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"text": "\n154703\nA prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis.\n\nSpeckmann, C\n\nDoerken, S\n\nAiuti, A\n\nAlbert, MH\n\nAl-Herz, W\n\nAllende, LM\n\nScarselli, A\n\nAvcin, T\n\nPerez-Becker, R\n\nCancrini, C\n\nCant, A\n\nDi Cesare, S\n\nFinocchi, A\n\nFischer, A\n\nGaspar, HB\n\nGhosh, S\n\nGennery, A\n\nGilmour, K\n\nGonzález-Granado, LI\n\nMartinez-Gallo, M\n\nHambleton, S\n\nHauck, F\n\nHoenig, M\n\nMoshous, D\n\nNeven, B\n\nNiehues, T\n\nNotarangelo, L\n\nPicard, C\n\nRieber, N\n\nSchulz, A\n\nSchwarz, K\n\nSeidel, MG\n\nSoler-Palacin, P\n\nStepensky, P\n\nStrahm, B\n\nVraetz, T\n\nWarnatz, K\n\nWinterhalter, C\n\nWorth, A\n\nFuchs, S\n\nUhlmann, A\n\nEhl, S\n\nP-CID study of the Inborn Errors Working Party of the EBMT\n\nBeiträge in Fachzeitschriften\nISI:000398771800025\n27658761.0\n10.1016/j.jaci.2016.07.040\nPMC6311415\nAbsent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions.\n We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome.\n In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome.\n A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution.\n The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.\n Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.\n\nSeidel, Markus\n\n\n"
},
{
"text": "\n183929\nDifferential endothelial signaling responses elicited by chemogenetic H<sub>2</sub>O<sub>2</sub> synthesis.\n\nSaeedi Saravi, SS\n\nEroglu, E\n\nWaldeck-Weiermair, M\n\nSorrentino, A\n\nSteinhorn, B\n\nBelousov, V\n\nMichel, T\n\nBeiträge in Fachzeitschriften\nISI:000571122400006\n32590330.0\n10.1016/j.redox.2020.101605\nPMC7322171\nHydrogen peroxide (H2O2) modulates critical phosphorylation pathways in vascular endothelial cells, many of which affect endothelial nitric oxide synthase (eNOS) signal transduction. Both intracellular and extracellular sources of H2O2 have been implicated in eNOS regulation, yet the specific endothelial pathways remain incompletely understood. Here we exploited chemogenetic approaches and live-cell imaging methods to both generate and detect H2O2 in different subcellular compartments (cytosol, nucleus, and caveolae) of cultured EA.hy926 human endothelial cells. We developed novel recombinant constructs encoding differentially-targeted yeast d-amino acid oxidase (DAAO), which generates H2O2 only when its d-amino acid substrate is provided. DAAO was expressed as a fusion protein with the new H2O2 biosensor HyPer7.2, which allowed us to quantitate intracellular H2O2 levels by ratiometric imaging in living endothelial cells following the activation of DAAO by d-alanine. The addition of extracellular H2O2 to the HyPer-DAAO-transfected cells led to increases in H2O2 throughout different regions of the cell, as measured using the differentially-targeted HyPer biosensor for H2O2. The sensor response to extracellular H2O2 was more rapid than that quantitated following the addition of d-alanine to transfected cells to activate differentially-targeted DAAO. The maximal intracellular levels of H2O2 observed in response to the addition of extracellular H2O2 vs. intracellular (DAAO-generated) H2O2 were quantitatively similar. Despite these similarities in the measured levels of intracellular H2O2, we observed a remarkable quantitative difference in the activation of endothelial phosphorylation pathways between chemogenetically-generated intracellular H2O2 and the phosphorylation responses elicited by the addition of extracellular H2O2 to the cells. Addition of extracellular H2O2 had only a nominal effect on phosphorylation of eNOS, kinase Akt or AMP-activated protein kinase (AMPK). By contrast, intracellular H2O2 generation by DAAO caused striking increases in the phosphorylation of these same key signaling proteins. We also found that the AMPK inhibitor Compound C completely blocked nuclear H2O2-promoted eNOS phosphorylation. However, Compound C had no effect on eNOS phosphorylation following H2O2 generation from cytosol- or caveolae-targeted DAAO. We conclude that H2O2 generated in the cell nucleus activates AMPK, leading to eNOS phosphorylation; in contrast, AMPK activation by cytosol- or caveolae-derived H2O2 does not promote eNOS phosphorylation via AMPK. These findings indicate that H2O2 generated in different subcellular compartments differentially modulates endothelial cell phosphorylation pathways, and suggest that dynamic subcellular localization of oxidants may modulate signaling responses in endothelial cells.\n Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.\n\nEROGLU, Emrah\n\nWaldeck-Weiermair, Markus\n\n\n"
},
{
"text": "\n88555\nATX-II effects on the apparent location of M cells in a computational model of a human left ventricular wedge.\n\nDos Santos, RW\n\nOtaviano Campos, F\n\nNeumann Ciuffo, L\n\nNygren, A\n\nGiles, W\n\nKoch, H\n\nBeiträge in Fachzeitschriften\nNone\n16686688.0\n10.1111/j.1540-8167.2006.00389.x\nNone\nINTRODUCTION: The apparent location of the myocytes (M cells) with the longest action potential duration (APD) in a canine left ventricular (LV) wedge have been reported to shift after application of a sea anemone toxin, ATX-II. This toxin slows inactivation of I(Na) and thus prolongs APD. Thus, M cells may exhibit dynamic functional states, rather than being a static, anatomically discrete, myocyte population. In this study, we attempted to further define and understand this phenomenon using a mathematical model of the human ventricular myocyte action potential incorporated into an in silico "wedge" preparation. Our simulations demonstrate that even under conditions of a fixed population and ratio of epicardial, M, and endocardial myocytes, the apparent anatomical position (transmural location) of the myocytes with the longest APD can shift following ATX-II treatment. This arises because the ATX-II effect, modeled as a small increase in the late or persistent Na(+) current, and consequent prolongation of APD significantly changes the electrotonic interactions between ventricular myocytes in this LV wedge preparation. METHODS AND RESULTS: This LV wedge model is based on bidomain equations. It corresponds to a rectangular tissue immersed in a passive and isotropic medium that represents the superfusion bath. In this theoretical work, the three known different and discrete populations