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"text": "\n165207\nEnlargement of the WHO international repository for platelet transfusion-relevant bacteria reference strains.\n\nSpindler-Raffel, E\n\nBenjamin, RJ\n\nMcDonald, CP\n\nRamirez-Arcos, S\n\nAplin, K\n\nBekeredjian-Ding, I\n\nde Korte, D\n\nGabriel, C\n\nGathof, B\n\nHanschmann, KM\n\nHourfar, K\n\nIngram, C\n\nJacobs, MR\n\nKeil, SD\n\nKou, Y\n\nLambrecht, B\n\nMarcelis, J\n\nMukhtar, Z\n\nNagumo, H\n\nNiekerk, T\n\nRojo, J\n\nMarschner, S\n\nSatake, M\n\nSeltsam, A\n\nSeifried, E\n\nSharafat, S\n\nStörmer, M\n\nSüßner, S\n\nWagner, SJ\n\nYomtovian, R\n\nISBT Working Party Transfusion-Transmitted Infectious Diseases (WP-TTID), Subgroup on Bacteria\n\nBeiträge in Fachzeitschriften\nISI:000414569600003\n28960367.0\n10.1111/vox.12548\nNone\nInterventions to prevent and detect bacterial contamination of platelet concentrates (PCs) have reduced, but not eliminated the sepsis risk. Standardized bacterial strains are needed to validate detection and pathogen reduction technologies in PCs. Following the establishment of the First International Reference Repository of Platelet Transfusion-Relevant Bacterial Reference Strains (the 'repository'), the World Health Organization (WHO) Expert Committee on Biological Standardisation (ECBS) endorsed further repository expansion.\n Sixteen bacterial strains, including the four repository strains, were distributed from the Paul-Ehrlich-Institut (PEI) to 14 laboratories in 10 countries for enumeration, identification and growth measurement on days 2, 4 and 7 after low spiking levels [10-25 colony-forming units (CFU)/PC bag]. Spore-forming (Bacillus cereusPEI-B-P-07-S, Bacillus thuringiensisPEI-B-P-57-S), Gram-negative (Enterobacter cloacaePEI-B-P-43, Morganella morganiiPEI-B-P-74, PEI-B-P-91, Proteus mirabilisPEI-B-P-55, Pseudomonas fluorescensPEI-B-P-77, Salmonella choleraesuisPEI-B-P-78, Serratia marcescensPEI-B-P-56) and Gram-positive (Staphylococcus aureusPEI-B-P-63, Streptococcus dysgalactiaePEI-B-P-71, Streptococcus bovisPEI-B-P-61) strains were evaluated.\n Bacterial viability was conserved after transport to the participating laboratories with one exception (M. morganiiPEI-B-P-74). All other strains showed moderate-to-excellent growth. Bacillus cereus, B. thuringiensis, E. coli, K. pneumoniae, P. fluorescens, S. marcescens, S. aureus and S. dysgalactiae grew to >106 CFU/ml by day 2. Enterobacter cloacae, P. mirabilis, S. epidermidis, S. bovis and S. pyogenes achieved >106 CFU/ml at day 4. Growth of S. choleraesuis was lower and highly variable.\n The WHO ECBS approved all bacterial strains (except M. morganiiPEI-B-P-74 and S. choleraesuisPEI-B-P-78) for repository enlargement. The strains were stable, suitable for spiking with low CFU numbers, and proliferation was independent of the PC donor.\n © 2017 International Society of Blood Transfusion.\n\n\n"
},
{
"text": "\n167871\nA clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts.\n\nPabinger, I\n\nvan Es, N\n\nHeinze, G\n\nPosch, F\n\nRiedl, J\n\nReitter, EM\n\nDi Nisio, M\n\nCesarman-Maus, G\n\nKraaijpoel, N\n\nZielinski, CC\n\nBüller, HR\n\nAy, C\n\nBeiträge in Fachzeitschriften\nISI:000436642600007\n29885940.0\n10.1016/S2352-3026(18)30063-2\nPMC7338218\nVenous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thromboembolism.\n We used data from the prospective Vienna Cancer and Thrombosis Study (CATS) cohort (n=1423) to select prognostic variables for inclusion in the model. We then validated the model in the prospective Multinational Cohort Study to Identify Cancer Patients at High Risk of Venous Thromboembolism (MICA) cohort (n=832). We calculated c-indices to show how the predicted incidence of objectively confirmed venous thromboembolism at 6 months compared with the cumulative 6-month incidences observed in both cohorts.\n Two variables were selected for inclusion in the final clinical prediction model: tumour-site risk category (low or intermediate vs high vs very high) and continuous D-dimer concentrations. The multivariable subdistribution hazard ratios were 1·96 (95% CI 1·41-2·72; p=0·0001) for high or very high versus low or intermediate and 1·32 (95% CI 1·12-1·56; p=0·001) per doubling of D-dimer concentration. The cross-validated c-indices of the final model were 0·66 (95% CI 0·63-0·67) in CATS and 0·68 (0·62-0·74) in MICA. The clinical prediction model was adequately calibrated in both cohorts.\n An externally validated clinical prediction model incorporating only one clinical factor (tumour-site category) and one biomarker (D-dimer) predicted the risk of venous thromboembolism in ambulatory patients with solid cancers. This simple model is a considerable improvement on previous models for predicting cancer-associated venous thromboembolism, and could aid physicians in selection of patients who will likely benefit from thromboprophylaxis.\n Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals.\n Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.\n\nPosch, Florian\n\n\n"
},
{
"text": "\n171036\nOncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.\n\nWeber, WP\n\nHaug, M\n\nKurzeder, C\n\nBjelic-Radisic, V\n\nKoller, R\n\nReitsamer, R\n\nFitzal, F\n\nBiazus, J\n\nBrenelli, F\n\nUrban, C\n\nPaulinelli, RR\n\nBlohmer, JU\n\nHeil, J\n\nHoffmann, J\n\nMatrai, Z\n\nCatanuto, G\n\nGalimberti, V\n\nGentilini, O\n\nBarry, M\n\nHadar, T\n\nAllweis, TM\n\nOlsha, O\n\nCardoso, MJ\n\nGouveia, PF\n\nRubio, IT\n\nde Boniface, J\n\nSvensjö, T\n\nBucher, S\n\nDubsky, P\n\nFarhadi, J\n\nFehr, MK\n\nFulco, I\n\nGanz-Blättler, U\n\nGünthert, A\n\nHarder, Y\n\nHauser, N\n\nKappos, EA\n\nKnauer, M\n\nLandin, J\n\nMechera, R\n\nMeani, F\n\nMontagna, G\n\nRitter, M\n\nSaccilotto, R\n\nSchwab, FD\n\nSteffens, D\n\nTausch, C\n\nZeindler, J\n\nSoysal, SD\n\nLohsiriwat, V\n\nKovacs, T\n\nTansley, A\n\nWyld, L\n\nRomics, L\n\nEl-Tamer, M\n\nPusic, AL\n\nSacchini, V\n\nGnant, M\n\nBeiträge in Fachzeitschriften\nISI:000450079300002\n30182349.0\n10.1007/s10549-018-4937-1\nPMC6245050\nIndications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion.\n The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology.\n Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference.\n In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.\n\nBjelic-Radisic, Vesna\n\n\n"
