound in the detection of cervical lymph node metastasis.\n\n\n"
},
{
"text": "\n174697\n[The Phenotypic Spectrum of Ophthalmic Changes in CEP290 Mutations].\n\nPreising, MN\n\nSchneider, U\n\nFriedburg, C\n\nGruber, H\n\nLindner, S\n\nLorenz, B\n\nBeiträge in Fachzeitschriften\nISI:000463082300007\n30897646.0\n10.1055/a-0842-3250\nNone\nInherited retinal diseases (IRDs) may be caused by variations in genes affecting the connecting cilium of photoreceptor cells and intraflagellar transport, manifested as ciliopathies. CEP290 is frequently mutated in non-syndromic, but also syndromic IRDs. In preparation for clinical treatment trials, detailed phenotypic work-up including longitudinal follow-up is mandatory.\n We performed genotype-phenotype correlations in 30 patients with biallelic mutations in CEP290. The study was approved by the IRB of the medical faculty of the Justus-Liebig University Giessen. The patients received a comprehensive clinical examination, including spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) recording, and electrophysiology whenever possible.\n Thirty patients aged 1 month to 84 years (median at first visit 0.6 y) were followed between 5 months and 25.7 years (median 4.8 y). Twenty-three of these patients carried the c.2991+1655A>G mutation (30/60 allele 2, 7 homozygous). The second most frequent mutation was p.K1575* (9/60 alleles). The full-field electroretinogram showed residual response in a few patients only. After progression, electrophysiological responses were below threshold in all patients. Severely reduced visual acuity persisted from birth. Eight patients had quantifiable best corrected visual acuity (BCVA, logMAR 2 - 0.3), in one case up to the age of 84 y. Absent fixation of targets was noted in 15 patients during the first months of life. Ten of these patients did not improve during follow-up past the second year of life. The other patients developed at least light perception (LP, n = 7) or hand movement (HM, n = 3). Better BCVA was not restricted to the c.2991+1655A>G mutation. Fundus photography documented degenerative changes throughout the retina with macular degeneration and circular increased fundus autofluorescence signals (9/30 patients) in the perimacular ring and in the rod ring, and spotty changes in the periphery. SD-OCT (6/30 patients) disclosed reduced photoreceptor layer (OPL to OS) thickness and preserved inner retinal thickness (RNFL to INL). Better BCVA did not correlate to genotype or central photoreceptor layer thickness.\n As reported earlier, CEP290 variations are one of the most frequent causes of IRDs with infancy onset. In our patient cohort of 30 patients, only 33% had no LP, 67% at least LP, and among these 26% logMAR 2 to 0.3. Together with preserved ganglion cell and nerve fibre cell layers, success with gene therapeutic approaches appears possible.\n Georg Thieme Verlag KG Stuttgart · New York.\n\n\n"
},
{
"text": "\n185376\nMinimally-invasive plate osteosynthesis in distal tibial fractures: Results and complications.\n\nVidović, D\n\nMatejčić, A\n\nIvica, M\n\nJurišić, D\n\nElabjer, E\n\nBakota, B\n\nBeiträge in Fachzeitschriften\nNone\n26584733.0\n10.1016/j.injury.2015.10.067\nNone\nDistal tibial or pilon fractures are usually the result of combined compressive and shear forces, and may result in instability of the metaphysis, with or without articular depression, and injury to the soft tissue. The complexity of injury, lack of muscle cover and poor vascularity make these fractures difficult to treat. Surgical treatment of distal tibial fractures includes several options: external fixation, IM nailing, ORIF and minimally-invasive plate osteosynthesis (MIPO). Management of distal tibial fractures with MIPO enables preservation of soft tissue and remaining blood supply. This is a report of a series of prospectively studied closed distal tibial and pilon fractures treated with MIPO.\n A total of 21 patients with closed distal tibial or pilon fractures were enrolled in the study between March 2008 and November 2013 and completed follow-up. Demographic characteristics, mechanism of injury, time required for union, ankle range of motion and complications were recorded. Fractures were classified according to the AO/OTA classification. Nineteen patients were initially managed with an ankle-spanning external fixator. When the status of the soft tissue had improved and swelling had subsided enough, a definitive internal fixation with MIPO was performed. Patients were invited for follow-up examinations at 3 and 6 weeks and then at intervals of 6 to 8 weeks until 12 months.