of myocytes in the human left ventricle have been included: the epicardial, M, and endocardial cells. The effects of ATX-II on I(Na) were simulated by altering the voltage-dependent steady-state inactivation of the parameters h (fast gate) and j (slow gate). As a result, in these ATX-II simulations a persistent late Na(+) current was generated in all three types of ventricular myocytes. However, the APDs were prolonged in a heterogeneous pattern. Our simulations demonstrate that after the ATX-II effects develop, alterations in transmural electrotonic interactions can produce changes in the transmural location of myocytes with the longest APD. CONCLUSIONS: The combination of intercellular electrotonic interactions, which tend to reduce and smooth out the discrete transmural APD variations, and the heterogeneous effects of ATX-II, which preferentially prolong the APD of M cells, can shift the location of the ventricular myocytes. This shift results in significantly altered transmural patterns of action potential durations, which would be expected to change localized refractory period and excitability. These cellular changes give rise to alterations in the corresponding surface electrograms and may change the overall substrates for conduction and rhythm disturbances.\n\n\n"
},
{
"text": "\n167474\nEffects of linagliptin on endothelial function and postprandial lipids in coronary artery disease patients with early diabetes: a randomized, placebo-controlled, double-blind trial.\n\nTripolt, NJ\n\nAberer, F\n\nRiedl, R\n\nUrl, J\n\nDimsity, G\n\nMeinitzer, A\n\nStojakovic, T\n\nAziz, F\n\nHödl, R\n\nBrachtl, G\n\nStrunk, D\n\nBrodmann, M\n\nHafner, F\n\nSourij, H\n\nBeiträge in Fachzeitschriften\nISI:000433130200001\n29773079.0\n10.1186/s12933-018-0716-x\nPMC5958406\nEarly glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements.\n In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances.\n We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. - 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549).\n Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).\n\nAberer, Felix\n\nBrodmann, Marianne\n\nDimsity, Gudrun\n\nHafner, Franz\n\nMeinitzer, Andreas\n\nRiedl, Regina\n\nSourij, Harald\n\nTripolt, Norbert\n\n\n"
},
{
"text": "\n79084\nIdeomotor limb apraxia in Huntington's disease: a case-control study.\n\nHödl, AK\n\nHödl, E\n\nOtti, DV\n\nHerranhof, B\n\nIlle, R\n\nBonelli, RM\n\nBeiträge in Fachzeitschriften\nISI:000254361100004\n18305889.0\n10.1007/s00415-008-0577-4\nNone\nINTRODUCTION : Ideomotor limb apraxia is the disturbance of planning and of execution of motor activity, hich is not caused by a dysfunction of the motor or sensory nervous system. Apraxia is a diagnostic criterion in dementialike Alzheimer's disease. However, this symptom may also occur in dementia with subcortical lesions like Huntington's disease (HD), a hereditary, devastating neurodegenerative disease leading to neurological and psychiatric dysfunction. The aim of our study is to determine the correlation between the occurrence of ideomotor limb apraxia and neuropsychological deficits in HD. METHODS : To assess the correlation between apraxia and neuropsychological abilities in HD, 41 patients with HD and 33 age- and sex-matched controls were examined. The De Renzi test for apraxia and an apraxia test battery containing tests of i) imitation of meaningless gestures of hands, ii) imitation of meaningless gestures of fingers, iii) performance of meaningful gestures on demand, and iv) pantomime of tool use were used to assess apraxia. Moreover, neuropsychological function was rated by the Mini Mental State Examination (MMSE), the Rey Complex Figure Memory Test, the Trail Making Test A and B, the California Verbal Learning Test (German version), the Stroop Color and Word Test, the Controlled Oral Word Association Test, and the Mehrfachwahl- Wortschatz-Intelligenztest for measuring verbal intelligence. Motor function was assessed in all HD patients by the Unified HD Rating Scale (UHDRS), rating oculomotor and orolingual function, fine motor tasks, parkinsonism, dystonia, chorea and statics and gait. RESULTS : Apraxic HD patients showed worse results than non-apraxic HD patients in three items of the Rey Complex Figure Memory Test (Organisation, short-term and longterm memory), but not in other assessed neuropsychological tests. In assessment of meaningful gestures on demand 39.3% of HD patients were apraxic, in assessment of pantomime of tool use 67.9% of HD patients showed apraxia. Patients with HD showed highly significant worse results than controls in the De Renzi test, in hands' and fingers' imitation, in performance of gestures on demand, in pantomime of tool use and every neuropsychological test except for the test measuring verbal intelligence. Apraxic HD patients showed worse results than non-apraxic HD patients in the UHDRS total motor score and the score for oculomotor function. CONCLUSION : This is the largest study on apraxia in HD. Ideomotor limb apraxia is a common sign in HD patients, occurring in a high percentage. In contrast to the opinion of several authors, occurrence of apraxia in HD is independent from neuropsychological decline and the severity of most neurological symptoms.\n\nHoll, Anna\n\n\n"
},
{
"text": "\n128585\nRivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF.\n\nHankey, GJ\n\nPatel, MR\n\nStevens, SR\n\nBecker, RC\n\nBreithardt, G\n\nCarolei, A\n\nDiener, HC\n\nDonnan, GA\n\nHalperin, JL\n\nMahaffey, KW\n\nMas, JL\n\nMassaro, A\n\nNorrving, B\n\nNessel, CC\n\nPaolini, JF\n\nRoine, RO\n\nSinger, DE\n\nWong, L\n\nCaliff, RM\n\nFox, KA\n\nHacke, W\n\nROCKET AF Steering Committee Investigators\n\nBeiträge in Fachzeitschriften\nISI:000301999600007\n22402056.0\n10.1016/S1474-4422(12)70042-X\nNone\nBackground In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). Methods In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2-0-3.0). Patients and investigators were masked to treatment allocation. Between Dec 18, 006, and June 17, 009, 4 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. Findings 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2.79% rivaroxaban vs 2.96% warfarin; hazard ratio [HR] 0-94, 5% CI 0.77-1.16) and those without (1.44% vs 1.88%; 0.77, 0.58-1-01; interaction p=0.23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13.31% rivaroxaban vs 13.87% warfarin; HR 0.96, 5% CI 0.87-1-07) and those without (16.69% vs 15.19%; 1.10, 0.99-1.21; interaction p=0.08). Interpretation There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.\n\nPilger, Ernst\n\n\n"
