TY - JOUR A1 - Fekete, Stefanie A1 - Egberts, K. A1 - Preissler, T. A1 - Wewetzer, C. A1 - Mehler-Wex, C. A1 - Romanos, M. A1 - Gerlach, M. T1 - Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride JF - European Journal of Clinical Pharmacology N2 - Purpose Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. Methods Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. Results In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97–19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. Conclusions This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml). KW - Tourette syndrome KW - therapeutic drug monitoring KW - serum concentration KW - paediatrics KW - pharmacokinetics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-279893 VL - 77 IS - 2 ER - TY - JOUR A1 - Guth, Sabine A1 - Hüser, Stephanie A1 - Roth, Angelika A1 - Degen, Gisela A1 - Diel, Patrick A1 - Edlund, Karolina A1 - Eisenbrand, Gerhard A1 - Engel, Karl-Heinz A1 - Epe, Bernd A1 - Grune, Tilman A1 - Heinz, Volker A1 - Henle, Thomas A1 - Humpf, Hans-Ulrich A1 - Jäger, Henry A1 - Joost, Hans-Georg A1 - Kulling, Sabine E. A1 - Lampen, Alfonso A1 - Mally, Angela A1 - Marchan, Rosemarie A1 - Marko, Doris A1 - Mühle, Eva A1 - Nitsche, Michael A. A1 - Röhrdanz, Elke A1 - Stadler, Richard A1 - van Thriel, Christoph A1 - Vieths, Stefan A1 - Vogel, Rudi F. A1 - Wascher, Edmund A1 - Watzl, Carsten A1 - Nöthlings, Ute A1 - Hengstler, Jan G. T1 - Contribution to the ongoing discussion on fluoride toxicity JF - Archives of Toxicology N2 - Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries. KW - pharmacology/toxicology KW - occupational medicine/industrial medicine KW - environmental health KW - biomedicine, general Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307161 SN - 0340-5761 SN - 1432-0738 VL - 95 IS - 7 ER - TY - JOUR A1 - Pinkawa, Michael A1 - Aebersold, Daniel M. A1 - Böhmer, Dirk A1 - Flentje, Michael A1 - Ghadjar, Pirus A1 - Schmidt-Hegemann, Nina-Sophie A1 - Höcht, Stefan A1 - Hölscher, Tobias A1 - Müller, Arndt-Christian A1 - Niehoff, Peter A1 - Sedlmayer, Felix A1 - Wolf, Frank A1 - Zamboglou, Constantinos A1 - Zips, Daniel A1 - Wiegel, Thomas T1 - Radiotherapy in nodal oligorecurrent prostate cancer JF - Strahlentherapie und Onkologie N2 - Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations. KW - prostate cancer KW - oligorecurrence KW - metastasis-directed therapy KW - radiation therapy KW - androgen deprivation therapy KW - stereotactic body radiotherapy KW - oligmometastases KW - lymph node metastases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307763 SN - 0179-7158 SN - 1439-099X VL - 197 IS - 7 ER - TY - JOUR A1 - Barile, Frank A. A1 - Berry, Colin A1 - Blaauboer, Bas A1 - Boobis, Alan A1 - Bolt, Herrmann M. A1 - Borgert, Christopher A1 - Dekant, Wolfgang A1 - Dietrich, Daniel A1 - Domingo, Jose L. A1 - Galli, Corrado L. A1 - Gori, Gio Batta A1 - Greim, Helmut A1 - Hengstler, Jan G. A1 - Heslop-Harrison, Pat A1 - Kacew, Sam A1 - Marquardt, Hans A1 - Mally, Angela A1 - Pelkonen, Olavi A1 - Savolainen, Kai A1 - Testai, Emanuela A1 - Tsatsakis, Aristides A1 - Vermeulen, Nico P. T1 - The EU chemicals strategy for sustainability: in support of the BfR position JF - Archives of Toxicology N2 - The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations. KW - pharmacology/toxicology KW - occupational medicine/industrial medicine KW - environmental health KW - biomedicine, general Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307154 SN - 0340-5761 SN - 1432-0738 VL - 95 IS - 9 ER - TY - JOUR A1 - Dorn, Franziska A1 - Herzberg, Moriz T1 - Response to Letter to the Editor “Keeping Late Thrombectomy Imaging Protocols Simple to Avoid Analysis Paralysis” JF - Clinical Neuroradiology KW - neuroradiology KW - neurosurgery KW - neurology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307023 SN - 1869-1439 SN - 1869-1447 VL - 31 IS - 3 ER - TY - JOUR A1 - Pennig, Lenhard A1 - Hoyer, Ulrike Cornelia Isabel A1 - Krauskopf, Alexandra A1 - Shahzad, Rahil A1 - Jünger, Stephanie T. A1 - Thiele, Frank A1 - Laukamp, Kai Roman A1 - Grunz, Jan-Peter A1 - Perkuhn, Michael A1 - Schlamann, Marc A1 - Kabbasch, Christoph A1 - Borggrefe, Jan A1 - Goertz, Lukas T1 - Deep learning assistance increases the detection sensitivity of radiologists for secondary intracranial aneurysms in subarachnoid hemorrhage JF - Neuroradiology N2 - Purpose To evaluate whether a deep learning model (DLM) could increase the detection sensitivity of radiologists for intracranial aneurysms on CT angiography (CTA) in aneurysmal subarachnoid hemorrhage (aSAH). Methods Three different DLMs were trained on CTA datasets of 68 aSAH patients with 79 aneurysms with their outputs being combined applying ensemble learning (DLM-Ens). The DLM-Ens was evaluated on an independent test set of 104 aSAH patients with 126 aneuryms (mean volume 129.2 ± 185.4 mm3, 13.0% at