},
{
"text": "\n184057\nCommon Mechanistic Pathways in Cancer and Heart Failure.\n\nde Boer, RA\n\nHulot, JS\n\nGabriele Tocchetti, C\n\nAboumsallem, JP\n\nAmeri, P\n\nAnker, SD\n\nBauersachs, J\n\nBertero, E\n\nCoats, AAJ\n\nČelutkienė, J\n\nChioncel, O\n\nDodion, P\n\nEschenhagen, T\n\nFarmakis, D\n\nBayes-Genis, A\n\nJäger, D\n\nJankowska, EA\n\nKitsis, RN\n\nKonety, SH\n\nLarkin, J\n\nLehmann, L\n\nLenihan, DJ\n\nMaack, C\n\nMoslehi, J\n\nMüller, OJ\n\nNowak-Sliwinska, P\n\nPiepoli, MF\n\nPonikowski, P\n\nPudil, R\n\nRainer, PP\n\nRuschitzka, F\n\nSawyer, D\n\nSeferovic, PM\n\nSuter, T\n\nThum, T\n\nvan der Meer, P\n\nVan Laake, LW\n\nvon Haehling, S\n\nHeymans, S\n\nLyon, AR\n\nBacks, J\n\nBeiträge in Fachzeitschriften\nISI:000588492800001\n33094495.0\n10.1002/ejhf.2029\nPMC7894564\nThe co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation, and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Further, genetic predisposition and clonal hematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Also, altered angiogenesis is a common hallmark for failing hearts and tumors and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the 2 pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. Also, preclinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including all ages, and men and women, with proper adjudication of both cancer and CV end points, are essential to accurately study these two pathologies at the same time.\n This article is protected by copyright. All rights reserved.\n\nRainer, Peter\n\n\n"
},
{
"text": "\n184622\nJejunal tube feeding in children and adolescents.\n\nBroekaert, I\n\nBildheim, V\n\nBrunert, A\n\nHauer, A\n\nSchwarz, C\n\nSchmidt-Choudhury, A\n\nBeiträge in Fachzeitschriften\nISI:000592158900003\nNone\n10.1007/s00112-020-01044-1\nNone\nJejunal tube feeding is increasingly becoming the standard of care for children in whom gastric tube feeding is insufficient to fulfil caloric needs. Jejunal tube feeding is defined as postpyloric feeding through a feeding tube with its tip placed distally to the Treitz ligament. The jejunal tube bypasses the stomach when gastric feeding is not tolerated or is associated with unacceptable complications including significant gastroesophageal reflux disease. There is growing evidence suggesting that feeding by jejunal tube is a safe and effective means of enteral feeding in children and adolescents; however, because of the frequent need for tube maintenance and replacement leading to increased morbidity, gastrojejunal tube feeding is more a temporary alternative to, for example, cutaneous jejunostomy and antireflux surgery. A number of factors should be considered before placement of a jejunal or a gastrojejunal tube. The symptoms of feeding failure, such as nausea, vomiting, gagging, retching and volume intolerance may be caused by anatomical or nongastrointestinal problems, which will need to be dealt with before considering placement of a jejunal tube. The decision to place a jejunal tube has to be made by a multidisciplinary team, working in close cooperation and providing active follow-up and care. The management of a child awaiting a jejunal feeding tube should begin well before its insertion. The multidisciplinary team should be familiar with and have access to a range of alternative strategies to the insertion of a jejunal feeding tube. These may include food or regimen changes, specific feeding therapy, speech and swallowing assessments and access to psychological support. The team should include a pediatric gastroenterologist, a dietitian, a psychologist, and a speech and language therapist. Adequate planning, including discussion of ethical issues, guarantees that all parties have a clear understanding of the indications and rationale for placement of a jejunal tube. In addition, ongoing and future strategies to increase possible oral feeding and enable weaning off the jejunal tube should be discussed. The aim of this article is to provide a comprehensive guide for healthcare professionals on the safe, effective, and appropriate use of jejunal feeding tubes in children and adolescents.\n\nHauer, Almuthe\n\nSchwarz, Christine\n\n\n"
},
{
"text": "\n187317\nThe European TeleCheck-AF project on remote app-based management of atrial fibrillation during the COVID-19 pandemic: centre and patient experiences.\n\nGawałko, M\n\nDuncker, D\n\nManninger, M\n\nvan der Velden, RMJ\n\nHermans, ANL\n\nVerhaert, DVM\n\nPison, L\n\nPisters, R\n\nHemels, M\n\nSultan, A\n\nSteven, D\n\nGupta, D\n\nHeidbuchel, H\n\nSohaib, A\n\nWijtvliet, P\n\nTieleman, R\n\nGruwez, H\n\nChun, J\n\nSchmidt, B\n\nKeaney, JJ\n\nMüller, P\n\nLodziński, P\n\nSvennberg, E\n\nHoekstra, O\n\nJansen, WPJ\n\nDesteghe, L\n\nde Potter, T\n\nTomlinson, DR\n\nNeubeck, L\n\nCrijns, HJGM\n\nPluymaekers, NAHA\n\nHendriks, JM\n\nLinz, D\n\nBeiträge in Fachzeitschriften\nNone\n33822029.0\n10.1093/europace/euab050\nPMC8083545\nTeleCheck-AF is a multicentre international project initiated to maintain care delivery for patients with atrial fibrillation (AF) during COVID-19 through teleconsultations supported by an on-demand photoplethysmography-based heart rate and rhythm monitoring app (FibriCheck®). We describe the characteristics, inclusion rates, and experiences from participating centres according the TeleCheck-AF infrastructure as well as characteristics and experiences from recruited patients.