Microvesicles from cerebrospinal fluid of patients with Alzheimer’s disease display reduced concentrations of tau and APP protein - Spitzer, Philipp; Mulzer, Linda-Marie; Oberstein, Timo; Munoz, Luis Enrique; Lewczuk, Piotr; Kornhuber, Johannes; Herrmann, Martin; Maler, Juan Manuel (Scientific Reports, 2019)
Microvesicles are small membranous particles generated during cellular activation or stress. The analysis of the content and the surface of microvesicles allow conclusions about the cells they are originating from and the underlying pathology. Therefore, CSF microvesicles have been suggested to be promising targets to monitor the (etio)pathology of neurodegenerative diseases. Microvesicles in the CSF of 15 patients with Alzheimer’s disease and 15 controls were analyzed by flow cytometry regarding the levels of CD3, CD4, CD45, CD64, BACE1, Aβ, APP and tau. The results were replicated in a second cohort comprising 14 patients with Alzheimer’s disease and 9 controls. The levels of tau and APP were reduced in microvesicles of Alzheimer’s disease patients. A significant change was neither observed in the number of microvesicles nor in the expression of the other antigens. Tau and APP in microvesicles separated patients with Alzheimer’s disease from controls with an AUC of 0.84 and 0.89 respectively. We conclude that tau and APP in CSF microvesicles are promising biomarkers which could directly provide information about the Alzheimer pathology on a cellular level.
CRIS-Team Scopus Importer:2019-05-21

Minimized Hemodiafiltration for Extracorporeal Membrane Oxygenation in Infants - Kwapil, Nicola; Teske, Andreas; Dittrich, Sven; Blumauer, Robert; Cuomo, Michela; Purbojo, Ariawan; Münch, Frank (Thoracic and Cardiovascular Surgeon, 2023)
BACKGROUND: Fluid overload is a serious complication in the treatment of infants with extracorporeal membrane oxygenation (ECMO). Volume overload leads to prolonged ECMO therapy if left untreated. The renal replacement therapy of choice in pediatric patients is peritoneal dialysis or conventional dialysis using a "large" hemofiltration machine via a Shaldon catheter or directly connected to the ECMO system. This study describes the implementation of a novel minimized hemodiafiltration (HDF) system in pediatric patients on ECMO. METHODS: This retrospective analysis included 13 infants up to 5 kg who underwent 15 veno-arterial (V-A) ECMO runs with HDF. A minimized HDF system is integrated into an existing ECMO system (18-mL priming volume), connected post-oxygenation to the venous line, before the ECMO pump. Two infusion pumps are attached to the inlet and outlet of the hemofilter to control the HDF system.In addition to retention values (creatine and urea) at six defined time points, flow rates, dialysis parameters, and volume withdrawal were examined, as well as the number of HDF system changes. RESULTS: With a mean ECMO runtime of 156 hours, the HDF system was utilized for 131 hours. The mean blood flow through the hemofilter was 192 mL/min. The mean dialysate flow was 170 mL/h, with a mean volume deprivation of 39 mL/h. The HDF system was changed once in seven cases and twice in three cases. CONCLUSION: There were no complications with the minimized HDF system in all 15 applications. It allows safe patient volume management when treating infants with ECMO, with effective elimination of urinary substances.
CRIS-Team Scopus Importer:2023-04-21

miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis - Benderska, Natalya; Dittrich, Anna-Lena; Knaup, Sabine; Rau, Tilman; Neufert, Clemens; Wach, Sven; Fahlbusch, Fabian B.; Rauh, Manfred; Wirtz, Ralph M.; Agaimy, Abbas; Srinivasan, Swetha; Mahadevan, Vijayalakshmi; et al. (Inflammatory Bowel Diseases, 2015)
Longstanding ulcerative colitis (UC) bears a high risk for development of UC-associated colorectal carcinoma (UCC). The inflammatory microenvironment influences microRNA expression, which in turn deregulates target gene expression. microRNA-26b (miR-26b) was shown to be instrumental in normal tissue growth and differentiation. Thus, we aimed to investigate the impact of miR-26b in inflammation-associated colorectal carcinogenesis.Two different cohorts of patients were investigated. In the retrospective group, a tissue microarray with 38 samples from 17 UC/UCC patients was used for miR-26b in situ hybridization and quantitative reverse transcription polymerase chain reaction analyses. In the prospective group, we investigated miR-26b expression in 25 fresh-frozen colon biopsies and corresponding serum samples of 6 UC and 15 non-UC patients, respectively. In silico analysis, Ago2-RNA immunoprecipitation, luciferase reporter assay, quantitative reverse transcription polymerase chain reaction examination, and miR-26b mimic overexpression were employed for target validation.miR-26b expression was shown to be upregulated with disease progression in tissues and serum of UC and UCC patients. Using miR-26b and Ki-67 expression levels, an UCC was predicted with high accuracy. We identified 4 novel miR-26b targets (DIP1, MDM2, CREBBP, BRCA1). Among them, the downregulation of the E3 ubiquitin ligase DIP1 was closely related to death-associated protein kinase stabilization along the normal mucosa-UC-UCC sequence. In silico functional pathway analysis revealed that the common cellular pathways affected by miR-26b are highly related to cancerogenesis and the development of gastrointestinal diseases.We suggest that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. Because miR-26b expression is downregulated in sporadic colon cancer, it could discriminate between UCC and the sporadic cancer type.
EVALuna2:1970