the posterior circulation), which were determined by two radiologists and one neurosurgeon in consensus using CTA and digital subtraction angiography scans. CTA scans of the test set were then presented to three blinded radiologists (reader 1: 13, reader 2: 4, and reader 3: 3 years of experience in diagnostic neuroradiology), who assessed them individually for aneurysms. Detection sensitivities for aneurysms of the readers with and without the assistance of the DLM were compared. Results In the test set, the detection sensitivity of the DLM-Ens (85.7%) was comparable to the radiologists (reader 1: 91.2%, reader 2: 86.5%, and reader 3: 86.5%; Fleiss κ of 0.502). DLM-assistance significantly increased the detection sensitivity (reader 1: 97.6%, reader 2: 97.6%,and reader 3: 96.0%; overall P=.024; Fleiss κ of 0.878), especially for secondary aneurysms (88.2% of the additional aneurysms provided by the DLM). Conclusion Deep learning significantly improved the detection sensitivity of radiologists for aneurysms in aSAH, especially for secondary aneurysms. It therefore represents a valuable adjunct for physicians to establish an accurate diagnosis in order to optimize patient treatment. KW - aneurysms KW - aneurysmal subarachnoid hemorrhage KW - CT angiography KW - deep learning KW - convolutional neural networks Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308117 SN - 0028-3940 SN - 1432-1920 VL - 63 IS - 12 ER - TY - JOUR A1 - Pilgram, Lisa A1 - Eberwein, Lukas A1 - Wille, Kai A1 - Koehler, Felix C. A1 - Stecher, Melanie A1 - Rieg, Siegbert A1 - Kielstein, Jan T. A1 - Jakob, Carolin E. M. A1 - Rüthrich, Maria A1 - Burst, Volker A1 - Prasser, Fabian A1 - Borgmann, Stefan A1 - Müller, Roman-Ulrich A1 - Lanznaster, Julia A1 - Isberner, Nora A1 - Tometten, Lukas A1 - Dolff, Sebastian T1 - Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease JF - Infection N2 - Purpose The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study’s aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. Methods We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. Results Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15–65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27–33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66–147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49–54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17–8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13–10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68–1.93, p = 0.611). Conclusion The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2. KW - chronic kidney disease KW - COVID-19 KW - LEOSS KW - predictive factor KW - SARS-CoV-2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308957 SN - 0300-8126 SN - 1439-0973 VL - 49 IS - 4 ER - TY - JOUR A1 - Horn, A. A1 - Krist, L. A1 - Lieb, W. A1 - Montellano, F. A. A1 - Kohls, M. A1 - Haas, K. A1 - Gelbrich, G. A1 - Bolay-Gehrig, S. J. A1 - Morbach, C. A1 - Reese, J. P. A1 - Störk, S. A1 - Fricke, J. A1 - Zoller, T. A1 - Schmidt, S. A1 - Triller, P. A1 - Kretzler, L. A1 - Rönnefarth, M. A1 - Von Kalle, C. A1 - Willich, S. N. A1 - Kurth, F. A1 - Steinbeis, F. A1 - Witzenrath, M. A1 - Bahmer, T. A1 - Hermes, A. A1 - Krawczak, M. A1 - Reinke, L. A1 - Maetzler, C. A1 - Franzenburg, J. A1 - Enderle, J. A1 - Flinspach, A. A1 - Vehreschild, J. A1 - Schons, M. A1 - Illig, T. A1 - Anton, G. A1 - Ungethüm, K. A1 - Finkenberg, B. C. A1 - Gehrig, M. T. A1 - Savaskan, N. A1 - Heuschmann, P. U. A1 - Keil, T. A1 - Schreiber, S. T1 - Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP) JF - Infection N2 - Purpose Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. Methods The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. Results As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once. Conclusion NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. Trial registration Registered at the German registry for clinical studies (DRKS00023742). KW - Long COVID KW - Sars-CoV-2 KW - on-site examination KW - internal medicine KW - neurological KW - population-based Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308960 SN - 0300-8126 SN - 1439-0973 VL - 49 IS - 6 ER - TY - JOUR A1 - Dichtl, Karl A1 - Koc, Özlem A1 - Forster, Johannes A1 - Scharf, Christina A1 - Suerbaum, Sebastian A1 - Andrassy, Joachim A1 - Wagener, Johannes A1 - Schroeder, Ines T1 - An invasive infection caused by the thermophilic mold Talaromyces thermophilus JF - Infection N2 - Background Increasing incidence of invasive infections caused by rare fungi was observed over the recent years. Case Here, we describe the first reported case of an infection caused by the thermophilic mold Talaromyces thermophilus. Cultivation and, hence, identification of this fastidious organism is challenging since standard incubation conditions are not sufficient. Retrospective analysis of patient samples and in vitro experiments