TY - JOUR A1 - Rapa, Shara Francesca A1 - Di Iorio, Biagio Raffaele A1 - Campiglia, Pietro A1 - Heidland, August A1 - Marzocco, Stefania T1 - Inflammation and oxidative stress in chronic kidney disease — Potential therapeutic role of minerals, vitamins and plant-derived metabolites JF - International Journal of Molecular Sciences N2 - Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary. KW - chronic kidney disease (CKD) KW - inflammation KW - oxidative stress KW - uremic toxins KW - minerals KW - vitamins KW - plant-derived metabolites Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284998 SN - 1422-0067 VL - 21 IS - 1 ER - TY - JOUR A1 - Rice, Carmel A1 - Eikema, Dirk-Jan A1 - Marsh, Judith C. W. A1 - Knol, Cora A1 - Hebert, Kyle A1 - Putter, Hein A1 - Peterson, Eefke A1 - Deeg, H. Joachim A1 - Halkes, Stijn A1 - Pidala, Joseph A1 - Anderlini, Paolo A1 - Tischer, Johanna A1 - Kroger, Nicolaus A1 - McDonald, Andrew A1 - Antin, Joseph H. A1 - Schaap, Nicolaas P. A1 - Hallek, Michael A1 - Einsele, Herman A1 - Mathews, Vikram A1 - Kapoor, Neena A1 - Boelens, Jaap-Jan A1 - Mufti, Ghulam J. A1 - Potter, Victoria A1 - de la Tour, Régis Pefault A1 - Eapen, Mary A1 - Dufour, Carlo T1 - Allogeneic Hematopoietic Cell Transplantation in Patients Aged 50 Years or Older with Severe Aplastic Anemia JF - Biology of Blood and Marrow Transplantation N2 - We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n =187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. KW - Aplastic anemia KW - Hematopoietic cell transplant KW - Survival Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225229 VL - 25 IS - 3 ER - TY - JOUR A1 - Brodehl, Andreas A1 - Pour Hakimi, Seyed Ahmad A1 - Stanasiuk, Caroline A1 - Ratnavadivel, Sandra A1 - Hendig, Doris A1 - Gaertner, Anna A1 - Gerull, Brenda A1 - Gummert, Jan A1 - Paluszkiewicz, Lech A1 - Milting, Hendrik T1 - Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect JF - Genes N2 - Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations. KW - cardiovascular genetics KW - restrictive cardiomyopathy KW - desmin KW - intermediate filaments KW - desmin-related myopathy KW - cardiomyopathy KW - desminopathy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193121 SN - 2073-4425 VL - 10 IS - 11 ER - TY - JOUR A1 - Sailer, Clara Odilia A1 - Wiedemann, Sophia Julia A1 - Strauss, Konrad A1 - Schnyder, Ingeborg A1 - Fenske, Wiebke Kristin A1 - Christ-Crain, Mirjam T1 - Markers of systemic inflammation in response to osmotic stimulus in healthy volunteers JF - Endocrine Connections N2 - Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium >= 150 mmol/L) by hypertonic saline infusion. Copeptin - a marker indicating vasopressin activity - serum sodium and osmolality, plasma IL-8 and TNF-alpha were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-alpha levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation. KW - TNF-alpha KW - interleukin-8 KW - interleukin-6 KW - copeptin KW - hyperosmolality KW - Hyperosmotic Stress KW - Interleukin-6 KW - Expression KW - Protein KW - Neurons Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227204 VL - 8 IS - 9 ER - TY - JOUR A1 - Salman Haider, Malik A1 - Schreiner, Jochen A1 - Kendl, Sabine A1 - Kroiss, Matthias A1 - Luxenhofer, Robert T1 - A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models JF - Macromolecular Bioscience N2 - Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro. KW - adrenocortical carcinoma KW - amphiphilic block copolymer KW - NCI-H295R KW - poly(2-oxazoline) KW - solubility enhancement Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206224 VL - 20 IS - 1 ER - TY - JOUR A1 - Dietrich, Georg A1 - Krebs, Jonathan A1 - Liman, Leon A1 - Fette, Georg A1 - Ertl, Maximilian A1 - Kaspar, Mathias A1 - Störk, Stefan A1 - Puppe, Frank T1 - Replicating medication trend studies using ad hoc information extraction in a clinical data warehouse JF - BMC Medical Informatics and Decision Making N2 - Background Medication trend studies show the changes of medication over the years and may be replicated using a clinical Data Warehouse (CDW). Even nowadays, a lot of the patient information, like medication data, in the EHR is stored in the format of free text. As the conventional approach of information extraction (IE) demands a high developmental effort, we used ad hoc IE instead. This technique queries information and extracts it on the fly from texts contained in the CDW. Methods We present a generalizable approach of ad hoc IE for pharmacotherapy (medications and their daily dosage) presented in hospital discharge letters. We added import and query features to the CDW system, like error tolerant queries to deal with misspellings and proximity search for the extraction of the daily dosage. During the data integration process in the CDW, negated, historical and non-patient context data are filtered. For