Miscarriages in families with an offspring that have classic congenital adrenal hyperplasia and 21-hydroxylase deficiency - Dörr, Helmuth-Günther; Hess, Johannes; Penger, Theresa; Marx, Martin; Oppelt, Patricia (BMC Pregnancy and Childbirth, 2018)
BACKGROUND: The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. METHODS: We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. RESULTS: Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling's families to date. CONCLUSION: Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated.
EVALuna2:35501

Missense variant c.1460 T > C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature - Himmelreich, Nastassja; Dimitrov, Bianca; Zielonka, Matthias; Hullen, Andreas; Hoffmann, Georg Friedrich; Juenger, Hendrik; Muller, Herbert; Lorenz, Imke; Busse, Birgit; Marschall, Christoph; Schluter, Gregor; Thiel, Christian (Molecular Genetics and Metabolism, 2022)
ALG9-CDG is a CDG-I defect within the group of Congenital Disorders of Glycosylation (CDG). We here describe the clinical symptoms of two new and unrelated ALG9-CDG patients, both carrying the novel homozygous missense variant c.1460 T > C (p.L487P) in the ALG9 gene which led to global developmental delay, psychomotor disability, facial dysmorphisms, brain and heart defects, hearing loss, hypotonia, as well as feeding problems. New clinical symptoms comprised West syndrome with hypsarrhythmia. Quantitative RT-PCR analysis revealed a significantly enhanced ALG9 mRNA transcript level, whereas the protein amount in fibroblasts was significantly reduced. This could be ascribed to a stronger degradation of the mutated ALG9 protein in patient fibroblasts. Lipid-linked oligosaccharide analysis showed an ALG9-CDG characteristic accumulation of Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol in patient cells. The clinical findings of our patients and of all previously published ALG9-CDG patients are brought together to further expand the knowledge about this rare N-glycosylation disorder. SYNOPSIS: Homozygosity for p.L487P in ALG9 causes protein degradation and leads to West syndrome.
CRIS-Team Scopus Importer:2022-08-19
Keywords: ALG9; CDG-I; Congenital disorders of glycosylation; Degradation; Mannosyltransferase; Protein instability

Mixture density networks for the indirect estimation of reference intervals - Hepp, Tobias; Zierk, Jakob; Rauh, Manfred; Metzler, Markus; Seitz, Sarem (BMC Bioinformatics, 2022)
Background: Reference intervals represent the expected range of physiological test results in a healthy population and are essential to support medical decision making. Particularly in the context of pediatric reference intervals, where recruitment regulations make prospective studies challenging to conduct, indirect estimation strategies are becoming increasingly important. Established indirect methods enable robust identification of the distribution of “healthy” samples from laboratory databases, which include unlabeled pathologic cases, but are currently severely limited when adjusting for essential patient characteristics such as age. Here, we propose the use of mixture density networks (MDN) to overcome this problem and model all parameters of the mixture distribution in a single step. Results: Estimated reference intervals from varying settings with simulated data demonstrate the ability to accurately estimate latent distributions from unlabeled data using different implementations of MDNs. Comparing the performance with alternative estimation approaches further highlights the importance of modeling the mixture component weights as a function of the input in order to avoid biased estimates for all other parameters and the resulting reference intervals. We also provide a strategy to generate partially customized starting weights to improve proper identification of the latent components. Finally, the application on real-world hemoglobin samples provides results in line with current gold standard approaches, but also suggests further investigations with respect to adequate regularization strategies in order to prevent overfitting the data. Conclusions: Mixture density networks provide a promising approach capable of extracting the distribution of healthy samples from unlabeled laboratory databases while simultaneously and explicitly estimating all parameters and component weights as non-linear functions of the covariate(s), thereby allowing the estimation of age-dependent reference intervals in a single step. Further studies on model regularization and asymmetric component distributions are warranted to consolidate our findings and expand the scope of applications.
CRIS-Team Scopus Importer:2022-08-12
Keywords: Distributional regression; Latent class regression; Mixture density networks; Reference intervals