\n Three surveys exploring centre characteristics (n = 25), centre experiences (n = 23), and patient experiences (n = 826) were completed. Self-reported patient characteristics were obtained from the app. Most centres were academic (64%) and specialized public cardiology/district hospitals (36%). Majority of the centres had AF outpatient clinics (64%) and only 36% had AF ablation clinics. The time required to start patient inclusion and total number of included patients in the project was comparable for centres experienced (56%) or inexperienced in mHealth use. Within 28 weeks, 1930 AF patients were recruited, mainly for remote AF control (31% of patients) and AF ablation follow-up (42%). Average inclusion rate was highest during the lockdown restrictions and reached a steady state at a lower level after easing the restrictions (188 vs. 52 weekly recruited patients). Majority (>80%) of the centres reported no problems during the implementation of the TeleCheck-AF approach. Recruited patients [median age 64 (55-71), 62% male] agreed that the FibriCheck® app was easy to use (94%).\n Despite different health care settings and mobile health experiences, the TeleCheck-AF approach could be set up within an extremely short time and easily used in different European centres during COVID-19.\n © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n\nManninger-Wünscher, Martin\n\n\n"
},
{
"text": "\n187709\nLong-term outcome and predictors of long-term disease activity in natalizumab-treated patients with multiple sclerosis: real life data from the Austrian MS Treatment Registry.\n\nGuger, M\n\nEnzinger, C\n\nLeutmezer, F\n\nDi Pauli, F\n\nKraus, J\n\nKalcher, S\n\nKvas, E\n\nBerger, T\n\nAustrian MS Treatment Registry (AMSTR)\n\nBeiträge in Fachzeitschriften\nISI:000642361400002\n33890167.0\n10.1007/s00415-021-10559-w\nNone\nTo evaluate long-term effectiveness of natalizumab (NTZ) and to determine demographic, clinical, and radiological predictors regarding long-term disease activity (≥ 7 years) in a nationwide observational cohort, using data collected prospectively in a real-life setting.\n We analysed data from 230 patients from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), who had started treatment with NTZ at any time since 2006 and stayed on NTZ for at least 7 years without treatment gap of more than three months.\n Estimated mean annualised relapse rates (ARR) over a mean treatment period of 9.3 years were 0.07 for NTZ. Sustained EDSS progression for 12 weeks was observed in 36 (19%) patients and for 24 weeks in 31 (16.3%) cases. Sustained EDSS regression for 12 and 24 weeks was seen in 45 (23.7%) and 42 (22.1%) cases. The baseline parameters ≥ 1 Gadolinium-enhancing MRI lesion(s) [incidence rate ratio (IRR) of 0.409 (95% CI 0.283-0.593), p = 0.001], ARR ≤ 1 in the prior 12 month before treatment initiation with NTZ [IRR of 0.353 (95% CI 0.200-0.623), p = 0.001] and EDSS ≤ 1 [incidence rate ratio (IRR) of 0.081 (95% CI 0.011-0.581), p = 0.012] were significantly associated with a reduced relapse risk, whereas a disease duration ≤ 5 years increased significantly the ARR [IRR of 1.851 (95% CI 1.249-2.743), p = 0.002]. The only predictive baseline parameter for experiencing EDSS progression (sustained for 12 and 24 weeks) was age > 35 years [HR of 2.482 (95% CI 1.110-5.549), p = 0.027, and HR of 2.492 (95% CI 1.039-5.978), p = 0.041, respectively].\n These real-life data show a stable disease course regarding relapse activity and disease progression under NTZ treatment for more than 7 years. The main predictors for disease activity were higher relapse rate before treatment initiation, higher disability, shorter disease duration and absence of Gadolinium-enhancing MRI lesions at baseline. Older age at NTZ start was the only significant risk factor for disease progression over long-term.\n\nEnzinger, Christian\n\n\n"
},
{
"text": "\n5335\nDiffuse hyperplastic oncocytosis of the parotid gland\n\nKontaxis, A\n\nZanarotti, U\n\nKainz, J\n\nBeham, A\n\nBeiträge in Fachzeitschriften\nISI:000220437000005\n15042484.0\n10.1055/s-2004-814267\nNone\nBackground: Oncocytes are epithelial cells characterized by an granular, eosinophilic cytoplasma, and a centrally situated, pycnotic nucleus. These cells were first observed by Hamperl 1931 in the salivary glands [1]. Ultrastructural studies have shown that the cytoplasma of these cells is filled with numerous large and bizarre mitochondria. The exact biological significance of oncocytes is unknown-Becker, Donath and Seifert suggest an intracellular metabolic disturbance associated with mitochondriopathy, caused by an age dependent metabolic defect [2]. Oncocytes are not specific for the salivary glands; they are also found in the thyroid gland, parathyroid gland, liver, pancreas, esophagus and the kidney [3]. Solitary oncocytes appear most often as incidental findings in aging salivary tissue, they are present in persons older than 70 years up to 80%. The diffuse hyperplastic oncocytosis of the parotid gland represents an extremely rare, non-tumorous alteration of the parotid gland. Caused by an extensive metaplasia of acinic and ductal cells nearly the entire gland consists of oncocytes. Clinically it is characterized by swelling of the parotid gland. Oncocytic adenomatous hyperplasia is a different disease. It represents a multifocal oncocytic proliferation of the duct system. In contrast to diffuse oncocytosis remnants of the original salivary tissue with acini and fatty tissue are usually present between the oncocytic nodules. Typical oncocytomas may possibly develop from such oncocytic proliferation by a tendency to confluent growth [2].Methods: Cases of diffuse hyperplastic oncocytosis of the parotid gland were identified by literature review.Results: Worldwide diffuse hyperplastic oncocytosis of the parotid gland has been observed in 8 cases (Fig.1) as of today.Patient: We report and discuss the case of a 78-year-old male, who was refered to our hospital because of a painless mass of the left parotid gland. MRI showed a tumorous lesion with a diameter of about 5 cm. Lateral parotidectomy was performed. Histology revealed an extremely rare case of diffuse hyperplastic oncocytosis. There has been no recurrence Of tumor after 2 years.Conclusions: Diffuse hyperplastic oncocytosis of the parotid gland is an extremely rare benign disorder, complete excision of the tumor-like lesion is curative. In literature there has been no report of recurrence, malignant transformation or metastasizing illness.\n\nKainz, Josef\n\n\n"