\n Mean age of the patients was 40.1 years (range 19-67 years). Eighteen cases were the result of high-energy trauma and three were the result of low-energy trauma. According to the AO/OTA classification there were extraarticular and intraarticular fractures, but only simple articular patterns without depression or comminution. The average time for fracture union was 19.7 weeks (range 12-38 weeks). Mean range of motion was 10° of dorsiflexion (range 5-15°) and 28.3° of plantar flexion (range 20-35°). Three cases were metalwork-related complications. Two patients underwent plate removal at 24 weeks because of plate impingement. There was one case of wound breakdown at 11 weeks. One patient had fracture union with tibial recurvatum of approximately 10°, without functional impairment. Two patients had delayed union.\n MIPO is a reliable method of treatment for distal tibial fractures; it provides a high union rate and good functional outcome with minimal soft tissue complications. Skin impingement remains a common complication with MIPO, but this can be solved by timely plate removal.\n Copyright © 2015 Elsevier Ltd. All rights reserved.\n\n\n"
},
{
"text": "\n175586\nWhite matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study.\n\nSchirmer, MD\n\nDalca, AV\n\nSridharan, R\n\nGiese, AK\n\nDonahue, KL\n\nNardin, MJ\n\nMocking, SJT\n\nMcIntosh, EC\n\nFrid, P\n\nWasselius, J\n\nCole, JW\n\nHolmegaard, L\n\nJern, C\n\nJimenez-Conde, J\n\nLemmens, R\n\nLindgren, AG\n\nMeschia, JF\n\nRoquer, J\n\nRundek, T\n\nSacco, RL\n\nSchmidt, R\n\nSharma, P\n\nSlowik, A\n\nThijs, V\n\nWoo, D\n\nVagal, A\n\nXu, H\n\nKittner, SJ\n\nMcArdle, PF\n\nMitchell, BD\n\nRosand, J\n\nWorrall, BB\n\nWu, O\n\nGolland, P\n\nRost, NS\n\nMRI-GENIE Investigators\n\nBeiträge in Fachzeitschriften\nISI:000485804400078\n31200151.0\n10.1016/j.nicl.2019.101884\nPMC6562316\nWhite matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.\n Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n181729\nCardiovascular magnetic resonance 4D flow analysis has a higher diagnostic yield than Doppler echocardiography for detecting increased pulmonary artery pressure.\n\nRamos, JG\n\nFyrdahl, A\n\nWieslander, B\n\nReiter, G\n\nReiter, U\n\nJin, N\n\nMaret, E\n\nEriksson, M\n\nCaidahl, K\n\nSörensson, P\n\nSigfridsson, A\n\nUgander, M\n\nBeiträge in Fachzeitschriften\nISI:000518983500001\n32143594.0\n10.1186/s12880-020-00428-9\nPMC7060590\nPulmonary hypertension is definitively diagnosed by the measurement of mean pulmonary artery (PA) pressure (mPAP) using right heart catheterization. Cardiovascular magnetic resonance (CMR) four-dimensional (4D) flow analysis can estimate mPAP from blood flow vortex duration in the PA, with excellent results. Moreover, the peak systolic tricuspid regurgitation (TR) pressure gradient (TRPG) measured by Doppler echocardiography is commonly used in clinical routine to estimate systolic PA pressure. This study aimed to compare CMR and echocardiography with regards to quantitative and categorical agreement, and diagnostic yield for detecting increased PA pressure.\n Consecutive clinically referred patients (n = 60, median [interquartile range] age 60 [48-68] years, 33% female) underwent echocardiography and CMR at 1.5 T (n = 43) or 3 T (n = 17). PA vortex duration was used to estimate mPAP using a commercially available time-resolved multiple 2D slice phase contrast three-directional velocity encoded sequence covering the main PA. Transthoracic Doppler echocardiography was performed to measure TR and derive TRPG. Diagnostic yield was defined as the fraction of cases in which CMR or echocardiography detected an increased PA pressure, defined as vortex duration ≥15% of the cardiac cycle (mPAP ≥25 mmHg) or TR velocity > 2.8 m/s (TRPG > 31 mmHg).\n Both CMR and echocardiography showed normal PA pressure in 39/60 (65%) patients and increased PA pressure in 9/60 (15%) patients, overall agreement in 48/60 (80%) patients, kappa 0.49 (95% confidence interval 0.27-0.71). CMR had a higher diagnostic yield for detecting increased PA pressure compared to echocardiography (21/60 (35%) vs 9/60 (15%), p < 0.001). In cases with both an observable PA vortex and measurable TR velocity (34/60, 56%), TRPG was correlated with mPAP (R2 = 0.65, p < 0.001).\n There is good quantitative and fair categorical agreement between estimated mPAP from CMR and TRPG from echocardiography. CMR has higher diagnostic yield for detecting increased PA pressure compared to echocardiography, potentially due to a lower sensitivity of echocardiography in detecting increased PA pressure compared to CMR, related to limitations in the ability to adequately visualize and measure the TR jet by echocardiography. Future comparison between echocardiography, CMR and invasive measurements are justified to definitively confirm these findings.\n\nReiter, Ursula\n\n\n"
},
{