},
{
"text": "\n8358\nDifferential effects of reserpine and 6-hydroxydopamine on neuropeptide Y (NPY) and noradrenaline in peripheral neurons.\n\nLundberg, JM\n\nSaria, A\n\nFranco-Cereceda, A\n\nHökfelt, T\n\nTerenius, L\n\nGoldstein, M\n\nBeiträge in Fachzeitschriften\nISI:A1985AGR2200019\n2858824.0\n10.1007/BF00515563\nNone\nThe effects of 6-hydroxydopamine (6-OHDA) and reserpine pretreatment on peripheral neuropeptide Y (NPY)- and noradrenaline (NA)-containing neurons were studied in guinea-pigs. Ten days after 6-OHDA pretreatment, a 60-80% reduction of the NA content was observed in the right atrium of the heart, stellate ganglion and spleen. The content of NPY-like immunoreactivity (LI) was reduced by about 50% in the heart, not changed in the spleen while it increased to 200% of control in the stellate ganglion. Immunohistochemistry showed a pronounced loss of NPY- and tyrosinehydroxylase (TH)-immunoreactive (IR) nerves in the heart but not in the spleen. Increased NPY-IR was seen in axons and cell bodies of the stellate ganglion. Reserpine pretreatment (thereshold dose 0.5 mg X kg-1) caused a dose- and time-dependent reduction of the content of NPY-LI in the heart. A maximal depletion of NPY-LI (about 80%) was observed 5 days after reserpine. Reserpine pretreatment also reduced the content of NPY-LI in the spleen, while no significant change was observed in the adrenal gland or vas deferens. The levels of NPY-LI increased in the stellate ganglion to about 180% of control 5 days after reserpine. Immunohistochemical analysis revealed an almost total loss of NPY-IR nerve fibres in the heart as well as around blood vessels in the lung and skeletal muscle. No detectable changes were observed in perivascular NPY-IR nerves in the spleen, vas deferens or kidney. TH-IR nerves remained unchanged after reserpine, thus indicating that the observed loss of NPY-IR nerves was due to a depletion of NPY and not a degeneration. No change in the levels of substance P-LI was observed in the right atrium 5 days after reserpine. NA was, in contrast to NPY, markedly depleted in all tissues investigated after reserpine treatment. The depletion of NA was more extensive, and occurred more rapidly and at much lower doses as compared to the effects on NPY-LI. Ligations of the sciatic nerve revealed that NPY-LI was transported axonally with a rapid rate (3 mm/h). Reserpine pretreatment significantly increased the amount of accumulated NPY-IR above the ligation, suggesting an increase in axonal transport. High performance liquid chromatography revealed that the NPY-LI consisted of two major peaks in the stellate ganglia, while only one peak closely corresponding to porcine NPY was seen in the right atrium. In conclusion, 6-OHDA pretreatment depletes NPY-LI in certain terminal regions and increases NPY-LI in ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)\n\n\n"
},
{
"text": "\n79834\nEarly complications of the Nuss procedure for pectus excavatum: a prospective study.\n\nCastellani, C\n\nSchalamon, J\n\nSaxena, AK\n\nHöellwarth, ME\n\nBeiträge in Fachzeitschriften\nISI:000255866600002\n18392631.0\n10.1007/s00383-008-2106-z\nNone\nThe Nuss procedure is a minimally invasive method for the correction of pectus excavatum, with several centers reporting its successful application. Complications related to the Nuss procedure are not uncommon and life-threatening complications have been reported. This study focuses on the incidence and management of complications in a series of 167 children and adults with funnel chest corrected by Nuss procedure. Guidelines and strategies to avoid the most common and typical complications are proposed. All patients with funnel chest, operated between April 2000 and 2006 were evaluated prospectively. Our surgical approach involved the submuscular insertion of the pectus bar under right-sided thoracoscopic control. The bar was secured in most cases with one stabilizer on the right side on the underlying rib to prevent bar displacement. Postoperative pain was primarily managed by epidural catheters. All data in the patient report forms was prospectively entered in a database. All complications were documented and classified into major or minor complication. A major complication was noted, if an organ injury occurred or if a significant surgical intervention became necessary. A minor complication was documented, if either an endoscopy or an evacuation of fluid or gas from the thorax by puncture were necessary. One hundred and sixty seven patients (136 males and 31 females) with a mean age of 16.3 (range 5-40 years) were included in this study. Major complications occurred in seven patients (4.2%) and consisted of one intraoperative heart perforation, one piercing of the liver with the trocar, bar infections (n = 2) and significant bar displacement (n = 3). Minor complications were seen in 122 patients (73.1%) and consisted of breakage of wires used to secure the lateral stabilizer plate (n = 48), pleural effusions (n = 28), intraoperative rupture of the intercostal muscle (n = 15), pericardial tears without clinical significance (n = 7) and lung atelectasia (n = 4). Major complications related to the Nuss procedure were rare but preventable and could mainly be attributed to the learning curve. Most minor complications can be avoided by changing the technique, e.g. fixation of the bar and the stabilizer onto the underlying rib, use of PDS cords instead of metal wires to fix the bar and the stabilizer, entrance into and exit of the thorax medial to the rim of the pectus excavatum, etc. Some complications are related to the technique, such as minor pleural effusion or remaining gas in the thorax. Clear guidelines in regard to the technique are presented to prevent the majority of complications and thereby shorten the learning curve.\n\nCastellani, Christoph\n\nHöllwarth, Michael\n\nSchalamon, Johannes\n\n\n"
},
{