},
{
"text": "\n19005\nHeparan sulfate levels in mucopolysaccharidoses and mucolipidoses.\n\nTomatsu, S\n\nGutierrez, MA\n\nIshimaru, T\n\nPeña, OM\n\nMontaño, AM\n\nMaeda, H\n\nVelez-Castrillon, S\n\nNishioka, T\n\nFachel, AA\n\nCooper, A\n\nThornley, M\n\nWraith, E\n\nBarrera, LA\n\nLaybauer, LS\n\nGiugliani, R\n\nSchwartz, IV\n\nFrenking, GS\n\nBeck, M\n\nKircher, SG\n\nPaschke, E\n\nYamaguchi, S\n\nUllrich, K\n\nIsogai, K\n\nSuzuki, Y\n\nOrii, T\n\nNoguchi, A\n\nBeiträge in Fachzeitschriften\nISI:000231759900015\n16151906.0\n10.1007/s10545-005-0069-y\nNone\nGlycosaminoglycans are accumulated in both mucopolysaccharidoses (MPS) and mucolipidoses (ML). MPS I, II, III and VII and ML II and ML III patients cannot properly degrade heparan sulphate (HS). In spite of the importance of HS storage in the metabolic pathway in these diseases, blood and urine HS levels have not been determined systematically using a simple and economical method. Using a new ELISA method using anti-HS antibodies, HS concentrations in blood and urine were determined in MPS and ML II and ML III patients. HS concentrations were determined in 156 plasma samples from MPS I (n = 23), MPS II (n = 26), MPS III (n = 24), MPS IV (n = 62), MPS VI (n = 5), MPS VII (n = 5), ML II (n = 8) and ML III (n = 3), and 205 urine samples from MPS I (n = 33), MPS II (n = 33), MPS III (n = 30), MPS IV (n = 82), MPS VI (n = 7), MPS VII (n = 9), ML II (n = 8) and ML III (n = 3). The ELISA method used monoclonal antibodies against HS. MPS I, II, III and VII and ML II and III patients had significant elevation in plasma HS, compared to the age-matched controls (p < 0.0001). Eighty-three out of 89 (93.3%) of individual values in the above MPS types and ML were above the mean +2SD of the controls. In urine samples, 75% of individual values in patients with those types were above the mean +2SD of the controls. In contrast to the previous understanding of the HS metabolic pathway, plasma HS levels in all five MPS VI and 15% of MPS IV patients were elevated above the mean +2SD of the controls. These findings suggest that HS concentration determined by ELISA, especially in plasma, could be a helpful marker for detection of the most severe MPS I, II, III, VI and VII and ML II, distinguishing them from normal populations.\n\n\n"
},
{
"text": "\n64050\nLeflunomide, a novel immunomodulating agent, prevents the development of allergic sensitization in an animal model of allergic asthma.\n\nEber, E\n\nUhlig, T\n\nMcMenamin, C\n\nSly, PD\n\nBeiträge in Fachzeitschriften\nISI:000072609600018\n9543089.0\nNone\nNone\nBACKGROUND: Leflunomide is a new anti-inflammatory and immunomodulating agent which is showing promise in several immune disorders, especially rheumatoid arthritis. Its activity profile suggests it may be of use in modulating allergic sensitization. OBJECTIVE: To investigate the effectiveness of leflunomide in preventing the development of allergic sensitization. METHODS: Fifty-three brown Norway rats were sensitized by intraperitoneal injection of ovalbumin and adjuvant (ricin) on day 0. To determine the ability of leflunomide to inhibit primary allergic sensitization six rats were treated with A77 1726, the active metabolite of leflunomide, from day 0 through day 5, six were treated from day 5 through day 10, and nine rats acted as controls. On day 14, ovalbumin-specific serum antibody levels and the magnitude of the early-phase airway response (EAR) after inhalation allergen challenge were assessed. To determine the ability of acute topical treatment with leflunomide to inhibit mast cell degranulation, three groups of five animals received either vehicle, 100 microg A77 1726, or 1000 g A77 1726 60 min prior to aerosol allergen challenge. To determine the effects of leflunomide treatment in vivo on mast cell function in vitro, mast cells were obtained by bronchoalveolar lavage from 17 rats (nine treated with leflunomide and eight controls). Allergen-specific and non-specific degranulation (48/80 induced) were studied. RESULTS: In the leflunomide treated rats both ovalbumin-specific IgE and IgG levels were significantly reduced, and the increases in lung resistance and lung elastance were essentially abolished, compared to those of the control group. Non significant differences were found in any of the parameters between the two leflunomide treated groups. Topical pre-treatment with leflunomide did not prevent the allergen-induced EAR. Treatment with leflunomide in vivo prevented allergen-induced mast cell degranulation in vitro because the mast cells lacked IgE on their surface. Non allergen-specific degranulation was normal and allergen-induced degranulation could be restored by passive sensitization. CONCLUSIONS: These data suggests that leflunomide can prevent primary allergic sensitization and prevent allergen-induced EAR by inhibiting production of allergen-specific IgE antibodies. Further studies in atopic conditions are warranted.\n\nEber, Ernst\n\n\n"
},
{