demonstrated that testing for fungal antigens, i.e., the cell wall components galactomannan and β-1,3-D-glucan, is a promising tool. KW - Talaromyces KW - invasive fungal infection KW - thermophile KW - antigen testing KW - serology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308970 SN - 0300-8126 SN - 1439-0973 VL - 49 IS - 6 ER - TY - JOUR A1 - Jockel-Schneider, Yvonne A1 - Schlagenhauf, Ulrich A1 - Petsos, Hari A1 - Rüttermann, Stefan A1 - Schmidt, Jana A1 - Ziebolz, Dirk A1 - Wehner, Christian A1 - Laky, Markus A1 - Rott, Thea A1 - Noack, Michael A1 - Noack, Barbara A1 - Lorenz, Katrin T1 - Impact of 0.1% octenidine mouthwash on plaque re-growth in healthy adults: a multi-center phase 3 randomized clinical trial JF - Clinical Oral Investigations N2 - Objectives To investigate plaque inhibition of 0.1% octenidine mouthwash (OCT) vs. placebo over 5 days in the absence of mechanical plaque control. Materials and methods For this randomized, placebo-controlled, double-blind, parallel group, multi-center phase 3 study, 201 healthy adults were recruited. After baseline recording of plaque index (PI) and gingival index (GI), collection of salivary samples, and dental prophylaxis, subjects were randomly assigned to OCT or placebo mouthwash in a 3:1 ratio. Rinsing was performed twice daily for 30 s. Colony forming units in saliva were determined before and after the first rinse. At day 5, PI, GI, and tooth discoloration index (DI) were assessed. Non-parametric van Elteren tests were applied with a significance level of p < 0.05. Results Treatment with OCT inhibited plaque formation more than treatment with placebo (PI: 0.36 vs. 1.29; p < 0.0001). OCT reduced GI (0.04 vs. placebo 0.00; p = 0.003) and salivary bacterial counts (2.73 vs. placebo 0.24 lgCFU/ml; p < 0.0001). Tooth discoloration was slightly higher under OCT (DI: 0.25 vs. placebo 0.00; p = 0.0011). Mild tongue staining and dysgeusia occurred. Conclusions OCT 0.1% mouthwash inhibits plaque formation over 5 days. It therefore can be recommended when regular oral hygiene is temporarily compromised. Clinical relevance When individual plaque control is compromised, rinsing with octenidine mouthwash is recommended to maintain healthy oral conditions while side effects are limited. KW - octenidine KW - mouthrinse KW - bacterial counts KW - plaque index KW - gingival index KW - discoloration index Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307629 SN - 1432-6981 SN - 1436-3771 VL - 25 IS - 7 ER - TY - JOUR A1 - Righesso, L. A. R. A1 - Terekhov, M. A1 - Götz, H. A1 - Ackermann, M. A1 - Emrich, T. A1 - Schreiber, L. M. A1 - Müller, W. E. G. A1 - Jung, J. A1 - Rojas, J. P. A1 - Al-Nawas, B. T1 - Dynamic contrast-enhanced magnetic resonance imaging for monitoring neovascularization during bone regeneration — a randomized in vivo study in rabbits JF - Clinical Oral Investigations N2 - Objectives Micro-computed tomography (μ-CT) and histology, the current gold standard methods for assessing the formation of new bone and blood vessels, are invasive and/or destructive. With that in mind, a more conservative tool, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), was tested for its accuracy and reproducibility in monitoring neovascularization during bone regeneration. Additionally, the suitability of blood perfusion as a surrogate of the efficacy of osteoplastic materials was evaluated. Materials and methods Sixteen rabbits were used and equally divided into four groups, according to the time of euthanasia (2, 3, 4, and 6 weeks after surgery). The animals were submitted to two 8-mm craniotomies that were filled with blood or autogenous bone. Neovascularization was assessed in vivo through DCE-MRI, and bone regeneration, ex vivo, through μ-CT and histology. Results The defects could be consistently identified, and their blood perfusion measured through DCE-MRI, there being statistically significant differences within the blood clot group between 3 and 6 weeks (p = 0.029), and between the former and autogenous bone at six weeks (p = 0.017). Nonetheless, no significant correlations between DCE-MRI findings on neovascularization and μ-CT (r =−0.101, 95% CI [−0.445; 0.268]) or histology (r = 0.305, 95% CI [−0.133; 0.644]) findings on bone regeneration were observed. Conclusions These results support the hypothesis that DCE-MRI can be used to monitor neovascularization but contradict the premise that it could predict bone regeneration as well. KW - animal experimentation KW - bone regeneration KW - multiparametric magnetic resonance imaging KW - neovascularization, physiologic KW - tissue engineering KW - translational medical research Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307614 SN - 1432-6981 SN - 1436-3771 VL - 25 IS - 10 ER - TY - JOUR A1 - Lenz, Dominic A1 - Pahl, Jens A1 - Hauck, Fabian A1 - Alameer, Seham A1 - Balasubramanian, Meena A1 - Baric, Ivo