"text": "\n183509\nThe secretome of stressed peripheral blood mononuclear cells increases tissue survival in a rodent epigastric flap model.\n\nHacker, S\n\nMittermayr, R\n\nTraxler, D\n\nKeibl, C\n\nResch, A\n\nSalminger, S\n\nLeiss, H\n\nHacker, P\n\nGabriel, C\n\nGolabi, B\n\nPauzenberger, R\n\nSlezak, P\n\nLaggner, M\n\nMildner, M\n\nMichlits, W\n\nAnkersmit, HJ\n\nBeiträge in Fachzeitschriften\nISI:000571566500001\nNone\n10.1002/btm2.10186\nNone\nReconstructive surgery transfers viable tissue to cover defects and to restore aesthetic and functional properties. Failure rates after free flap surgery range from 3 to 7%. Co-morbidities such as diabetes mellitus or peripheral vascular disease increase the risk of flap failure up to 4.5-fold. Experimental therapeutic concepts commonly use a monocausal approach by applying single growth factors. The secretome of gamma-irradiated, stressed peripheral blood mononuclear cells (PBMCsec) resembles the physiological environment necessary for tissue regeneration. Its application led to improved wound healing rates and a two-fold increase in blood vessel counts in previous animal models. We hypothesized that PBMCsec has beneficial effects on the survival of compromised flap tissue by reducing the necrosis rate and increasing angiogenesis. Surgery was performed on 39 male Sprague-Dawley rats (control, = 13; fibrin sealant, = 14; PBMCsec, = 12). PBMCsec was produced according to good manufacturing practices (GMP) guidelines and 2 ml were administered intraoperatively at a concentration of 2.5 x 10(7)cells/ml using fibrin sealant as carrier substance. Flap perfusion and necrosis (as percentage of the total flap area) were analyzed using Laser Doppler Imaging and digital image planimetry on postoperative days 3 and 7. Immunohistochemical stainings for von Willebrand factor (vWF) and Vascular Endothelial Growth Factor-receptor-3 (Flt-4) were performed on postoperative day 7 to evaluate formation of blood vessels and lymphatic vessels. Seroma formation was quantified using a syringe and flap adhesion and tissue edema were evaluated clinically through a cranial incision by a blinded observer according to previously described criteria on postoperative day 7. We found a significantly reduced tissue necrosis rate (control: 27.8% +/- 8.6; fibrin: 22.0% +/- 6.2; 20.9% reduction, = .053 vs. control; PBMCsec: 19.1% +/- 7.2; 31.1% reduction, = .012 vs. control; 12.9% reduction, 0.293 vs. fibrin) together with increased vWF+ vessel counts (control: 70.3 +/- 16.3 vessels/4 fields at 200x magnification; fibrin: 67.8 +/- 12.1; 3.6% reduction, = .651, vs. control; PBMCsec: 85.9 +/- 20.4; 22.2% increase, = .045 vs. control; 26.7% increase, = .010 vs. fibrin) on postoperative day 7 after treatment with PBMCsec. Seroma formation was decreased after treatment with fibrin sealant with or without the addition of PBMCsec. (control: 11.9 +/- 9.7 ml; fibrin: 1.7 +/- 5.3, 86.0% reduction, 0.004 vs. control; PBMCsec: 0.6 +/- 2.0; 94.8% reduction, = .001 vs. control; 62.8% reduction, = .523 vs. fibrin). We describe the beneficial effects of a secretome derived from gamma-irradiated PBMCs on tissue survival, angiogenesis, and clinical parameters after flap surgery in a rodent epigastric flap model.\n\n\n"
},
{
"text": "\n161361\nA retrospective study of isolated fractures of the alveolar process in the permanent dentition.\n\nMarotti, M\n\nEbeleseder, KA\n\nSchwantzer, G\n\nJauk, S\n\nBeiträge in Fachzeitschriften\nISI:000404514600003\n28177588.0\n10.1111/edt.12325\nNone\nThere is a lack of studies of fractures of the alveolar process (FAP). Only five were published in the last 50 years. The aim of this study was to analyze the risk of pulp necrosis and infection (PN), pulp canal obliteration (PCO), infection-related root resorption (IRR), ankylosis-related resorption (ARR), marginal bone loss (MBL), and tooth loss (TL) as well as to identify the possible risk factors for teeth involved in an isolated alveolar process fracture. In the second part, any late complications of the involved teeth were reported in patients who responded to a follow-up examination.\n This study was a retrospective analysis of 126 patients with 329 traumatized permanent teeth treated in a regional dental trauma clinic. Follow-up examination was performed on 31 (24.6%) patients with 75 (22.8%) teeth. The risks of PN, PCO, RR, MBL, and TL were analyzed using the Kaplan-Meier method. Possible risk factors for PN (stage of root development, fracture position in relation to the root apex, concomitant injury, treatment delay, and antibiotics) were analyzed using univariate and multivariate Cox regression and generalized estimating equation. The level of significance was 5%.\n Pulp necrosis was observed in 43% of the teeth, and it was significantly associated with the presence of a concomitant injury and complete root formation. PCO was recorded in 2.8%, root resorption (RR, IRR, and ARR) in 4%, MBL in 8%, and TL in 0.6% of the teeth. Thirty-four percent of the teeth were assumed to have normal pulps, but they did not respond to pulp sensibility testing. At the follow-up examination, PN was found in 49%, PCO in 28%, RR (IRR and ARR) in 4%, MBL in 17%, and TL in 5%. Estimated risk after a 5-years follow up was as follows: PN: 48.2% (95% confidence interval (CI): 42.0-54.5), IRR: 7.2 (95% CI: 3.5-10.9), ARR: 33.0% (95% CI: 22.4-43.6), BL: 16.7% (95% CI: 9.6-23.8), TL: 4.0% (95% CI: 0.0-8.5). The following factors significantly increased the risk of PN: mature root development (hazard ratio [HR]: 7.50 [95% CI: 1.84-30.64], P=.005) and concomitant injury (HR: 2.68 [95% CI: 1.76-4.09], P<.001). In a logistic regression model, teeth with mature roots had a threefold risk of becoming non-responsive to pulp testing.\n Teeth involved in an isolated alveolar process fracture and managed with a conservative treatment approach appear to have a good prognosis. The most common complication was PN which did not negatively affect the survival of the teeth after root canal treatment.\n © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.\n\nEbeleseder, Kurt\n\nSchwantzer, Gerold\n\n\n"
},
{