"text": "\n65117\nClinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria\n\nMoslinger, D\n\nStockler-Ipsiroglu, S\n\nScheibenreiter, S\n\nTiefenthaler, M\n\nMuhl, A\n\nSeidl, R\n\nStrobl, W\n\nPlecko, B\n\nSuormala, T\n\nBaumgartner, ER\n\nBeiträge in Fachzeitschriften\nISI:000168525000002\nNone\n10.1007/s004310100740\nNone\nNewborn screening for biotinidase deficiency (BD) provides prevention of neurological sequelae in patients with low residual enzyme activity by early treatment with oral biotin substitution. Screening 1.1 million newborns in Austria and consecutive family studies led to the identifcation of 21 patients with profound BD (residual activity <10%) (incidence: 1:59, 00) and to 12 patients with partial BD (residual activity 10%-30%) (incidence 1:89, 00). Application of an HPLC assay using the natural substrate biocytin allowed exact quantification of extremely low residual biotinidase activities and thus subdivision of patients with profound BD into a group with a residual activity 0%-1% of normal activity (n = 5) and >1%-<10% (n = 16) respectively. Evaluation of clinical and neuropsychological outcome showed that only patients with a biotinidase activity <1% (n = 3/5) exhibited characteristic clinical symptoms within the first weeks of life, while five patients with a residual activity of 1.2%-.6% did not develop clinical symptoms even when not treated until 3.5-21 years. In all patients with residual activity <10% and biotin substitution within the first weeks of life, neuropsychological outcome was normal, while abnormal in three out of five patients tested for IQ and treated after the age of 3.5 years. In five out of nine patients with poor compliance or delayed or no treatment, visual and brainstem auditory evoked potentials were measured and were within age-related normal values. All patients with partial BD available for follow-up remained clinically and neuropsychologically asymptomatic without treatment at ages 2.5-10 years. Conclusion The incidence of biotinidase deficiency in Austria is comparable to other European countries. Subdivision of the group of patients with profound biotinidase deficiency suggests that only patients with residual activities <1% are prone to develop clinical symptoms early in life, while patients with residual activities >1% may remain asymptomatic even without treatment, as do patients with partial deficiency. Moderate mental retardation might represent a possible manifestation of cerebral dysfunction in patients with profound biotinidase deficiency.\n\nPlecko, Barbara\n\n\n"
},
{
"text": "\n66014\nChanges in lipid metabolism during 12 months of treatment with two oral contraceptives containing 30 micrograms ethinylestradiol and 75 micrograms gestodene or 150 micrograms desogestrel.\n\nMärz, W\n\nJung-Hoffmann, C\n\nHeidt, F\n\nGross, W\n\nKuhl, H\n\nBeiträge in Fachzeitschriften\nISI:A1990CT22800002\n2138973.0\n10.1016/0010-7824(90)90066-5\nNone\nThe effect of two oral contraceptives containing 30 micrograms ethinylestradiol + 75 micrograms gestodene (EE/GSD) or 30 micrograms ethinylestradiol + 150 micrograms desogestrel (EE/DG) upon serum lipids and lipoproteins were measured in 11 women each on days 1, 10, and 21 of the first, third, sixth, and twelfth treatment cycle and compared to the levels on days 1, 10, and 21 of the preceding control cycle. There was no change in total cholesterol (CH) and phospholipids (PL), while total triglycerides (TG) were significantly elevated only during treatment with EE/GSD. After 3 and 6 months of intake of both oral contraceptives, a transitory increase in the TG content of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and a decrease in LDL-PL was observed. After 12 months, VLDL-CH, VLDL-PL, and apolipoprotein B were significantly elevated, while VLDL-TG and all components of LDL were unchanged. Most of the components of high-density lipoprotein (HDL) were increased due to a rise in HDL3 and apolipoprotein A-II, while HDL2 and apolipoprotein A-I were not altered. There was no significant difference between the effects of the two preparations, although those of EE/GSD were mostly more pronounced. The time-dependent change in the effects of the oral contraceptives on various parameters of lipid metabolism demonstrates that the relevance of results of short-time studies may be questionable. There was also a significant alteration in some parameters between day 1 and 10 of the treatment cycles and a tendency to return to the pretreatment levels during the pill-free week, e.g., in total TG and in the PL component of VLDL, LDL and HDL. The increase in HDL, VLDL, and total TG reflects a slight preponderance of the effect of ethinylestradiol on lipid metabolism. The unchanged total CH and LDL-CH and the elevated HDL levels indicate that the risk of the development of atherosclerosis is in all probability not increased during treatment with both preparations.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n128001\nGender differences in clinicopathological features and survival in surgically treated patients with renal cell carcinoma: an analysis of the multicenter CORONA database.\n\nMay, M\n\nAziz, A\n\nZigeuner, R\n\nChromecki, T\n\nCindolo, L\n\nSchips, L\n\nDe Cobelli, O\n\nRocco, B\n\nDe Nunzio, C\n\nTubaro, A\n\nComan, I\n\nTruss, M\n\nDalpiaz, O\n\nHoschke, B\n\nGilfrich, C\n\nFeciche, B\n\nStoltze, A\n\nFenske, F\n\nFritsche, HM\n\nFigenshau, RS\n\nMadison, K\n\nSánchez-Chapado, M\n\nMartin, Mdel C\n\nSalzano, L\n\nLotrecchiano, G\n\nJoniau, S\n\nWaidelich, R\n\nStief, C\n\nBrookman-May, S\n\nMembers of the CORONA project the Young Academic Urologists Renal Cancer Group\n\nBeiträge in Fachzeitschriften\nISI:000325025500009\n23568445.0\n10.1007/s00345-013-1071-x\nNone\nTo investigate gender differences in clinicopathological features and to analyze the prognostic impact of gender in renal cell carcinoma (RCC) patients undergoing surgery.