A1 - Boy, Nikolas A1 - Church, Joseph A. A1 - Crushell, Ellen A1 - Dick, Anke A1 - Distelmaier, Felix A1 - Gujar, Jidnyasa A1 - Indolfi, Giuseppe A1 - Lurz, Eberhard A1 - Peters, Bianca A1 - Schwerd, Tobias A1 - Serranti, Daniele A1 - Kölker, Stefan A1 - Klein, Christoph A1 - Hoffmann, Georg F. A1 - Prokisch, Holger A1 - Greil, Johann A1 - Cerwenka, Adelheid A1 - Giese, Thomas A1 - Staufner, Christian T1 - NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency JF - Journal of Clinical Immunology N2 - Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity. KW - NBAS KW - inborn error of immunity KW - NK cell deficiency KW - B cell deficiency KW - vesicle trafficking KW - familial hemophagocytic lymphohistiocytosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308362 SN - 0271-9142 SN - 1573-2592 VL - 41 IS - 8 ER - TY - JOUR A1 - Holländer, Olivia A1 - Schwender, Kristina A1 - Böhme, Petra A1 - Fleckhaus, Jan A1 - Haas, Cordula A1 - Han, Yang A1 - Heidorn, Frank A1 - Klein-Unseld, Rachel A1 - Lichtenwald, Julia A1 - Naue, Jana A1 - Neubauer, Jacqueline A1 - Poetsch, Micaela A1 - Schneider, Peter M. A1 - Wagner, Wolfgang A1 - Vennemann, Marielle T1 - Forensische DNA-Methylierungsanalyse T1 - Forensic DNA methylation analysis : First technical collaborative exercise by the working group on molecular age estimation of the German Society of Legal Medicine BT - Erster, technischer Ringversuch der Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin JF - Rechtsmedizin N2 - Die quantitative Analyse der relativen DNA-Methylierung gilt als eine der vielversprechendsten Methoden der molekularen Altersschätzung. Viele Studien der letzten Jahre identifizierten geeignete Positionen im Genom, deren DNA-Methylierung sich altersabhängig verändert. Für den Einsatz dieser Methode in der Routine- bzw. Fallarbeit ist es von großer Bedeutung, angewandte Analysetechniken zu validieren. Als ein Teilaspekt dieser Validierung sollte die Vergleichbarkeit der Analyseergebnisse zur DNA-Methylierung mithilfe der Mini- und Pyrosequenzierung zwischen verschiedenen Laboren evaluiert werden. Die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) führte hierzu den ersten, technischen Ringversuch durch, der 4 Positionen in den Genen PDE4C, EDARADD, SST und KLF14 umfasste. Diese Marker waren in vorangegangenen Studien als altersabhängige Biomarker charakterisiert worden. Am Ringversuch nahmen 12 Labore teil, wobei jedes die Wahl zwischen der Minisequenzierung und/oder der Pyrosequenzierung für die quantitative Methylierungsanalyse hatte. Jedem teilnehmenden Labor wurden Blut- und Speichelproben von 3 Personen unterschiedlichen Alters übersandt. Die Wahl der Reagenzien für die Probenbearbeitung wurde den Teilnehmern freigestellt. Die Ergebnisse der Minisequenzierung zeigten systematische Abweichungen zwischen den Laboren, die am ehesten auf die Verwendung unterschiedlicher Reagenzien und Analyseplattformen zurückzuführen sein können. Die Resultate der Pyrosequenzierung hingegen wiesen nicht auf systematische Abweichungen zwischen den Laboren hin, hier zeigte sich jedoch die Tendenz einer markerabhängigen Abweichung. Darüber hinaus konnten Unterschiede hinsichtlich technischer Probleme zwischen Laboren mit mehr Erfahrung in der jeweiligen Sequenzierungsmethode und Laboren mit weniger Erfahrung festgestellt werden. Sowohl die Beobachtung von systematischen als auch die von markerabhängigen Abweichungen lässt den Schluss zu, dass eine Übertragung von Analysemethoden zwischen Laboren grundsätzlich möglich ist, eine Anpassung des jeweiligen Modells zur Altersschätzung jedoch notwendig sein kann. N2 - Quantitative analysis of relative DNA methylation is currently one of the most promising methods of molecular age estimation. In recent years numerous studies identified potential DNA methylation markers showing age-dependent changes in their relative methylation state. For routine application of this method validation is an important prerequisite. One aspect of validation is the degree of comparability of analytical data between laboratories. The working group on molecular age estimation of the German Society for Legal Medicine (DGRM) conducted a first technical proficiency test comprising four age estimation markers within the genes PDE4C, EDARADD, SST and KLF14. These positions were previously characterized as age-dependent biomarkers. A total of 12 laboratories participated using pyrosequencing and/or minisequencing techniques for quantitative analysis of DNA methylation. Each laboratory received blood and buccal swab samples from three individuals of different ages. Laboratories were free in their choice of reagents and material for sequencing. Minisequencing results showed systematic deviations between laboratories, which are believed to originate from differing reagents and sequencing platforms. The results of pyrosequencing did not show clear