"text": "\n178404\nMortality Assessment of Paclitaxel-Coated Balloons: Patient-Level Meta-Analysis of the ILLUMENATE Clinical Program at 3 Years.\n\nGray, WA\n\nJaff, MR\n\nParikh, SA\n\nAnsel, GM\n\nBrodmann, M\n\nKrishnan, P\n\nRazavi, MK\n\nVermassen, F\n\nZeller, T\n\nWhite, R\n\nOuriel, K\n\nAdelman, MA\n\nLyden, SP\n\nBeiträge in Fachzeitschriften\nISI:000494957400010\n31567024.0\n10.1161/CIRCULATIONAHA.119.040518\nPMC6784772\nA recent summary-level meta-analysis comprising randomized, controlled trials (RCTs) of femoropopliteal paclitaxel-coated balloon and stent intervention identified excess late mortality in the paclitaxel-treated patients.\n We evaluated the safety of the Stellarex drug-coated balloon (DCB) for femoropopliteal artery disease with an independently performed meta-analysis of patient-level data from all patients in the Stellarex femoropopliteal clinical program. To compare mortality after DCB or uncoated percutaneous transluminal angioplasty (PTA), we aggregated data from 2 RCTs comprising 419 patients treated with DCB and 170 patients treated with PTA. In an additional analysis, data were aggregated from 6 poolable Stellarex DCB studies (2 RCTs, 3 single-arm studies, and 1 registry). All serious adverse events including deaths were adjudicated by a blinded, third-party, independent Clinical Events Committee. Kaplan-Meier estimates in the RCTs were compared with restricted mean survival time. Predictors of death were assessed with hazard ratios (HRs) and Cox proportional hazards modeling.\n Baseline characteristics were similar in the patients treated with DCB and PTA in the pooled RCT analysis, with the exception that the DCB cohort was younger (67.4±9.7 versus 69.4±9.4 years, P=0.02), smoked more frequently (86.6% versus 78.8%, P=0.02), and were less often treated for recurrent lesions (8.8% versus 14.7%, P=0.04). In the RCTs, patients treated with DCB had all-cause mortality rates that were not different from those of patients treated with PTA (Kaplan-Meier estimates 1.8±0.7% versus 1.3±0.9%, 6.5±1.2% versus 5.9±1.9%, and 9.3±1.5% versus 9.9±2.4% at 1, 2, and 3 years, respectively, P=0.86). All-cause mortality rates were similar in a 1906-patient pooled nonrandomized DCB data set (Kaplan-Meier estimates of 2.1%, 4.9%, and 7.0% at 1, 2, and 3 years, respectively). Clinical Events Committee-adjudicated causes of death were balanced between the DCB and PTA cohorts. Multivariable Cox modeling identified age (HR, 1.06; 95% CI, 1.04-1.08; P<0.001), diabetes mellitus (HR, 1.42; 95% CI, 1.01-2.00; P=0.04), congestive heart failure (HR, 1.88; 95% CI, 1.12-3.16; P=0.02), and renal insufficiency (HR, 2.00; 95% CI, 1.33-3.01; P<0.001) as predictors of mortality. Paclitaxel exposure was unrelated to mortality (HR, 1.04; 95% CI, 0.98-1.10; P=0.23).\n The mortality rates for patients treated with the DCB and uncoated PTA were indistinguishable over 3-year follow-up. Additional patient-level, adequately powered meta-analyses with larger RCT data sets will be needed to confirm the generalizability of these findings.\n URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110524, NCT01858363, NCT01858428, NCT03421561, NCT01912937, NCT01927068, and NCT02769273.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n32654\nThe role of nuclear factor-kappa B in bacterial translocation in cholestatic rats.\n\nWeber-Mzell, D\n\nZaupa, P\n\nPetnehazy, T\n\nKobayashi, H\n\nSchimpl, G\n\nFeierl, G\n\nKotanko, P\n\nHöllwarth, M\n\nBeiträge in Fachzeitschriften\nISI:000234444100008\n16333628.0\n10.1007/s00383-005-1599-y\nNone\nXanthinoxidase (XO) derived radical species are involved in bacterial translocation (BT) in cholestatic rats. The mechanism by which XO influences remains unclear. It has been shown recently that nuclear factor-kappa B (NF-kappaB), a ubiquitous transcription factor, can be activated by oxidative stress and thereby promote the process of BT. We investigated the effects of NF-kappaB inactivation on the incidence of BT in cholestatic rats. Sprague-Dawley rats were randomly assigned to one of eight groups: groups 1-4 were sham laparotomized rats either untreated (S1) or treated for 5 days with thalidomide (S2), curcumin (S3), or Inchin-ko (ICK; S4); groups 5-8 underwent common bile duct ligation (CBDL) for 5 days and were either untreated (C1) or treated with thalidomide (C2), curcumin (C3), or ICK (C4). After 5 days bacteriological cultures were performed from portal blood and V. cava, from the central mesenteric lymph node complex (MLN), spleen, and liver. The intensity of the activated NF-kappaB-subunit p65/p50 in the ileum mucosa was estimated by light microscopy and a scoring system from 1 to 20. Malondialdehyde (MDA) and myeloperoxidase activity (MPO) in the ileum were evaluated and expressed as U/g dry weight. Thalidomide and ICK reduced in CBDL-rats significantly the BT rate (63% vs. 18%, 63% vs. 30%, P<0.01). Enzyme estimations (MDA, MPO, and GSH) in sham operated animals showed no significant changes in the untreated groups compared with the treated groups. CBDL-rats pre-treatment with all three compounds caused a significant increase of MDA levels if groups were compared with the untreated C1-group (C1 31.6+/-7.7, C2 54.5+/-12.2, C3 53.3+/-11.2, and C4 47.2+/-9.4). GSH was reduced after the pre-treatment by all compounds but only significantly after curcumin pre-treatment (C1 vs. C3: 13.9+/-1.8 vs. 7.1+/-1.8; P<0.05). MPO estimations were significantly higher in the untreated C1-group if compared with groups C2, C3, and C4 (C1 1036.4+/-340.9, C2 709.9+/-125.9, C3 545.2+/-136.6, and C4 556.7+/-247.4; P<0.05). Thalidomide inhibited significantly the activation of NF-kappaB (C2 vs. C1: 6.0+/-4.5 vs. 12.7+/-5.3; P<0.01). Likewise, Curcumin and ICK suppressed NF-kappaB activation, but this did not reach significance in this experiment. NF-kappaB is involved in the process of BT in cholestatic rats and may be activated by XO derived ROS. We assume that the activated NF-kappaB initiates transcription of target genes inducing cytokine production, which in turn disrupts the tight junctions leading to BT from the intestinal lumen to the MLNs and circulation.\n\nFeierl, Gebhard\n\nHöllwarth, Michael\n\nSperl, Daniela Ingrid\n\nZaupa, Paola\n\n\n"
},
{