\n A total of 6, 34 patients (eleven centers; Europe and USA) treated by radical or partial nephrectomy were included in this retrospective study (median follow-up 59 months; IQR 30-106). Gender differences in clinicopathological parameters were assessed. Multivariable Cox regression models were applied to determine the influence of parameters on disease-specific survival (DSS) and overall survival (OS).\n A total of 3, 51 patients of the study group were male patients (60.2 %), who were significantly younger at diagnosis and received more frequently NSS than women. Significantly, more often high-grade tumors and simultaneous metastasis were present in men. Whereas tumor size and pTN stages did not differ between genders, clear-cell and chromophobe RCC was diagnosed less frequently, but papillary RCC more often in men. Gender also independently influenced DSS (HR 0.75, p < 0.001) and OS (HR 0.80, p < 0.001) with a benefit for women. However, inclusion of gender in multivariable models did not significantly gain predictive accuracies (PA) for DSS (0.868-0.870, p = 0.628) and OS (0.775-0.777, p = 0.522). Furthermore, no significantly different DSS and OS rates were found in patients undergoing NSS.\n This study demonstrates important gender differences in clinicopathological features and outcome of RCC patients with improved DSS and OS for women compared to men, even if solely patients with clear-cell RCC or M0-stage are taken into evaluation. However, inclusion of gender in multivariable models does not significantly gain PA of multivariable models.\n\nDalpiaz, Orietta\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n151535\nReference values of galectin-3 and cardiac troponins derived from a single cohort of healthy blood donors.\n\nMueller, T\n\nEgger, M\n\nLeitner, I\n\nGabriel, C\n\nHaltmayer, M\n\nDieplinger, B\n\nBeiträge in Fachzeitschriften\nISI:000375357900004\n26920637.0\n10.1016/j.cca.2016.02.014\nNone\nHere we describe the determination of upper reference limits (URL) for galectin-3, high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in a single cohort of healthy blood donors using routine assays.\n For this reference value study, we used a cohort of 402 consecutive blood donors (64% were male and 36% were female). The median individuals' age was 35.0 years (range, 18.0-64.4). Individuals of this reference population were free of cardiovascular disease, diabetes mellitus, renal disease, cancer, current infection and chronic inflammatory disease. Plasma concentrations of galectin-3 were measured with the "routine Galectin-3" assay (Abbott Diagnostics), of hs-cTnI with the "STAT High Sensitive Troponin-I" assay (Abbott Diagnostics), and of hs-cTnT with the "Troponin T hs" assay (Roche Diagnostics). URLs were calculated by using a non-parametric percentile method.\n The 97.5th percentile URL for galectin-3 was 16 ng/mL in males and 17 ng/mL in females; the 99 th percentile URL for hs-cTnI was 39 ng/L in males and 24 ng/L in females; and the 99 th percentile URL for hs-cTnT was 14 ng/L in males and 11 ng/L in females. Those individuals with hs-cTnI values ≥ 15 ng/L (n=8) were different from those individuals with hs-cTnT values ≥ 10 ng/L (n=7). Of the 402 individuals, none had galectin-3 values below the limit of detection (LOD, <1.0 ng/mL), 290 (72%) had hs-cTnI values below the LOD (i.e., 1.9 ng/L), and 359 (89%) had hs-cTnT values below the LOD (i.e., 5.0 ng/L).\n Plasma concentrations of galectin-3, hs-cTnI and hs-cTnT and corresponding 99 th percentile URLs were rather low in our cohort of healthy blood donors compared with previously published data. In our reference population, analyte plasma concentrations above the LOD were detectable in 100% of the individuals with the Abbott galectin-3 assay, but only in less than 50% for both the Abbott hs-cTnI assay and the Roche hs-cTnT assay.\n Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.\n\n\n"
},
{
"text": "\n167794\nGvmR - A Novel LysR-Type Transcriptional Regulator Involved in Virulence and Primary and Secondary Metabolism of <i>Burkholderia pseudomallei</i>.\n\nDuong, LT\n\nSchwarz, S\n\nGross, H\n\nBreitbach, K\n\nHochgräfe, F\n\nMostertz, J\n\nEske-Pogodda, K\n\nWagner, GE\n\nSteinmetz, I\n\nKohler, C\n\nBeiträge in Fachzeitschriften\nISI:000432293200002\n29867844.0\n10.3389/fmicb.2018.00935\nPMC5964159\nBurkholderia pseudomallei is a soil-dwelling bacterium able to survive not only under adverse environmental conditions, but also within various hosts which can lead to the disease melioidosis. The capability of B. pseudomallei to adapt to environmental changes is facilitated by the large number of regulatory proteins encoded by its genome. Among them are more than 60 uncharacterized LysR-type transcriptional regulators (LTTRs). Here we analyzed a B. pseudomallei mutant harboring a transposon in the gene BPSL0117 annotated as a LTTR, which we named gvmR (globally acting virulence and metabolism regulator). The gvmR mutant displayed a growth defect in minimal medium and macrophages in comparison with the wild type. Moreover, disruption of gvmR rendered B. pseudomallei avirulent in mice indicating a critical role of GvmR in infection. These defects of the mutant were rescued by ectopic expression of gvmR. To identify genes whose expression is modulated by GvmR, global transcriptome analysis of the B. pseudomallei wild type and gvmR mutant was performed using whole genome tiling microarrays. Transcript levels of 190 genes were upregulated and 141 genes were downregulated in the gvmR mutant relative to the wild type. Among the most downregulated genes in the gvmR mutant were important virulence factor genes (T3SS3, T6SS1, and T6SS2), which could explain the virulence defect of the gvmR mutant. In addition, expression of genes related to amino acid synthesis, glyoxylate shunt, iron-sulfur cluster assembly, and syrbactin metabolism (secondary metabolite) was decreased in the mutant. On the other hand, inactivation of GvmR increased expression of genes involved in pyruvate metabolism, ATP synthesis, malleobactin, and porin genes. Quantitative real-time PCR verified the differential expression of 27 selected genes. In summary, our data show that GvmR acts as an activating and repressing global regulator that is required to coordinate expression of a diverse set of metabolic and virulence genes essential for the survival in the animal host and under nutrient limitation.\n\nSteinmetz, Ivo\n\nWagner-Lichtenegger, Gabriel\n\n\n"