signs of systematic deviation but did show differences in the comparability between markers. Different levels of technical problems were reported, which correlated with the amount of experience with the sequencing technology. Both systematic and specific differences between analytical data produced in different laboratory settings lead to the conclusion that while it is generally possible to transfer an age estimation method to another laboratory, a mathematical model for age estimation might need to be adjusted accordingly. KW - DNA-Methylierung KW - Pyrosequenzierung KW - Minisequenzierung KW - Ergebnisreproduzierbarkeit KW - Laborleistungstests KW - DNA methylation KW - minisequencing KW - pyrosequencing KW - reproducibility of results KW - laboratory proficiency testing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307131 SN - 0937-9819 SN - 1434-5196 VL - 31 IS - 3 ER - TY - JOUR A1 - Adolph, Jonas E. A1 - Fleischhack, Gudrun A1 - Gaab, Christine A1 - Mikasch, Ruth A1 - Mynarek, Martin A1 - Rutkowski, Stefan A1 - Schüller, Ulrich A1 - Pfister, Stefan M. A1 - Pajtler, Kristian W. A1 - Milde, Till A1 - Witt, Olaf A1 - Bison, Brigitte A1 - Warmuth-Metz, Monika A1 - Kortmann, Rolf-Dieter A1 - Dietzsch, Stefan A1 - Pietsch, Torsten A1 - Timmermann, Beate A1 - Tippelt, Stephan T1 - Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies JF - Journal of Neuro-Oncology N2 - Purpose Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. Methods Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. Results Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. Conclusion No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation. KW - ependymoma KW - chemotherapy KW - recurrence KW - children KW - sirolimus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308302 SN - 0167-594X SN - 1573-7373 VL - 155 IS - 2 ER - TY - JOUR A1 - Denk, S. A1 - Schmidt, S. A1 - Schurr, Y. A1 - Schwarz, G. A1 - Schote, F. A1 - Diefenbacher, M. A1 - Armendariz, C. A1 - Dejure, F. A1 - Eilers, M. A1 - Wiegering, Armin T1 - CIP2A regulates MYC translation (via its 5′UTR) in colorectal cancer JF - International Journal of Colorectal Disease N2 - Background Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that decreasing MYC expression may have significant therapeutic value. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level. Methods To determine the mechanism by which CIP2A regulates MYC in CRC, we dissected MYC translation and stability dependent on CIP2A in CRC cell lines. Results Knockdown of CIP2A reduced MYC protein levels without influencing MYC stability in CRC cell lines. Interfering with proteasomal degradation of MYC by usage of FBXW7-deficient cells or treatment with the proteasome inhibitor MG132 did not rescue the effect of CIP2A depletion on MYC protein levels. Whereas CIP2A knockdown had marginal influence on global protein synthesis, we could demonstrate that, by using different reporter constructs and cells expressing MYC mRNA with or without flanking UTR, CIP2A regulates MYC translation. This interaction is mainly conducted by the MYC 5′UTR. Conclusions Thus, instead of targeting MYC protein stability as reported for other tissue types before, CIP2A specifically regulates MYC mRNA translation in CRC but has only slight effects on global mRNA translation. In conclusion, we propose as novel mechanism that CIP2A regulates MYC on a translational level rather than affecting MYC protein stability in CRC. KW - CIP2A KW - MYC KW - translation KW - colon cancer Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-280092 VL - 36 IS - 5 ER - TY - JOUR A1 - Reddersen, Kirsten A1 - Güllmar, André A1 - Tonndorf-Martini, Silke A1 - Sigusch, Bernd W. A1 - Ewald, Andrea A1 - Dauben, Thomas J. A1 - Martin, Karin A1 - Wiegand, Cornelia T1 - Critical parameters in cultivation of experimental biofilms using the example of Pseudomonas fluorescens JF - Journal of Materials Science: Materials in Medicine N2 - Formation and treatment of biofilms present a great challenge for health care and industry. About 80% of human infections are associated with biofilms including biomaterial centered infections, like infections of prosthetic heart valves, central venous catheters, or urinary catheters. Additionally, biofilms can cause food and drinking water contamination. Biofilm research focusses on application of experimental biofilm models to study initial adherence processes, to optimize physico-chemical properties of medical materials for reducing interactions between materials and bacteria, and to investigate biofilm treatment under controlled conditions. Exploring new antimicrobial strategies plays a key role in a variety of scientific disciplines, like medical material research, anti-infectious research, plant engineering, or wastewater treatment. Although a variety of biofilm models exist, there is a lack of standardization for experimental