"text": "\n52800\nLarge-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: The GENOMOS study\n\nRalston, SH\n\nUitterlinden, AG\n\nBrandi, ML\n\nBalcells, S\n\nLangdahl, BL\n\nLips, P\n\nLorenc, R\n\nObermayer-Pietsch, B\n\nScollen, S\n\nBustamante, M\n\nHusted, LB\n\nCarey, AH\n\nDiez-Perez, A\n\nDunning, AM\n\nFalchetti, A\n\nKarczmarewicz, E\n\nKruk, M\n\nvan Leeuwen, JPTM\n\nvan Meurs, JBJ\n\nMangion, J\n\nMcGuigan, FEA\n\nMellibovsky, L\n\ndel Monte, F\n\nPols, HAP\n\nReeve, J\n\nReid, DM\n\nRenner, W\n\nRivadeneira, F\n\nvan Schoor, NM\n\nSherlock, RE\n\nIoannidis, JPA\n\nBeiträge in Fachzeitschriften\nISI:000237548200020\n16475872.0\n10.1371/journal.pmed.0030090\nPMC1370920\nBackground Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. Methods and Findings Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20, 86 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. Conclusions Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.\n\nObermayer-Pietsch, Barbara\n\nRenner, Wilfried\n\n\n"
},
{
"text": "\n135991\nAssessment of the effect on blood loss and transfusion requirements when adding a polyethylene glycol sealant to the anastomotic closure of aortic procedures: a case-control analysis of 102 patients undergoing Bentall procedures.\n\nNatour, E\n\nSuedkamp, M\n\nDapunt, OE\n\nBeiträge in Fachzeitschriften\nISI:000310033000001\n23043723.0\n10.1186/1749-8090-7-105\nPMC3477041\nThe use of CoSeal(®), a polyethylene glycol sealant, in cardiac and vascular surgery for prevention of anastomotic bleeding has been subject to prior investigations. We analysed our perioperative data to determine the clinical benefit of using polyethylene glycol sealant to inhibit suture line bleeding in aortic surgery.\n From January 2004 to June 2006, 124 patients underwent aortic surgical procedures such as full root replacements, reconstruction and/or replacement of ascending aorta and aortic arch procedures. A Bentall procedure was employed in 102 of these patients. In 48 of these, a polyethylene glycol sealant was added to the anastomotic closure of the aortic procedure (sealant group) and the other 54 patients did not have this additive treatment to the suture line (control group).\n There were no significant between-group differences in the demographic characteristics of the patients undergoing Bentall procedures. Mean EuroSCORES (European System for Cardiac Operative Risk Evaluation) were 13.7 ± 7.7 (sealant group) and 14.4 ± 6.2 (control group), p = NS. The polyethylene glycol sealant group had reduced intraoperative and postoperative transfusion requirements (red blood cells: 761 ± 863 versus 1248 ± 1206 ml, p = 0.02; fresh frozen plasma: 413 ± 532 versus 779 ± 834 ml, p = 0.009); and less postoperative drainage loss (985 ± 972 versus 1709 ± 1302 ml, p = 0.002). A trend towards a lower rate of rethoracotomy was observed in the sealant group (1/48 versus 6/54, p = 0.07) and there was significantly less time spent in the intensive care unit or hospital (both p = 0.03). Based on hypothesis-generating calculations, the resulting economic benefit conferred by shorter intensive care unit and hospital stays, reduced transfusion requirements and a potentially lower rethoracotomy rate is estimated at €1, 43 per patient in this data analysis.\n The use of this polymeric surgical sealant demonstrated improved intraoperative and postoperative management of anastomotic bleeding in Bentall procedures, leading to reduced postoperative drainage loss, less transfusion requirements, and a trend towards a lower rate of rethoracotomy. Hypothesis-generating calculations indicate that the use of this sealant translates to cost savings. Further studies are warranted to investigate the clinical and economic benefits of CoSeal in a prospective manner.\n\n\n"
},
{
"text": "\n145446\nGenetically determined height and coronary artery disease.\n\nNelson, CP\n\nHamby, SE\n\nSaleheen, D\n\nHopewell, JC\n\nZeng, L\n\nAssimes, TL\n\nKanoni, S\n\nWillenborg, C\n\nBurgess, S\n\nAmouyel, P\n\nAnand, S\n\nBlankenberg, S\n\nBoehm, BO\n\nClarke, RJ\n\nCollins, R\n\nDedoussis, G\n\nFarrall, M\n\nFranks, PW\n\nGroop, L\n\nHall, AS\n\nHamsten, A\n\nHengstenberg, C\n\nHovingh, GK\n\nIngelsson, E\n\nKathiresan, S\n\nKee, F\n\nKönig, IR\n\nKooner, J\n\nLehtimäki, T\n\nMärz, W\n\nMcPherson, R\n\nMetspalu, A\n\nNieminen, MS\n\nO'Donnell, CJ\n\nPalmer, CN\n\nPeters, A\n\nPerola, M\n\nReilly, MP\n\nRipatti, S\n\nRoberts, R\n\nSalomaa, V\n\nShah, SH\n\nSchreiber, S\n\nSiegbahn, A\n\nThorsteinsdottir, U\n\nVeronesi, G\n\nWareham, N\n\nWiller, CJ\n\nZalloua, PA\n\nErdmann, J\n\nDeloukas, P\n\nWatkins, H\n\nSchunkert, H\n\nDanesh, J\n\nThompson, JR\n\nSamani, NJ\n\nCARDIoGRAM+C4D Consortium\n\nBeiträge in Fachzeitschriften\nISI:000353294000006\n25853659.0\n10.1056/NEJMoa1404881\nPMC4648271\nThe nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.\n We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65, 66 cases and 128, 83 controls. Using individual-level genotype data from 18, 49 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.\n We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.\n There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).\n\nMärz, Winfried\n\n\n"
}
]
}