the replication studies, we used a drug list grouped by ATC (Anatomical Therapeutic Chemical Classification System) codes as input for queries to the CDW. Results We achieve an F1 score of 0.983 (precision 0.997, recall 0.970) for extracting medication from discharge letters and an F1 score of 0.974 (precision 0.977, recall 0.972) for extracting the dosage. We replicated three published medical trend studies for hypertension, atrial fibrillation and chronic kidney disease. Overall, 93% of the main findings could be replicated, 68% of sub-findings, and 75% of all findings. One study could be completely replicated with all main and sub-findings. Conclusion A novel approach for ad hoc IE is presented. It is very suitable for basic medical texts like discharge letters and finding reports. Ad hoc IE is by definition more limited than conventional IE and does not claim to replace it, but it substantially exceeds the search capabilities of many CDWs and it is convenient to conduct replication studies fast and with high quality. KW - data warehouse KW - medication extraction KW - information extraction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200409 VL - 19 ER - TY - JOUR A1 - Maniuc, Octavian A1 - Salinger, Tim A1 - Anders, Fabian A1 - Müntze, Jonas A1 - Liu, Dan A1 - Hu, Kai A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Nordbeck, Peter T1 - Impella CP use in patients with non‐ischaemic cardiogenic shock JF - ESC Heart Failure N2 - Aims From the various mechanical cardiac assist devices and indications available, the use of the percutaneous intraventricular Impella CP pump is usually restricted to acute ischaemic shock or prophylactic indications in high‐risk interventions. In the present study, we investigated clinical usefulness of the Impella CP device in patients with non‐ischaemic cardiogenic shock as compared with acute ischaemia. Methods and results In this retrospective single‐centre analysis, patients who received an Impella CP at the University Hospital Würzburg between 2013 and 2017 due to non‐ischaemic cardiogenic shock were age‐matched 2:1 with patients receiving the device due to ischaemic cardiogenic shock. Inclusion criteria were therapy refractory haemodynamic instability with severe left ventricular systolic dysfunction and serum lactate >2.0 mmol/L at implantation. Basic clinical data, indications for mechanical ventricular support, and outcome were obtained in all patients with non‐ischaemic as well as ischaemic shock and compared between both groups. Continuous variables are expressed as mean ± standard deviation or median (quartiles). Categorical variables are presented as count and per cent. Twenty‐five patients had cardiogenic shock due to non‐ischaemic reasons and were compared with 50 patients with cardiogenic shock due to acute myocardial infarction. Resuscitation rates before implantation of Impella CP were high (32 vs. 42%; P = 0.402). At implantation, patients with non‐ischaemic cardiogenic shock had lower levels of high‐sensitive troponin T (110.65 [57.87–322.1] vs. 1610 [450.8–3861.5] pg/mL; P = 0.001) and lactate dehydrogenase (377 [279–608] vs. 616 [371.3–1109] U/L; P = 0.007), while age (59 ± 16 vs. 61.7 ± 11; P = 0.401), glomerular filtration rate (43.5 [33.2–59.7] vs. 48 [35.75–69] mL/min; P = 0.290), C‐reactive protein (5.17 [3.27–10.26] vs. 10.97 [3.23–17.2] mg/dL; P = 0.195), catecholamine index (30.6 [10.6–116.9] vs. 47.6 [11.7–90] μg/kg/min; P = 0.663), and serum lactate (2.6 [2.2–5.8] vs. 2.9 [1.3–6.6] mmol/L; P = 0.424) were comparable between both groups. There was a trend for longer duration of Impella support in the non‐ischaemic groups (5 [2–7.5] vs. 3 [2–5.25] days, P = 0.211). Rates of haemodialysis (52 vs. 47%; P = 0.680) and transition to extracorporeal membrane oxygenation (13.6 vs. 22.2%; P = 0.521) were comparable. No significant difference was found regarding both 30 day survival (48 vs. 30%; P = 0.126) and in‐hospital mortality (66.7 vs. 74%; P = 0.512), although there was a trend for better survival in the non‐ischaemic group. Conclusions These data suggest that temporary use of the Impella CP device might be a useful therapeutic option for bridge to recovery not only in ischaemic but also in non‐ischaemic cardiogenic shock. KW - Impella KW - Non‐ischaemic cardiogenic shock Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202794 VL - 6 IS - 4 ER - TY - JOUR A1 - Müller-Scholden, Lara A1 - Kirchhof, Jan A1 - Morbach, Caroline A1 - Breunig, Margret A1 - Meijer, Rudy A1 - Rücker, Viktoria A1 - Tiffe, Theresa A1 - Yurdadogan, Tino A1 - Wagner, Martin A1 - Gelbrich, Götz A1 - Bots, Michiel L. A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Segment-specific association of carotid-intima-media thickness with cardiovascular risk factors – findings from the STAAB cohort study JF - BMC Cardiovascular Disorders N2 - Background The guideline recommendation to not measure carotid intima-media thickness (CIMT) for cardiovascular risk prediction is based on the assessment of just one single carotid segment. We evaluated whether there is a segment-specific association between different measurement locations of CIMT and cardiovascular risk factors. Methods Subjects from the population-based STAAB cohort study comprising subjects aged 30 to 79 years of the general population from Würzburg, Germany, were investigated. CIMT was measured on the far wall of both sides in three different predefined locations: common carotid artery (CCA), bulb, and internal carotid artery (ICA). Diabetes, dyslipidemia, hypertension, smoking, and obesity were considered as risk factors. In multivariable logistic regression analysis, odds ratios of risk factors per location were estimated for the endpoint of individual age- and sex-adjusted 75th percentile of CIMT. Results 2492 subjects were included in the analysis. Segment-specific CIMT was highest in the bulb, followed by CCA, and lowest in the ICA. Dyslipidemia, hypertension, and smoking were associated with CIMT, but not diabetes and obesity. We observed no relevant segment-specific association between the three different locations and risk factors, except for a possible interaction between smoking and ICA. Conclusions As no segment-specific association between cardiovascular risk factors and CIMT became evident, one simple measurement of one location may suffice to assess the cardiovascular risk of an individual. KW - Carotid intima-media thickness (CIMT) KW - Carotid segment KW - Carotid ultrasound KW - Cardiovascular risk factors KW - Cardiovascular risk prediction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200720 VL - 19 IS - 84 ER - TY - JOUR A1 - Heidenreich, Julius F. A1 - Weng, Andreas M. A1 - Donhauser, Julian A1 - Greiser, Andreas A1 - Chow, Kelvin A1 - Nordbeck, Peter A1 - Bley, Thorsten A. A1 - Köstler, Herbert T1 - T1- and ECV-mapping in clinical routine at 3 T: differences between MOLLI, ShMOLLI and SASHA JF - BMC Medical Imaging N2 - Background T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T. Methods Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences. Results T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19% lower and ShMOLLI T1 times 25% lower compared to SASHA. Native blood T1 times from MOLLI were 13% lower than SASHA, while post-contrast MOLLI T1-times were only 5% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences. Conclusion Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values. KW - T1 mapping KW - MOLLI KW - ShMOLLI KW - SASHA KW - Extracellular volume KW - 3 T Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201999 VL - 19 ER - TY - JOUR A1 - Haring, Bernhard A1 - Crandall, Carolyn J A1 - Carbone, Laura A1 - Liu, Simin A1 - Li, Wenjun A1 - Johnson, Karen C A1 - Wactawski-Wende, Jean A1 - Shadyab, Aladdin H A1 - Gass, Margery L A1 - Kamensky, Victor A1 - Cauley, Jane A A1 - Wassertheil-Smoller, Sylvia T1 - Lipoprotein(a) plasma levels, bone mineral density and risk of hip fracture: a post hoc analysis of the Women’s Health Initiative, USA JF - BMJ Open N2 - Objectives Elevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women. Design Post hoc analysis of data from the Women’s Health Initiative (WHI), USA. Setting 40 clinical centres in the USA. Participants The current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and osteoporotic fractures among postmenopausal women. Recruitment for WHI took place from 1 October 1993 to 31 December 1998. Exposures Plasma Lp(a) levels were measured at baseline. Outcome measures Incident hip fractures were ascertained annually and confirmed by medical records with follow-up through 29 August 2014. BMD at the femoral neck was measured by dual X-ray absorptiometry in a subset of participants at baseline. Statistical analyses Cox proportional hazards and logistic regression models were used to evaluate associations of quartiles of plasma Lp(a) levels with hip fracture events and hip BMD T-score, respectively. Results During a mean follow-up of 13.8 years, 454 incident cases of hip fracture were observed. In analyses adjusting for confounding variables including age, body mass index, history of hysterectomy, smoking, physical activity, diabetes mellitus, general health status, cardiovascular disease, use of menopausal hormone therapy, use of bisphosphonates, calcitonin or selective-oestrogen receptor modulators, baseline dietary and supplemental calcium and vitamin D intake and history of fracture, no significant association of plasma Lp(a) levels with low hip BMD T-score or hip fracture risk was detected. Conclusions These findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women. KW - hip fracture Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201139 VL - 9 ER -