protocols, and designing experimental setups remains a challenge. In this study, a number of experimental parameters critical for material research have been tested that influence formation and stability of an experimental biofilm using the non-pathogenic model strain of Pseudomonas fluorescens. These parameters include experimental time frame, nutrient supply, inoculum concentration, static and dynamic cultivation conditions, material properties, and sample treatment during staining for visualization of the biofilm. It was shown, that all tested parameters critically influence the experimental biofilm formation process. The results obtained in this study shall support material researchers in designing experimental biofilm setups. KW - biomaterials KW - biomedical engineering and bioengineering KW - regenerative medicine/tissue engineering KW - polymer sciences KW - ceramics, glass, composites, natural materials KW - surfaces and interfaces, thin films Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-309911 SN - 0957-4530 SN - 1573-4838 VL - 32 IS - 9 ER - TY - GEN A1 - Baur, Johannes A1 - Ramser, Michaela A1 - Keller, Nicola A1 - Muysoms, Filip A1 - Dörfer, Jörg A1 - Wiegering, Armin A1 - Eisner, Lukas A1 - Dietz, Ulrich A. T1 - Erratum to: Robotic hernia repair II. English version Robotic primary ventral and incisional hernia repair (rv-TAPP and r-Rives or r-TARUP). Video report and results of a series of 118 patients T2 - Der Chirurg N2 - No abstract available. KW - erratum Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-326357 VL - 92 IS - SUPPL 1 SP - S27 ER - TY - JOUR A1 - Nowotny, Hanna A1 - Ahmed, S. Faisal A1 - Bensing, Sophie A1 - Beun, Johan G. A1 - Brösamle, Manuela A1 - Chifu, Irina A1 - Claahsen van der Grinten, Hedi A1 - Clemente, Maria A1 - Falhammar, Henrik A1 - Hahner, Stefanie A1 - Husebye, Eystein A1 - Kristensen, Jette A1 - Loli, Paola A1 - Lajic, Svetlana A1 - Reisch, Nicole T1 - Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis JF - Endocrine N2 - Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives. KW - adrenal insufficiency KW - congenital adrenal hyperplasia KW - adrenal crisis KW - glucocorticoid replacement KW - hydrocortisone KW - stress instructions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308769 SN - 1355-008X SN - 1559-0100 VL - 71 IS - 3 ER - TY - JOUR A1 - Li, Minghao A1 - Pamporaki, Christina A1 - Fliedner, Stephanie M. J. A1 - Timmers, Henri J. L. M. A1 - Nölting, Svenja A1 - Beuschlein, Felix A1 - Prejbisz, Aleksander A1 - Remde, Hanna A1 - Robledo, Mercedes A1 - Bornstein, Stefan R. A1 - Lenders, Jacques W. M. A1 - Eisenhofer, Graeme A1 - Bechmann, Nicole T1 - Metastatic pheochromocytoma and paraganglioma: signs and symptoms related to catecholamine secretion JF - Discover Oncology N2 - Background The presence or future development of metastatic pheochromocytomas or paragangliomas (mPPGLs) can be difficult to diagnose or predict at initial presentation. Since production of catecholamines from mPPGLs is different from non-metastatic tumors (non-mPPGLs), this study aimed to clarify whether presenting catecholamine-related signs and symptoms (cSS) might also differ. Methods The study included 249 patients, 43 with mPPGL and 206 with non-mPPGL. Clinical data at the time of biochemical diagnosis (i.e. at entry into the study) were used to generate a cumulative score of cSS for each patient. Results Patients with mPPGL were significantly younger (43.3 ± 14 vs. 48.9 ± 16.1 years) and included a lower proportion of females (39.5% vs. 60.7%) than patients with non-mPPGLs. Frequencies of signs and symptoms did not differ between the two groups. Patients with mPPGLs had lower (P < 0.001) urinary excretion of epinephrine (3.5 (IQR, 1.9—6.5) µg/day) than those with non-mPPGLs (19.1 (IQR, 4.3—70.2) µg/day). There was no difference in urinary excretion of norepinephrine. In patients with mPPGLs a high cSS score was associated with high urinary excretion of norepinephrine and normetanephrine. In contrast, in patients with non-mPPGLs, a high cSS was associated with high urinary excretion of epinephrine and metanephrine. Conclusion Although presenting signs and symptoms were associated with production of norepinephrine in patients with mPPGLs and of epinephrine in patients with non-mPPGLs, there were no differences in signs and symptoms between the two groups. Therefore, consideration of signs and symptoms does not appear helpful for distinguishing patients with and without mPPGLs. KW - pheochromocytoma KW - paraganglioma KW - metastatic KW - signs KW - symptoms KW - catecholamines Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-309901 SN - 2730-6011 VL - 12 ER - TY - JOUR A1 - Minner, S. A1 - Schreiner, J. A1 - Saeger, W. T1 - Adrenal cancer: relevance of different grading systems and subtypes JF - Clinical and Translational Oncology N2 - Purpose The subclassification of