Mobile applications in radiation oncology—current choices and future potentials - Janssen, Stefan; El Shafie, Rami A.; Ruder, Arne M.; Buergy, Daniel; Scafa, Davide; Giordano, Frank A.; Nicolay, Nils H.; Vogel, Marco M.E.; Combs, Stephanie E.; Fahlbusch, Fabian; Rades, Dirk; Käsmann, Lukas (Strahlentherapie und Onkologie, 2023)
Purpose: To review existing scientific literature on mobile applications (apps) in the field of radiation oncology and to evaluate characteristics of commercially available apps across different platforms. Methods: A systematic review of the literature for publications presenting apps in the field of radiation oncology was carried out using the PubMed database, Cochrane library, Google Scholar, and annual meetings of major radiation oncology societies. Additionally, the two major marketplaces for apps, App Store and Play Store, were searched for available radiation oncology apps for patients and health care professionals (HCP). Results: A total of 38 original publications which met the inclusion criteria were identified. Within those publications, 32 apps were developed for patients and 6 for HCP. The vast majority of patient apps focused on documenting electronic patient-reported outcomes (ePROs). In the two major marketplaces, 26 apps were found, mainly supporting HCP with dose calculations. Conclusion: Apps used in (and for) scientific research in radiation oncology are rarely available for patients and HCP in common marketplaces.
CRIS-Team Scopus Importer:2023-03-03
Keywords: Digitalization; Electronic health (e-health); Electronic patient reported outcome (ePROs); Radiotherapy; Smart phone apps

Mobility and freedom of movement: A novel out-of-hospital treatment for pediatric patients with terminal cardiac insufficiency and a ventricular assist device - Rottermann, Kathrin; Dittrich, Sven; Dewald, Oliver; Teske, Andreas; Kwapil, Nicola; Bleck, Steffen; Purbojo, Ariawan; Münch, Frank (Frontiers in Cardiovascular Medicine, 2022)
Background: Due to rapid medical and technological progress, more and more pediatric patients with terminal cardiac insufficiency are being implanted with a ventricular assist device as a bridge to transplant without legal approval for hospital discharge. EXCOR (R) Active is a recently developed mobile driving unit for the EXCOR (R) ventricular assist device (EXCOR (R) VAD) with a long-lasting battery life that can manage small blood pumps, offering improved mobility for pediatric patients. This study strives to elaborate the requirements necessary for a safe home healthcare environment (HHE) for pediatric patients on EXCOR (R) VAD powered by the EXCOR (R) Active driving unit. Materials and methods: Patient- and device-related preconditions (medical, ethical, psychological, technical, structural, organizational) were analyzed with regard to feasibility and safety in three individual patient cases. Included were pediatric patients with terminal cardiac insufficiency in a stable medical condition receiving in-hospital treatment with a univentricular or biventricular EXCOR (R) VAD powered by EXCOR (R) Active. Analysis was single-center, data was obtained 05/2020-02/2022. Results: A total of three patients on EXCOR (R) VAD were identified for HHE treatment with the EXCOR (R) Active driving unit. Switch was performed safely and increased mobility led to improved psychomotor development and improved quality of life. No complications directly related to HHE-treatment occurred. One patient recently underwent an orthotopic heart transplant, one patient remains in HHE, and one patient died due to a complication not related to the HHE. Ethical approval for off-label use was obtained and patients and parents were given the required technical training and psychological support. Caregivers and medical professionals involved in the patients' care at home were briefed intensely. Remote consultations were implemented and interdisciplinary in-hospital checks reduced to a long-term 4-week-scheme. Conclusion: While it is challenging to discharge pediatric patients being treated with a paracorporeal ventricular assist device (EXCOR (R) VAD) from hospital, it is feasible and can be managed safely with the novel driving unit EXCOR (R) Active. A HHE may help to improve patients' psychomotor development, offer normalized social contacts and strengthen both patients' and parents' physical and mental resources. Legal approval and another study with a larger sample size are warranted.
CRIS-Team WoS Importer:2022-12-30