"text": "\n129214\nAssessment of glucose metabolism in polycystic ovary syndrome: HbA1c or fasting glucose compared with the oral glucose tolerance test as a screening method.\n\nLerchbaum, E\n\nSchwetz, V\n\nGiuliani, A\n\nObermayer-Pietsch, B\n\nBeiträge in Fachzeitschriften\nISI:000323596400026\n23756702.0\n10.1093/humrep/det255\nNone\nAre HbA1c and fasting glucose (FG) useful in predicting the presence of prediabetes and type 2 diabetes (T2DM) in a large cohort of women with polycystic ovary syndrome (PCOS)?\n HbA1c and FG are not suitable as screening tools for prediabetes in a large cohort of PCOS women but do show a good level of agreement with T2DM.\n Women with PCOS have an increased risk of prediabetes and T2DM. As performing an oral glucose tolerance test (OGTT) is time consuming, HbA1c and FG have been suggested as screening tools for prediabetes and T2DM.\n This was a cross-sectional study of 671 women with PCOS conducted from 2006 to 2012.\n The study was carried out at the endocrinological outpatient department of the Medical University of Graz, Austria. We performed 75 g 2-h OGTTs and measured HbA1c in 671 women with PCOS aged 16-45 years with a median BMI of 24.2 (21.3-30.1) kg/m². PCOS was defined according to the Rotterdam criteria. Prediabetes (FG 100-125 mg/dl and/or 2-h glucose 140-199 mg/dl and/or HbA1c 5.7-6.4%) and T2DM (FG ≥ 126 mg/dl and/or 2-h glucose ≥200 mg/dl and/or HbA1c ≥ 6.5%) were diagnosed according to the American Diabetes Association (ADA) criteria. Levels of agreement between different definitions were analyzed using κ-index.\n According to the ADA criteria, we found prediabetes and T2DM in 12.8% (n = 76) and 1.5% (n = 9) of PCOS women, respectively. When using elevated HbA1c (5.7-6.4%) for defining prediabetes, 19 (3.2%) of all PCOS women had prediabetes with a κ-index of 0.36. When using elevated FG (100-125 mg/dl) for defining prediabetes, 31 (5.2%) of all the PCOS women were diagnosed with prediabetes with a κ-index of 0.05. Further, elevated HbA1c (≥6.5% defining T2DM) was found in six (0.9%) PCOS women (κ-index 0.80), and elevated FG (≥126 mg/dl diagnosing T2DM) was found in seven PCOS women (1%; κ-index 0.82).\n Our results are limited to an Austrian cohort of PCOS women diagnosed by Rotterdam criteria with a median BMI in the normal weight range.\n Our results are in line with results from previous smaller PCOS cohorts. Our findings do not support the recommendation that FG or HbA1c can be used for the screening of prediabetes in women with PCOS. For such women, OGTT should be performed for screening of prediabetes. Whether this finding is generalizable to other cohorts remains to be determined in further studies.\n\nLerchbaum, Elisabeth\n\nObermayer-Pietsch, Barbara\n\nTheiler-Schwetz, Verena\n\n\n"
},
{
"text": "\n169482\nFormation of different abzymes in autoimmune-prone MRL-lpr/lpr mice is associated with changes in colony formation of haematopoietic progenitors.\n\nAndryushkova, AA\n\nKuznetsova, IA\n\nBineva, VN\n\nToporkova, LB\n\nSakhno, LV\n\nTikhonova, MA\n\nChernykh, ER\n\nOrlovskaya, IA\n\nNevinsky, GA\n\nBeiträge in Fachzeitschriften\nISI:000249014400014\n17635644.0\n10.1111/j.1582-4934.2007.00048.x\nPMC3922359\nIt was shown that IgGs from the sera of 2-7-month-old control non-autoimmune (CBA x C57BL)F1 and BALB/c mice and 2-3-month-old autoimmune prone MRL-lpr/lpr mice (conditionally healthy mice) are catalytically inactive. During spontaneous development of deep systemic lupus erythematosus (SLE)-like pathology a specific reorganization of immune system of these mice leads to conditions associated with a production of IgGs hydrolyzing DNA, ATP and polysaccharides with low catalytic activities (conditionally pre-diseased mice).A significant increase in DNase, ATPase and amylase IgG relative activities associated with a transition from pre-diseased to deep diseased mice is correlated with additional changes in differentiation and proliferation of mice bone marrow haematopoietic stem cells (HSCs) and lymphocyte proliferation in different organs. The highest increase in all abzyme activities was found in mice immunized with DNA, which in comparison with pre-diseased and diseased mice are characterized by a different profile of HSC differentiation and by a suppression of cell apoptosis. Abzyme activities in the serum of pregnant females were comparable with those for pre-diseased mice, but the profile of HSC differentiation and cell apoptosis levels in pregnant and pre-diseased mice were quite different. Right after the beginning of lactation (4 days after delivery) and in a late time of lactation (14 days after delivery) there was an observed increase in cell apoptosis and two different stages of significant change in the HSC differentiation profiles; the first stage was accompanied with a significant increase and the second with a remarkable decrease in abzyme activities. Overall, all mouse groups investigated are characterized by a specific relationship between abzyme activities, HSC differentiation profiles, levels of lymphocyte proliferation, and cell apoptosis in different organs. From our point of view, the appearance of ATPase, DNase activities may be considered the earliest statistically significant marker of mouse spontaneous SLE and a further significant increase in their activities correlates with the appearance of SLE visible markers and with an increase in concentrations of anti-DNA Abs and urine protein. However, development of autoimmune (AI)-reactions and the increase in the sera anti-DNA antibodies (Abs) and in the abzyme activities in pregnant and lactating mice do not associate with SLE visible markers and proteinuria. The possible differences in immune system reorganizations during pre-disease, disease, pregnancy and lactation leading to production of different auto-antibodies and abzymes are discussed.\n\n\n"
},
{