adrenal cancers according to the WHO classification in ordinary, myxoid, oncocytic, and sarcomatoid as well as pediatric types is well established, but the criteria for each subtype are not sufficiently determined and the relative frequency of the different types of adrenal cancers has not been studied in large cohorts. Therefore, our large collection of surgically removed adrenal cancers should be reviewed o establish the criteria for the subtypes and to find out the frequency of the various types. Methods In our series of 521 adrenal cancers the scoring systems of Weiss et al., Hough et al., van Slooten et al. and the new Helsinki score system were used for the ordinary type of cancer (97% of our series) and the myxoid type (0.8%). For oncocytic carcinomas (2%), the scoring system of Bisceglia et al. was applied. Results Discrepancies between benign and malignant diagnoses from the first thee classical scoring systems are not rare (22% in our series) and could be resolved by the Helsinki score especially by Ki-67 index (more than 8% unequivocally malignant). Since all our cancer cases are positive in the Helsinki score, this system can replace the three elder systems. For identification of sarcomatoid cancer as rarest type in our series (0.2%), the scoring systems are not practical but additional immunostainings used for soft tissue tumors and in special cases molecular pathology are necessary to differentiate these cancers from adrenal sarcomas. According to the relative frequencies of the different subtypes of adrenal cancers the main type is the far most frequent (97%) followed by the oncocytic type (2%), the myxoid type (0.8%) and the very rare sarcomatoid type (0.2%). Conclusions The Helsinki score is the best for differentiating adrenal carcinomas of the main, the oncocytic, and the myxoid type in routine work. Additional scoring systems for these carcinomas are generally not any longer necessary. Signs of proliferation (mitoses and Ki-67 index) and necroses are the most important criteria for diagnosis of malignancy. KW - adrenal KW - cancer KW - cancer types KW - classification Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308479 SN - 1699-048X SN - 1699-3055 VL - 23 IS - 7 ER - TY - JOUR A1 - Danysz, Wojciech A1 - Dekundy, Andrzej A1 - Scheschonka, Astrid A1 - Riederer, Peter T1 - Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials JF - Journal of Neural Transmission N2 - The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson’s disease symptoms and viral infections. Considering amantadine’s affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington’s disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine’s therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia. KW - Amantadine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-330133 VL - 128 IS - 2 ER - TY - JOUR A1 - Naue, Jana A1 - Pfeifer, Manuel A1 - Augustin, Christa A1 - Becker, Julia A1 - Fleckhaus, Jan A1 - Grabmüller, Melanie A1 - Han, Yang A1 - Heidorn, Frank A1 - Hollaender, Olivia A1 - Klein-Unseld, Rachel A1 - Kulstein, Galina A1 - Lichtenwald, Julia A1 - Neubauer, Jacqueline A1 - Suarez, Philippe A1 - Haas, Cordula A1 - Schneider, Peter M. A1 - Vennemann, Marielle A1 - Böhme, Petra T1 - Forensische DNA-Methylierungsanalyse T1 - Forensic DNA methylation analysis : Second technical collaborative exercise by the working group on “molecular age estimation” of the German Society of Legal Medicine BT - Zweiter, technischer Ringversuch der Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin JF - Rechtsmedizin N2 - Mit der Entdeckung altersabhängiger epigenetischer Veränderungen, der DNA-Methylierung (DNAm), hat sich eine neue Möglichkeit aufgezeigt, das Alter eines Individuums zu schätzen. Die Methode wurde intensiv erforscht und ihre Anwendung in der forensischen Fallarbeit durch die Aktualisierung des § 81e der Strafprozessordnung (StPO) in Deutschland reguliert. Zur Untersuchung des DNAm-Grades müssen neue Techniken etabliert und validiert werden. Dies macht die Prüfung der Vergleichbarkeit von Messergebnissen aus verschiedenen forensischen Laboren erforderlich. Hierzu führte die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) im Winter 2019/2020 den 2. Ringversuch (RV) zur quantitativen DNAm-Analyse mithilfe der Mini- und der Pyrosequenzierung durch. Dieser basierte auf den Erfahrungen des 1. RV 2018/2019, dessen Ergebnisse in dieser Ausgabe ebenfalls vorgestellt werden. Die aktuelle Studie umfasst Analyseergebnisse aus 12 Laboren (ingesamt 14 teilnehmende Labore), von denen einige beide Methoden angewandt haben. Zusätzlich führten 4 Labore eine Altersschätzung an den RV-Proben mit eigenen Markerkombinationen und Modellen durch. Da diese auf unterschiedlichen Referenzdaten und Markerkombinationen beruhen, erfolgte kein qualitativer Vergleich der Modelle, sondern das grundsätzliche Potenzial der Methodik wurde