Model-Based Simulation of Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia - Jost, Felix; Zierk, Jakob; Le, Thuy T.T.; Raupach, Thomas; Rauh, Manfred; Suttorp, Meinolf; Stanulla, Martin; Metzler, Markus; Sager, Sebastian (Frontiers in Physiology, 2020)
Acute lymphoblastic leukemia is the most common malignancy in childhood. Successful treatment requires initial high-intensity chemotherapy, followed by low-intensity oral maintenance therapy with oral 6-mercaptopurine (6MP) and methotrexate (MTX) until 2–3 years after disease onset. However, intra- and inter-individual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of 6MP and MTX make it challenging to balance the desired antileukemic effects with undesired excessive myelosuppression during maintenance therapy. A model to simulate the dynamics of different cell types, especially neutrophils, would be a valuable contribution to improving treatment protocols (6MP and MTX dosing regimens) and a further step to understanding the heterogeneity in treatment efficacy and toxicity. We applied and modified a recently developed semi-mechanistic PK/PD model to neutrophils and analyzed their behavior using a non-linear mixed-effects modeling approach and clinical data obtained from 116 patients. The PK model of 6MP influenced the accuracy of absolute neutrophil count (ANC) predictions, whereas the PD effect of MTX did not. Predictions based on ANC were more accurate than those based on white blood cell counts. Using the new cross-validated mathematical model, simulations of different treatment protocols showed a linear dose-effect relationship and reduced ANC variability for constant dosages. Advanced modeling allows the identification of optimized control criteria and the weighting of specific influencing factors for protocol design and individually adapted therapy to exploit the optimal effect of maintenance therapy on survival.
CRIS-Team Scopus Importer:2020-04-14
Keywords: 6-mercaptopurine; childhood acute lymphoblastic leukemia; maintenance therapy; methotrexate; neutropenia; non-linear mixed-effects modeling; population pharmacokinetics/pharmacodynamics

Modelling and Simulation of Piezoelectric Actuation and Reliability of Micropumps - Zhu, M.; Kirby, P.B.; Richter, M.; Congar, Y.; Diehl, Alexander; Völkl, Ralf (4M 2006, 2nd International Conference on Multi-Material Micro Manufacture, 20.-22.09.2006, Grenoble, France, 2006)
LFT Import::2019-08-05 (1322)

Modelling cardiac mechanics and electrophysiology of a rat left ventricle: A case study. - Duong, Minh Tuan; Wenger, Theresa; Herrnböck, Ludwig; Ach, Theresa; Holz, David; Kreipp, Anika; Binnewitt, Svea Vanessa; Stegmann, Hedwig; Dittrich, Sven; Alkassar, Muhannad; Leyendecker, Sigrid (International Conference on Biomedical Technology, 2017)
Keywords: mechanics; electrophysiology; rat left ventricle; fibres; FEM.

Modelling human lower urinary tract malformations in zebrafish - Kolvenbach, Caroline M.; Dworschak, Gabriel C.; Rieke, Johanna M.; Woolf, Adrian S.; Reutter, Heiko Martin; Odermatt, Benjamin; Hilger, Alina Christine (Molecular and Cellular Pediatrics, 2023)
Advances in molecular biology are improving our understanding of the genetic causes underlying human congenital lower urinary tract (i.e., bladder and urethral) malformations. This has recently led to the identification of the first disease-causing variants in the gene BNC2 for isolated lower urinary tract anatomical obstruction (LUTO), and of WNT3 and SLC20A1 as genes implicated in the pathogenesis of the group of conditions called bladder-exstrophy-epispadias complex (BEEC). Implicating candidate genes from human genetic data requires evidence of their influence on lower urinary tract development and evidence of the found genetic variants’ pathogenicity. The zebrafish (Danio rerio) has many advantages for use as a vertebrate model organism for the lower urinary tract. Rapid reproduction with numerous offspring, comparable anatomical kidney and lower urinary tract homology, and easy genetic manipulability by Morpholino®-based knockdown or CRISPR/Cas editing are among its advantages. In addition, established marker staining for well-known molecules involved in urinary tract development using whole-mount in situ hybridization (WISH) and the usage of transgenic lines expressing fluorescent protein under a tissue-specific promoter allow easy visualization of phenotypic abnormalities of genetically modified zebrafish. Assays to examine the functionality of the excretory organs can also be modeled in vivo with the zebrafish. The approach of using these multiple techniques in zebrafish not only enables rapid and efficient investigation of candidate genes for lower urinary tract malformations derived from human data, but also cautiously allows transferability of causality from a non-mammalian vertebrate to humans.
CRIS-Team Scopus Importer:2023-04-14

Möglichkeiten und Perspektiven der Modellierung und Simulation - Holz, David; Duong, Minh Tuan; Martonová, Denisa; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Thorax-, Herz- und Gefäßchirurgie, 2019)