"text": "\n182225\nAge-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study.\n\nBeaudet, G\n\nTsuchida, A\n\nPetit, L\n\nTzourio, C\n\nCaspers, S\n\nSchreiber, J\n\nPausova, Z\n\nPatel, Y\n\nPaus, T\n\nSchmidt, R\n\nPirpamer, L\n\nSachdev, PS\n\nBrodaty, H\n\nKochan, N\n\nTrollor, J\n\nWen, W\n\nArmstrong, NJ\n\nDeary, IJ\n\nBastin, ME\n\nWardlaw, JM\n\nMunõz Maniega, S\n\nWitte, AV\n\nVillringer, A\n\nDuering, M\n\nDebette, S\n\nMazoyer, B\n\nBeiträge in Fachzeitschriften\nISI:000536353400001\n32425831.0\n10.3389/fpsyt.2020.00342\nPMC7212692\nParameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20, 05 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process.\n Copyright © 2020 Beaudet, Tsuchida, Petit, Tzourio, Caspers, Schreiber, Pausova, Patel, Paus, Schmidt, Pirpamer, Sachdev, Brodaty, Kochan, Trollor, Wen, Armstrong, Deary, Bastin, Wardlaw, Munõz Maniega, Witte, Villringer, Duering, Debette and Mazoyer.\n\nPirpamer, Lukas\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n129415\nEffect of B-Vitamins and Lowering Homocysteine on Cognitive Impairment in Patients With Previous Stroke or Transient Ischemic Attack: A Prespecified Secondary Analysis of a Randomized, Placebo-Controlled Trial and Meta-Analysis.\n\nHankey, GJ\n\nFord, AH\n\nYi, Q\n\nEikelboom, JW\n\nLees, KR\n\nChen, C\n\nXavier, D\n\nNavarro, JC\n\nRanawaka, UK\n\nUddin, W\n\nRicci, S\n\nGommans, J\n\nSchmidt, R\n\nAlmeida, OP\n\nvan Bockxmeer, FM\n\non Behalf of the VITATOPS Trial Study Group\n\nBeiträge in Fachzeitschriften\nISI:000329982400038\n23765945.0\n10.1161/STROKEAHA.113.001886\nNone\nBackground and Purpose High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack 6 months previously. Methods A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 g) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score <24 on 2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. Results A total of 3089 participants (38%) voluntarily undertook the MMSE >6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE 24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 mol/L versus 14.2 mol/L; P<0.001) but no change from baseline in the mean MMSE score (-0.22 points versus -0.25 points; difference, 0.03; 95% confidence interval, -0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69-1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67-1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75-1.27; P=0.855). Conclusions Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. Clinical Trial Registration URL: http://www.controlled-trials.com. Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097669.\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n159306\nComparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.\n\nde Vries, PS\n\nSabater-Lleal, M\n\nChasman, DI\n\nTrompet, S\n\nAhluwalia, TS\n\nTeumer, A\n\nKleber, ME\n\nChen, MH\n\nWang, JJ\n\nAttia, JR\n\nMarioni, RE\n\nSteri, M\n\nWeng, LC\n\nPool, R\n\nGrossmann, V\n\nBrody, JA\n\nVenturini, C\n\nTanaka, T\n\nRose, LM\n\nOldmeadow, C\n\nMazur, J\n\nBasu, S\n\nFrånberg, M\n\nYang, Q\n\nLigthart, S\n\nHottenga, JJ\n\nRumley, A\n\nMulas, A\n\nde Craen, AJ\n\nGrotevendt, A\n\nTaylor, KD\n\nDelgado, GE\n\nKifley, A\n\nLopez, LM\n\nBerentzen, TL\n\nMangino, M\n\nBandinelli, S\n\nMorrison, AC\n\nHamsten, A\n\nTofler, G\n\nde Maat, MP\n\nDraisma, HH\n\nLowe, GD\n\nZoledziewska, M\n\nSattar, N\n\nLackner, KJ\n\nVölker, U\n\nMcKnight, B\n\nHuang, J\n\nHolliday, EG\n\nMcEvoy, MA\n\nStarr, JM\n\nHysi, PG\n\nHernandez, DG\n\nGuan, W\n\nRivadeneira, F\n\nMcArdle, WL\n\nSlagboom, PE\n\nZeller, T\n\nPsaty, BM\n\nUitterlinden, AG\n\nde Geus, EJ\n\nStott, DJ\n\nBinder, H\n\nHofman, A\n\nFranco, OH\n\nRotter, JI\n\nFerrucci, L\n\nSpector, TD\n\nDeary, IJ\n\nMärz, W\n\nGreinacher, A\n\nWild, PS\n\nCucca, F\n\nBoomsma, DI\n\nWatkins, H\n\nTang, W\n\nRidker, PM\n\nJukema, JW\n\nScott, RJ\n\nMitchell, P\n\nHansen, T\n\nO'Donnell, CJ\n\nSmith, NL\n\nStrachan, DP\n\nDehghan, A\n\nBeiträge in Fachzeitschriften\nISI:000392405300006\n28107422.0\n10.1371/journal.pone.0167742\nPMC5249120\nAn increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91, 53 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n139747\nAssociation of LDL cholesterol and inflammation with cardiovascular events and mortality in hemodialysis patients with type 2 diabetes mellitus.\n\nKrane, V\n\nWinkler, K\n\nDrechsler, C\n\nLilienthal, J\n\nMärz, W\n\nWanner, C\n\nGerman Diabetes and Dialysis Study Investigators\n\nBeiträge in Fachzeitschriften\nISI:000271485000017\n19781835.0\n10.1053/j.ajkd.2009.06.029\nNone\nIn the general population, C-reactive protein (CRP) in addition to low-density lipoprotein (LDL) cholesterol level is useful in predicting cardiovascular events. In hemodialysis patients, the additive value is unknown. The association between LDL cholesterol level and outcome previously was suggested to be inverse and confounded by inflammation.\n Prospective cohort study.\n 1, 55 hemodialysis patients with type 2 diabetes mellitus randomly assigned to atorvastatin versus placebo in the German Diabetes Dialysis Study.\n Baseline LDL cholesterol level.\n Combined vascular end point (cardiac death, myocardial infarction, and stroke), mortality, myocardial infarction, sudden death, and stroke.\n During 4 years, 465 combined vascular events, 612 deaths, 160 sudden deaths, 200 myocardial infarctions, and 99 strokes occurred. Median LDL cholesterol level was 123 mg/dL. LDL cholesterol level (millimoles per liter and quartiles) was not predictive of outcome. This was analyzed further in patients with and without inflammation. In patients with inflammation (CRP level > 5 mg/L), the adjusted relative risk of combined vascular events was 29% greater compared with those without inflammation and a low LDL cholesterol level (LDL cholesterol < or = 123 mg/dL). This was irrespective of whether LDL cholesterol level was low or high (hazard ratio [HR] for LDL < 123 mg/dL [HR (for LDL< or =123 mg/dL)], 1.29, with 95% confidence interval [CI], 0.98 to 1.70; HR(LDL>123 mg/dL), 1.29, with 95% CI, 0.99 to 1.69). Similar results were found for all-cause death (HR(LDL< or =123 mg/dL), 1.47 [95% CI, 1.16 to 1.86]; HR(LDL>123 mg/dL), 1.48 [95% CI, 1.16 to 1.88]), sudden death (HR(LDL< or =123 mg/dL), 1.98 [95% CI, 1.23 to 3.20]; HR(LDL>123 mg/dL), 1.66 [95% CI, 1.01 to 2.75]), and myocardial infarction (HR(LDL< or =123 mg/dL), 1.74 [95% CI, 1.14 to 2.66]; HR(LDL>123 mg/dL), 1.54 [95% CI, 0.99 to 2.38]). In patients without inflammation, the respective risks did not differ significantly between patients with varying LDL cholesterol levels. However, there was a trend toward an increased risk of myocardial infarction (HR(LDL>123 mg/dL), 1.45 [95% CI, 0.95 to 2.21]) in patients with high compared with low LDL cholesterol levels. P values for the interaction between CRP and LDL cholesterol levels were 0.9 (composite vascular end point), 0.5 (mortality), 0.9 (sudden death), 0.09 (stroke), and 0.2 (myocardial infarction).\n Selected patient cohort, post hoc analysis.\n Because CRP level more than LDL cholesterol level determined outcome, the value of regular LDL cholesterol measurements in long-term hemodialysis patients with type 2 diabetes needs reassessment.