},
{
"text": "\n66105\nPlasmacytoid dendritic cells are absent in skin lesions of polymorphic light eruption.\n\nWackernagel, A\n\nMassone, C\n\nHoefler, G\n\nSteinbauer, E\n\nKerl, H\n\nWolf, P\n\nBeiträge in Fachzeitschriften\nISI:000243756200005\n17254032.0\n10.1111/j.1600-0781.2007.00267.x\nNone\nBACKGROUND/PURPOSE: Polymorphic light eruption (PLE) is a common photodermatosis of potential autoimmune origin, and an overlap with lupus erythematosus (LE) has been described. Plasmacytoid dendritic cell (PDC)-induced expression of interferon (IFN)-alpha has been found to be present in LE skin lesions and plays a pivotal role in the pathogenesis of LE by promoting autoimmunity. We therefore asked whether PDCs may also be involved in the pathogenesis of PLE and searched for those cells [which can be identified by their high levels of interleukin (IL)-3 receptor alpha chain (CD123), combined with other cell markers such as CD68] in skin lesions. METHODS: Paraffin-embedded biopsy specimens from a total of 27 patients with clinically and histologically confirmed PLE (nine women, mean age 32.7 years, age range 18-43), LE (seven women, four men, CCLE: n=4, SCLE: n=2, lupus tumidus: n=5, mean age 48.5 years, age range 41-65) or psoriasis (four women, three men, mean age 43.3 years, age range 19-54) (as control group) were analyzed by immunohistochemical CD68/CD123 double staining. Quantification of the immunohistochemical staining was performed by visual cell counting of CD68-/CD123+, CD68+/123-, and CD68+/CD123+ cells separately in the epidermis and dermis of the samples in at least 10 random fields per sample at x 400 microscopic magnification by two of the investigators in a blinded fashion. RESULTS: Microscopic examination of the immunohistochemically stained sections revealed that CD68+/CD123+ cells were present in most specimens obtained from LE [10/11 (91%)] and psoriasis [6/7 (86%)] patients but not at all in those obtained from PLE patients. Quantification and statistical analysis of the dermal infiltrate revealed that CD68+/CD123+ cells were present at a mean+/-SEM field density of 5.6+/-1.3 in LE, 1.6+/-0.6 in psoriasis but totally absent in PLE (P=0.0010 vs. LE, P=0.0135 vs. psoriasis by an unpaired Student's t-test). CONCLUSION: The results confirm the potential significance of PDCs in LE and psoriasis, however the absence of PDCs in PLE contradicts the hypothesis that these cells might play a role in the latter disease.\n\nGruber-Wackernagel, Alexandra\n\nHöfler, Gerald\n\nKerl, Helmut\n\nWolf, Peter\n\n\n"
},
{
"text": "\n74184\nEnhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts.\n\nWheatley, AM\n\nButkow, N\n\nMarcus, RH\n\nLippe, IT\n\nRosendorff, C\n\nBeiträge in Fachzeitschriften\nISI:A1988R666800008\n3223880.0\n10.1007/BF01906958\nNone\nIt is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dtmax) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dtmax (4196 +/- 74 mm Hg s-1) and beating rate (322 +/- 8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p less than 0.001) than those of the euthyroid hearts (3267 +/- 115 mm Hg s-1 and 260 +/- 6 beats/min at an external Ca2+ of 2.5 mM). At 2.5 mM Ca2+, the working hyperthyroid hearts again displayed enhanced contractility (5636 +/- 179 mm Hg s-1 vs 4508 +/- 172 mm Hg s-1; p less than 0.001) but the spontaneous beating rate (275 +/- 7 beats/min) was not significantly different from euthyroid (261 +/- 8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p less than 0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H2O to 120 cm H2O caused significant changes in left ventricular pressure and dP/dtmax in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H2O; hyperthyroid, 294 +/- 9 beats/min; euthyroid, 224 +/- 10 beats/min; p less than 0.001). Alteration of the preload (10 to 25 cm H2O) and afterload (75 to 105 cm H2O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dtmax but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.\n\nLippe, Irmgard\n\n\n"
},
{
"text": "\n118211\nPlatelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study.\n\nMahla, E\n\nSuarez, TA\n\nBliden, KP\n\nRehak, P\n\nMetzler, H\n\nSequeira, AJ\n\nCho, P\n\nSell, J\n\nFan, J\n\nAntonino, MJ\n\nTantry, US\n\nGurbel, PA\n\nBeiträge in Fachzeitschriften\nISI:000311705400020\n22396581.0\n10.1161/CIRCINTERVENTIONS.111.967208\nNone\nBackground-Aspirin and clopidogrel therapy is associated with a variable bleeding risk in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the role of platelet function testing in clopidogrel-treated patients undergoing CABG.