Molecular Composition of Genomic TMPRSS2-ERG Rearrangements in Prostate Cancer - Krumbholz, Manuela; Agaimy, Abbas; Stöhr, Robert; Burger, Maximilian; Wach, Sven; Taubert, Helge; Wullich, Bernd; Hartmann, Arndt; Metzler, Markus (Disease Markers, 2019)
There is increasing interest in the use of cell-free circulating tumor DNA (ctDNA) as a serum marker for therapy assessment in prostate cancer patients. Prostate cancer is characterized by relatively low numbers of mutations, and, in contrast to many other common epithelial cancers, commercially available single nucleotide mutation assays for quantification of ctDNA are insufficient for therapy assessment in this disease. However, prostate cancer shares some similarity with translocation-affected mesenchymal tumors (e.g., leukemia and Ewing sarcoma), which are common in pediatric oncology, where chromosomal translocations are used as biomarkers for quantification of the tumor burden. Approximately 50% of prostate cancers carry a chromosomal translocation resulting in generation of the TMPRSS2-ERG fusion gene, which is unique to the tumor cells of each individual patient because of variability in the fusion breakpoint sites. In the present study, we examined the structural preconditions for TMPRSS2-ERG fusion sites in comparison with mesenchymal tumors in pediatric patients to determine whether the sequence composition is suitable for the establishment of tumor-specific quantification assays in prostate cancer patients. Genomic repeat elements represent potential obstacles to establishment of quantification assays, and we found similar proportions of repeat elements at fusion sites in prostate cancer to those reported for mesenchymal tumors, where genomic fusion sequences are established as biomarkers. Our data support the development of the TMPRSS2-ERG fusion gene as a noninvasive tumor marker for therapy assessment, risk stratification, and relapse detection to improve personalized therapy strategies for patients with prostate cancer.
CRIS-Team WoS Importer:2020-01-07

Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update - Peschel, Nicolai; Wright, John T.; Koster, Maranke I.; Clarke, Angus J.; Tadini, Gianluca; Fete, Mary; Hadj-Rabia, Smail; Sybert, Virginia P.; Norderyd, Johanna; Maier-Wohlfart, Sigrun; Fete, Timothy J.; Pagnan, Nina; et al. (Genes, 2022)
To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term "ectodermal dysplasia", referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.
CRIS-Team WoS Importer:2023-01-06

Molekulare Tumortherapie: Phase-I/II-Netzwerkstruktur der Gesellschaft für Pädiatrische Onkologie und Hämatologie - Nesper-Brock, Martina; Metzler, Markus; Wotschofsky, Zofia; Reinhardt, Dirk; Fischer, Matthias; Rutkowski, Stefan; Kratz, Christian; Thorwarth, Anne; Graf Einsiedel, Hagen; Schrappe, Martin; Mauz-Körholz, Christine; Witt, Olaf (Onkologe, 2021)
Background: To enable the rapid and efficient implementation of early clinical trials for pediatric patients and provide comprehensive access to novel treatment options for pediatric relapse or high-risk patients, five regional phase I/II trial networks have been established under the auspices of the Society for Pediatric Oncology and Hematology (GPOH). The network structure secures, bundles and organizes required competencies and resources and has established processes to optimize operational trial efficiency. The INFORM study is a population-based molecular diagnostic study for children and adolescents with recurrent cancer in Germany and 11 other countries. Preliminary data show that precision medicine in pediatric oncology is possible in an international multicenter setting, provides clinical benefit for subgroups of patients and helps to identify hereditary predispositions, to refine diagnoses and to match patients in suitable phase I/II clinical trials. Conclusions: The portfolio of innovative biomarker driven phase I/II clinical trials for children and adolescents with recurrent tumor diseases in Germany is currently limited. Therefore, the development of innovative, targeted therapy concepts and combination therapies is an important task in the coming years.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Clinical trial; phase I as topic; Clinical trial; phase II as topic; Molecular diagnostic techniques; Molecular targeted therapy; Precision medicine

More drug treatment safety for children Mehr Arzneimitteltherapiesicherheit für Kinder - Rascher, Wolfgang (Monatsschrift Kinderheilkunde, 2022)
CRIS-Team Scopus Importer:2022-03-25

Mortality of ECMO Because of Truncus Arteriosus Repair: Is the Surgical Strategy the Problem? - Cuomo, Michela; Dittrich, Sven; Cesnjevar, Robert (Annals of Thoracic Surgery, 2021)
CRIS-Team Scopus Importer:2021-04-02