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n167338\nChanges in the tryptophan-kynurenine axis in association to therapeutic response in clinically depressed patients undergoing psychiatric rehabilitation.\n\nReininghaus, B\n\nRiedrich, K\n\nDalkner, N\n\nBengesser, SA\n\nBirner, A\n\nPlatzer, M\n\nHamm, C\n\nGostner, JM\n\nFuchs, D\n\nReininghaus, EZ\n\nBeiträge in Fachzeitschriften\nISI:000436913400004\n29753175.0\n10.1016/j.psyneuen.2018.04.029\nNone\nIn recent decades a number of studies have shown an association between the Tryptophan (Trp)-Kynurenine (Kyn) axis and neuropsychiatric disorders. However, the role of the Trp-Kyn pathway on the affective status in a general psychiatric cohort requires clarification. This study aimed to measure peripheral changes in Trp, Kyn and the Kyn/Trp-ratio as well as in the inflammatory markers high sensitive C-reactive protein (hsCRP) and interleukine-6 (IL-6) in individuals undergoing a six-week course of intensive treatment program comparing subgroups of treatment responders and non-responders.\n In this investigation 87 currently depressed individuals with a life-time history of depressive disorders were divided into treatment responders (n = 48) and non-responders (n = 39). The individuals were selected for an extreme group comparison out of 598 patients undergoing a 6-week psychiatric rehabilitation program in Austria. Responders were defined according to great changes in Becks Depression Inventory (BDI-II) between time of admission and discharge (BDI-II > 29 to BDI-II <14), while non-responders had no or minimal changes (BDI >20, max. 4 points change over time). Differences in the levels of Trp, Kyn, and the Kyn/Trp ratio as well as levels of hsCRP and IL-6, were compared between groups. Differences were analyzed at the time of admission as well as at discharge.\n A significant group x time interaction was found for Kyn [F(1.82) = 5.79; p = 0.018] and the Kyn/Trp ratio [F(1.85) = 4.01, p = 0.048]. Importantly, Kyn increased significantly in the non-responder group, while the Kyn/Trp ratio decreased significantly in the responder group over time. Furthermore, changes in Kyn as well as hsCRP levels correlated significantly with changes in the body mass index over time (Kyn: r=0.24, p = 0.030; hsCRP: r=0.25, p = 0.021). No significant interactions were found for Trp and hsCRP, although they increased significantly over time.\n Given the limitations of the study, we could show that the therapeutic response to a multimodal treatment in clinically depressed patients not receiving cytokine treatment is associated with changes in Kyn levels and the Kyn/Trp ratio as well as with hsCRP. However, it is too early to draw any causal conclusion. Future research should clarify relevant clinical and neurobiological parameters associated with changes in Kyn levels and Kyn/Trp ratio, especially in regard to clinical response.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\nBengesser, Susanne\n\nBirner, Armin\n\nDalkner, Nina\n\nHamm, Carlo\n\nPlatzer, Martina\n\nReininghaus, Eva\n\n\n"
},
{
"text": "\n127\nActivation of microsomal cytochrome P450 mono-oxygenase by Ca2+ store depletion and its contribution to Ca2+ entry in porcine aortic endothelial cells.\n\nHoebel, BG\n\nKostner, GM\n\nGraier, WF\n\nBeiträge in Fachzeitschriften\nISI:A1997XQ88700010\n9283690.0\n10.1038/sj.bjp.0701304\nPMC1564862\n1. We investigated how microsomal cytochrome P450 mono-oxygenase (Cyp450 MO) is regulated in cultured porcine aortic endothelial cells. The hypothesis that a Cyp450 MO-derived metabolite links Ca2+ store depletion and Ca2+ entry was studied further. 2. Microsomal Cyp450 MO was monitored fluorometrically by dealkylation of 1-ethoxypyrene-3, , -tris-(dimethyl-sulphonamide; EPSA) in saponin permeabilized cells or in subcellular compartments. Endothelial Ca2+ signalling was measured by a standard fura-2 technique, membrane potential was determined with the potential-sensitive fluorescence dye, bis-(1, -dibutylbarbituric acid) pentamethine oxonol (DiBAC4(5)) and tyrosine kinase was quantified by measuring the phosphorylation of a immobilized substrate with a horseradish peroxidase labelled phosphotyrosine specific antibody. 3. Depletion of cellular Ca2+ pools with inositol 1, , -trisphosphate (IP3), thapsigargin or cyclopiazonic acid activated microsomal Cyp450 MO. Similar to direct Ca2+ store depletion, chelating of intramicrosomal Ca2+ with oxalate stimulated Cyp450 MO activity, while changing cytosolic free Ca2+ failed to influence Cyp450 MO activity. These data indicate that microsomal Cyp450 MO is activated by depletion of IP3-sensitive stores. 4. Besides the common cytochrome P450 inhibitors, econazole, proadifen and miconazole, thiopentone sodium and methohexitone inhibited Cyp450 MO in a concentration-dependent manner. The physiological substrate of Cyp450 MO, arachidonic acid, inhibited EPSA dealkylation. In contrast to most other cytochrome P450 inhibitors used in this study, thiopentone sodium did not directly interfere with Ca2+ entry pathways, membrane hyperpolarization due to K+ channel activation or tyrosine kinase activity. 5. Inhibition of Cyp450 MO by thiopentone sodium diminished Ca2+/Mn2+ entry to Ca2+ store depletion by 43%, while it did not interfere with intracellular Ca2+ release by IP3 or thapsigargin. 6. Cyp450 MO inhibition with thiopentone sodium diminished autacoid-induced membrane hyperpolarization. 7. Induction of Cyp450 MO with dexamethasone/clofibrate for 72 h yielded increases in thapsigargin-induced Cyp450 MO activity (by 35%), Ca2+/Mn2+ entry (by 105%) and membrane hyperpolarization (by 40%). 8. The Cyp450 MO-derived compounds, 11, 2 and 5, -epoxyeicosatrienoic acids (EETs) yielded membrane hyperpolarization, insensitive to thiopentone sodium. 9. These data demonstrate that endothelial Cyp450 MO is activated by Ca2+ store depletion and Cyp450 MO produced compounds that hyperpolarize endothelial cells. 10. The data presented and our previous findings indicate that Cyp450 MO plays a crucial role in the regulation of store-operated Ca2+ influx. We propose that Cyp450 MO-derived EETs constitute a signal for Ca2+ entry activation and increase the driving force for Ca2+ entry by membrane hyperpolarization in porcine aortic endothelial cells.\n\nGraier, Wolfgang\n\nKostner, Gerhard\n\n\n"
}
]
}