\nMethods and Results-One hundred eighty patients on background aspirin with/without clopidogrel therapy undergoing elective first time isolated on-pump CABG were enrolled in a prospective single-center, nonrandomized, unblinded investigation (Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG [TARGET-CABG] study) between September 2008 and January 2011. Clopidogrel responsiveness (ADP-induced platelet-fibrin clot strength [MAADP]) was determined by thrombelastography; CABG was done within 1 day, 3-5 days, and ANDgt; 5 days in patients with an MA(ADP) ANDgt; 50 mm, 35-50 mm, and ANDlt; 35 mm, respectively. The primary end point was 24-hour chest tube drainage and key secondary end point was total number of transfused red blood cells. Equivalence was defined as ANDlt;= 25% difference between groups. ANCOVA was used to adjust for confounders. Mean 24-hour chest tube drainage in clopidogrel-treated patients was 93% (95% confidence interval, 81-107%) of the amount observed in clopidogrel-naive patients, and the total amount of red blood cells transfused did not differ between groups (1.80 U versus 2.08 U, respectively, P=0.540). The total waiting period in clopidogrel-treated patients was 233 days (mean, 2.7 days per patient).\nConclusions-A strategy based on preoperative platelet function testing to determine the timing of CABG in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and approximate to 50% shorter waiting time than recommended in the current guidelines.\nClinical Trial Registration-URL: http://www.clinicaltrials.gov.Unique identifier: NCT00857155. (Circ Cardiovasc Interv. 2012;5:261-269.)\n\nMahla, Elisabeth\n\nMetzler, Helfried\n\n\n"
},
{
"text": "\n156349\nTemporal and spatial variability of chemical and isotopic composition of soil solutions from cambisols - field study and experiments.\n\nSchön, W\n\nMittermayr, F\n\nLeis, A\n\nMischak, I\n\nDietzel, M\n\nBeiträge in Fachzeitschriften\nISI:000387807200099\n27542629.0\n10.1016/j.scitotenv.2016.08.015\nNone\nThe chemical and isotopic composition of soil solutions is highly relevant for environmental and forensic tasks. We investigated interstitial solutions from soil horizons of three cambisols in Styria (Austria). The soils consisted mainly of quartz, feldspar and clay minerals with a vertical variability. Two soil solution fractions from meso-, macro- and micropores (m) and micropores only (μ) were extracted at two subsequent hydraulic pressure steps corresponding to matrix potentials of up to pF 5.43 and from 5.43 to 5.73, respectively. While solute concentrations indicated diverse distribution in soil solution fractions m and μ, heavy stable hydrogen and oxygen isotopes of H2O (-92.5‰<δ2H<-34.4‰; -11.9‰<δ18O<-4.0‰, VSMOW) are clearly enriched in the μ versus m fractions. Principal component analysis on the hydrochemical data set indicates that the intensity of the overall silicate weathering is higher in autumn versus spring, whereas the anthropogenic impact on weathering behaves inversely. The anthropogenic impact is related to seasonal variability of nitrification of N-fertilizers. In consequence of evaluated signals for overall silicate weathering about three-fourths of the soil solutions sampled in autumn indicated elevated total dissolved solid concentration vs. those in spring accompanied with washing out solutes from the soil cover following precipitation events in autumn before sampling. Isotopic shift of soil solutions from the local meteoric water line in spring obviously followed an evaporation trend because of less precipitation and high evaporation before sampling. Experimentally simulated evaporation of soil samples confirmed the observed isotopic evaporation trend. Wetting experiments indicated the infiltration of water within minutes into the micropores of the soils. Exchange of water molecules between micro-, meso- and macropores is an almost instantaneous process and soil solutions in micropores are not as isolated from the soil water system as it was formerly suggested, e.g. for plant uptake. Highly dynamic and complex mechanisms in the gas-water-solid system of soils have to be considered for the application of elemental and isotope proxies related to environmental, forensic and agricultural tasks.\n Copyright © 2016 Elsevier B.V. All rights reserved.\n\n\n"
},
{
"text": "\n173006\nHistamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions.\n\nPfanzagl, B\n\nZevallos, VF\n\nSchuppan, D\n\nPfragner, R\n\nJensen-Jarolim, E\n\nBeiträge in Fachzeitschriften\nISI:000457877300006\n30540489.0\n10.1152/ajpgi.00261.2018\nNone\nThe P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellular calcium concentration ([Ca2+]i) via histamine 1 receptors involving T-type voltage-gated calcium channels (VGCCs). Sensitivity to histamine was enhanced by pretreatment with the inflammatory cytokine tumor necrosis factor-α (TNF-α). In accordance with the relief it offers some inflammatory bowel disease patients, otilonium bromide, a gut-impermeable inhibitor of T-type (and L-type) VGCCs and muscarinic ACh receptors, efficiently inhibited the [Ca2+]i responses induced by histamine plus ACh or by histamine alone in P-STS cells. It will take clinical studies to show whether otilonium bromide has promise for the treatment of adverse food reactions. The cells did not react to the nutrient constituents glutamate, capsaicin, cinnamaldehyde, or amylase-trypsin inhibitors and the transient receptor potential channel vanilloid 4 agonist GSK-1016790A. The bacterial product butyrate evoked a rise in [Ca2+]i only when added together with ACh. Lipopolysaccharide had no effect on [Ca2+]i despite the presence of Toll-like receptor 4 protein. Our results indicate that inflammatory conditions with elevated levels of TNF-α might enhance histamine-induced serotonin release from intestinal neuroendocrine cells. NEW & NOTEWORTHY We show that histamine synergistically enhances the intracellular calcium response to the physiological agonist acetylcholine in human ileal enterochromaffin tumor cells. This synergistic activation and cell activation by histamine alone largely depend on T-type voltage-gated calcium channels and are inhibited by the antispasmodic otilonium bromide. The cells showed no response to wheat amylase-trypsin inhibitors, suggesting that enterochromaffin cells are not directly involved in nongluten wheat sensitivity.\n\n\n"
}
]
}