MR imaging in children with transverse myelitis and acquired demyelinating syndromes - El Naggar, Ines; Cleaveland, Robert; Wendel, Eva Maria; Bertolini, Annikki; Schanda, Kathrin; Karenfort, Michael; Thiels, Charlotte; Della Marina, Adela; Schimmel, Mareike; Leiz, Steffen; Lechner, Christian; Baumann, Matthias; et al. (Multiple Sclerosis and Related Disorders, 2022)
Background: Transverse myelitis (TM) occurs isolated or within other acquired demyelinating syndromes (ADS) such as neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD). Objective: To describe and compare clinical and MRI features of children with ADS presenting with TM grouped according to antibody status and diagnosis of MS and NMOSD. Patients and methods: Children with TM, radiological involvement of the myelon, MOG and aquaporin-4 antibody status were elegible. Results: 100 children were identified and divided into MOGAD (n=33), NMOSD (n=7), double seronegative TM (n=34), and MS (n=26). MOGAD children had mainly acute disseminated encephalomyelitis + TM/ longitudinally extensive TM (LETM) (42%) or isolated LETM (30%). In MOGAD, LETM was present in more than half of all children (55%) with predominant involvement of only the grey matter (73%). Leptomeningeal enhancement was highly predictive of MOGAD (16/30; p=0.003). In MS patients spinal MRI showed single (50%) or multiple short lesions (46%) with involvement of grey and white matter (68%). Double seronegative children presented with LETM (74%) and brain lesions were less frequent compared to the other groups (30%). Conclusion: Children with ADS presenting with TM reveal important radiological differences such as LETM with predominant involvement of spinal grey matter and leptomeningeal enhancement in MOGAD.
CRIS-Team Scopus Importer:2022-09-02
Keywords: Acquired Demyelinating Syndrome; MOG; Neuroinflammation; Paediatric; Radiologic; Transverse Myelitis

Mucosal Mast Cell Distribution in the Gastrointestinal Tract of Children: A Preliminary Study for Establishing Reference Values - Ehrsam, Christoph; Rechenauer, Tobias; Allabauer, Ida; Siebenlist, Gregor; Kaspar, Sonja; Rieger, Daniel; Schmid, Margit; Ruckel, Aline; Wölfle, Joachim; Hartmann, Arndt; Rieker, Ralf; Raithel, Martin; et al. (Journal of Pediatric Gastroenterology and Nutrition, 2022)
Objectives: The physiological number and distribution of mast cells (MCs) in the pediatric gastrointestinal (GI) tract is not well defined and reference values of normality are missing. To define a physiological and disease defining cut-off, a systematic histological exploration of MC distribution from the esophagus to the rectum in healthy as well as in patients with gastrointestinal food allergies (GFA) was performed. Methods: Nine pediatric subjects that exhibited unremarkable histopathological evaluations or underwent endoscopy for surveillance reasons after a previous polypectomy of single colonic juvenile polyps served as reference cohort. In all of these subjects, a chronic inflammatory disease (eg, inflammatory bowel disease, celiac disease) or allergy was excluded. In addition, a group of 15 patients with gastrointestinal complaints suspected to be caused by a GFA were investigated. Immunohistochemistry was performed from all biopsies using CD117 (c-Kit) as a reliable marker to identify MCs in the lamina propria. Results: There were distinct differences of MC counts in all parts of the pediatric GI tract. The highest counts of MCs in both symptomatic patients and control cohort, were found in the duodenum, terminal ileum, cecum and ascending colon. The lowest counts were found in the esophagus. Significant disparities between GFA and healthy subjects were found in the gastric corpus (22.1 +/- 4.0/ high power field [HPF] vs 32.0 +/- 10.1/HPF; P = 0.034) and ascending colon (44.8 +/- 10.4/HPF vs 60.4 +/- 24.3/HPF; P = 0.047). Conclusions: Mucosal MC counts in the pediatric GI tract are higher than previously reported, with a considerable overlap between healthy and GFA patients. These results provide detailed information on distribution and numbers of MCs in pediatric allergic patients while allowing estimates of physiological values in childhood for the first time. With regard to diagnostic procedures in GFA further laboratory parameters have to be integrated.
CRIS-Team WoS Importer:2022-01-07

Multidisciplinary Late Effects Clinics for Childhood Cancer Survivors in Germany - a Two-Center Study - Gebauer, Judith; Rieken, Sarah; Schuster, Sonja; Hahn, Birgit; Gebauer, Niklas; Meidenbauer, Norbert; Brabant, Georg; Metzler, Markus; Langer, Thorsten (Oncology Research and Treatment, 2018)
EVALuna2:34277