verdeutlicht. Ziele des RV waren die Evaluierung der Vergleichbarkeit der DNAm-Messungen und die Bewertung möglicher Einflussfaktoren, wie Extraktionsmethode und verwendetes Gerät. Die Ergebnisse zeigen, dass sich die gemessenen DNAm-Werte der untersuchten Marker sowohl zwischen Mini- und Pyrosequenzierung als auch innerhalb der jeweiligen Methode zwischen den Laboren unterscheiden können, sodass mit Schwankungen gerechnet werden muss. N2 - With the discovery of age-related epigenetic changes DNA methylation (DNAm) has shown new possibilities for the estimation of the age of an individual. The method has been intensively researched and its application in forensic casework is regulated by an amendment of § 81e of the German Code of Criminal Procedures (StPO). To investigate the degree of DNAm new techniques must be established and validated. This necessitates investigation of the comparability of measurement results from different forensic laboratories. In winter 2019/2020 the molecular age estimation working group of the German Society of Legal Medicine (DGRM) conducted a second proficiency test to investigate this comparability using minisequencing and pyrosequencing for quantitative analysis of DNAm. This was based on the experience from the first proficiency test in 2018/2019, the results of which are presented in this edition of the journal. The current study includes the results of DNAm analysis from 12 laboratories (in total 14 participating laboratories), some of which have used both methods. In addition, four laboratories performed an age estimation using their own marker combinations and models. As these are based on different reference data and marker combinations, no qualitative comparison of the models was done but the fundamental potential of the methodology was clarified. The aim of the interlaboratory comparison was to evaluate the comparability of the DNAm measurements and to assess possible influencing factors, such as the extraction method and the device used. The results showed that the measured DNAm values of the investigated markers can differ between minisequencing and pyrosequencing as well as within the respective method between laboratories, so that fluctuations are to be expected. KW - Epigenetik KW - Biomarker KW - Minisequenzierung KW - Pyrosequenzierung KW - Laborleistungstests KW - epigenetics KW - biomarker KW - minisequencing KW - pyrosequencing KW - laboratory proficiency testing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307129 SN - 0937-9819 SN - 1434-5196 VL - 31 IS - 3 ER - TY - JOUR A1 - Potreck, Arne A1 - Mutke, Matthias A. A1 - Weyland, Charlotte S. A1 - Pfaff, Johannes A. R. A1 - Ringleb, Peter A. A1 - Mundiyanapurath, Sibu A1 - Möhlenbruch, Markus A. A1 - Heiland, Sabine A1 - Pham, Mirko A1 - Bendszus, Martin A1 - Hoffmann, Angelika T1 - Combined Perfusion and Permeability Imaging Reveals Different Pathophysiologic Tissue Responses After Successful Thrombectomy JF - Translational Stroke Research N2 - Despite successful recanalization of large-vessel occlusions in acute ischemic stroke, individual patients profit to a varying degree. Dynamic susceptibility-weighted perfusion and dynamic T1-weighted contrast-enhanced blood-brain barrier permeability imaging may help to determine secondary stroke injury and predict clinical outcome. We prospectively performed perfusion and permeability imaging in 38 patients within 24 h after successful mechanical thrombectomy of an occlusion of the middle cerebral artery M1 segment. Perfusion alterations were evaluated on cerebral blood flow maps, blood-brain barrier disruption (BBBD) visually and quantitatively on ktrans maps and hemorrhagic transformation on susceptibility-weighted images. Visual BBBD within the DWI lesion corresponded to a median ktrans elevation (IQR) of 0.77 (0.41–1.4) min−1 and was found in all 7 cases of hypoperfusion (100%), in 10 of 16 cases of hyperperfusion (63%), and in only three of 13 cases with unaffected perfusion (23%). BBBD was significantly associated with hemorrhagic transformation (p < 0.001). While BBBD alone was not a predictor of clinical outcome at 3 months (positive predictive value (PPV) = 0.8 [0.56–0.94]), hypoperfusion occurred more often in patients with unfavorable clinical outcome (PPV = 0.43 [0.10–0.82]) compared to hyperperfusion (PPV = 0.93 [0.68–1.0]) or unaffected perfusion (PPV = 1.0 [0.75–1.0]). We show that combined perfusion and permeability imaging reveals distinct infarct signatures after recanalization, indicating the severity of prior ischemic damage. It assists in predicting clinical outcome and may identify patients at risk of stroke progression. KW - permeability imaging KW - perfusion imaging KW - mechanical thrombectomy KW - secondary stroke injury KW - hyperperfusion Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308946 SN - 1868-4483 SN - 1868-601X VL - 12 IS - 5 ER -