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden - Peneder, Peter; Stütz, Adrian M.; Surdez, Didier; Krumbholz, Manuela; Semper, Sabine; Chicard, Mathieu; Sheffield, Nathan C.; Pierron, Gaelle; Lapouble, Eve; Tötzl, Marcus; Ergüner, Bekir; Barreca, Daniele; et al. (Nature Communications, 2021)
Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
CRIS-Team Scopus Importer:2021-06-11

Multimodality 3D-roadmap for cardiovascular interventions in congenital heart disease - A single-center, retrospective analysis of 78 cases - Glöckler, Martin; Halbfass, Julia; Koch, Andreas; Achenbach, Stephan; Dittrich, Sven (Catheterization and Cardiovascular Interventions, 2013)
Background Modern fluoroscopic angiography systems permit rendering of three-dimensional volumetric data sets using rotational angiography (3D-RA). Along with magnetic resonance imaging (MRI) or multi-detector-row computed tomography (MDCT) data sets, they can be fused with live fluoroscopy images for roadmapping during therapeutic procedures, but the value of multimodality fused data sets has not been clarified. Methods In a pediatric cardiac catheterization laboratory, we analyzed 78 interventional cardiovascular procedures in which 3D models of 3D-RA, MRI, or MDCT were used for 3D-guidance. Accuracy of 2D-3D registration as well as overall procedural benefit was independently rated by two pediatric interventionalists. Fluoroscopy time, radiation dose, and contrast dye consumption were evaluated and, grouping a subgroup analysis, the parameters were compared between patients who underwent stenting of aortic coarctation with and without 3D-roadmapping. Results 3D-guiding was used in 78 cases, 75 of these cases were with accurate 2D-3D registration. 3D-roadmapping was rated superior to conventional biplane imaging in 74 cases. 3D-guidance was used in 64 cases to define the ideal C-arm angulation and in 60 cases for accurate device positioning. Median dose-area product in the total investigation was 706.3 μGym2 (104.8-7249.7 μGym2), 3.3 ml/kg (0.9-13.7 ml/kg) of contrast dye was used, and total fluoroscopy time was 14.5 min (2.9-68.1 min). Fluoroscopy time for 3D-guided stenting of aortic coarctation is significantly lower (8.35 versus 10.2 min; P = 0.04). Conclusion 3D-image fusion with live fluoroscopy can be applied successfully in catheter-based interventions of congenital heart disease. 3D-guidance facilitates catheter manipulations and interventions, allows preselection of ideal projection angles, reduces fluoroscopic time and the number of control angiographies. © 2013 Wiley Periodicals, Inc.
CRIS-Team Scopus Importer:2023-03-08
Keywords: 3D-guidance; catheter-based interventions; image fusion; multimodality imaging; rotational angiography

Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma - Machiela, Mitchell J.; Gruenewald, Thomas G.; Surdez, Didier; Reynaud, Stephanie; Mirabeau, Olivier; Karlins, Eric; Rubio, Rebeca Alba; Zaidi, Sakina; Grossetete-Lalami, Sandrine; Ballet, Stelly; Lapouble, Eve; Laurence, Valerie; et al. (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Multisite measurement of regional oxygen saturation in Fontan patients with and without protein-losing enteropathy at rest and during exercise - Schroeer, Simon; Fahlbusch, Fabian B.; Münch, Frank; Alkassar, Muhannad; Toka, Hakan R.; Rauh, Manfred; Rueffer, Andre; Cesnjevar, Robert; Dittrich, Sven; Toka, Okan; Moosmann, Julia (Pediatric Research, 2019)
Background: Protein-losing enteropathy (PLE) is a severe complication of Fontan circulation with increased risk of end-organ dysfunction. We evaluated tissue oxygenation via near-infrared spectroscopy (NIRS) at different exercise levels in Fontan patients. Methods: Assessment of multisite NIRS during cycle ergometer exercise and daily activities in three groups: Fontan patients with PLE; without PLE; patients with dextro-transposition of the great arteries (d-TGA); comparing univentricular with biventricular circulation and Fontan with/without PLE. Renal threshold analysis (<65%;<55%;<45%) of regional oxygen saturation (rSO2) was performed. Results: Fontan patients showed reduced rSO2 (p < 0.05) in their quadriceps femoris muscle compared with biventricular d-TGA patients at all time points. rSO2 in renal tissue was reduced at baseline (p = 0.002), exercise (p = 0.0062), and daily activities (p = 0.03) in Fontan patients with PLE. Renal threshold analysis identified critically low renal rSO2 (rSO2 < 65%) in Fontan patients with PLE during exercise (95% of monitoring time below threshold) and daily activities (83.7% time below threshold). Conclusion: Fontan circulation is associated with decreased rSO2 values in skeletal muscle and hypoxemia of renal tissue solely in patients with PLE. Reduced rSO2 already during activities of daily life, might contribute to comorbidities in patients with Fontan circulation, including PLE and renal failure.
CRIS-Team Scopus Importer:2019-05-21

Multispectral optoacoustic tomography enables assessment of disease activity in paediatric inflammatory bowel disease - Regensburger, Adrian; Eckstein, Markus; Wetzl, Matthias; Raming, Roman; Paulus, Lars-Philip; Bühler, Adrian; Nedoschill, Emmanuel; Danko, Vera; Jüngert, Jörg; Wagner, Alexandra; Schnell, Alexander; Rückel, Aline; et al. (Photoacoustics, 2024)
Multispectral optoacoustic tomography (MSOT) allows non-invasive molecular disease activity assessment in adults with inflammatory bowel disease (IBD). In this prospective pilot-study, we investigated, whether increased levels of MSOT haemoglobin parameters corresponded to inflammatory activity in paediatric IBD patients, too. 23 children with suspected IBD underwent MSOT of the terminal ileum and sigmoid colon with standard validation (e.g. endoscopy). In Crohn‘s disease (CD) and ulcerative colitis (UC) patients with endoscopically confirmed disease activity, MSOT total haemoglobin (HbT) signals were increased in the terminal ileum of CD (72.1 ± 13.0 a.u. vs. 32.9 ± 15.4 a.u., p = 0.0049) and in the sigmoid colon of UC patients (62.9 ± 13.8 a.u. vs. 35.1 ± 16.3 a.u., p = 0.0311) as compared to controls, respectively. Furthermore, MSOT haemoglobin parameters correlated well with standard disease activity assessment (e.g. SES-CD and MSOT HbT (rs =0.69, p = 0.0075). Summarizing, MSOT is a novel technology for non-invasive molecular disease activity assessment in paediatric patients with inflammatory bowel disease.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Multispectral optoacoustic tomography; Optoacoustic imaging; Paediatric inflammatory bowel disease

Multispectral Optoacoustic Tomography for Assessment of Crohn's Disease Activity - Knieling, Ferdinand; Neufert, Clemens; Hartmann, Arndt; Claussen, Jing; Urich, Alexander; Egger, Cornelia; Vetter, Marcel; Fischer, Sarah; Pfeifer, Lukas; Hagel, Alexander; Kielisch, Christian; Görtz, Rüdiger; et al. (New England Journal of Medicine, 2017)
EVALuna2:33821

Multispectral optoacoustic tomography for non-invasive disease phenotyping in pediatric spinal muscular atrophy patients - Regensburger, Adrian; Wagner, Alexandra; Danko, Vera; Jüngert, Jörg M.; Federle, Anna; Klett, Daniel; Schüssler, Stephanie; Buehler, Adrian; Neurath, Markus; Roos, Andreas; Lochmüller, Hanns; Wölfle, Joachim; et al. (Photoacoustics, 2022)
Proximal spinal muscular atrophy (SMA) is a rare progressive, life limiting genetic motor neuron disease. While promising causal therapies are available, meaningful prognostic biomarkers for therapeutic monitoring are missing. We demonstrate handheld Multispectral Optoacoustic Tomography (MSOT) as a novel non-invasive imaging approach to visualize and quantify muscle wasting in pediatric SMA. While MSOT signals were distributed homogeneously in muscles of healthy volunteers (HVs), SMA patients showed moth-eaten optoacoustic signal patterns. Further signal quantification revealed greatest differences between groups at the isosbestic point for hemoglobin (SWL 800 nm). The SWL 800 nm signal intensities further correlated with clinical phenotype tested by standard motor outcome measures. Therefore, handheld MSOT could enable non-invasive assessment of disease burden in SMA patients.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Multispectral optoacoustic tomography; Optoacoustics; Photoacoustics; Spinal muscular atrophie

Multispectral Optoacoustic Tomography in Crohn's disease - A First-in-human Diagnostic Clinical Trial - Knieling, Ferdinand; Hartmann, Arndt; Uter, Wolfgang; Urich, Alexander; Claussen, Jing; Atreya, Raja; Rascher, Wolfgang; Waldner, Maximilian (2017)
EVALuna2:33902

Multispectral Optoacoustic Tomography in Ulcerative Colitis - A First-in-human Diagnostic Clinical Trial - Knieling, Ferdinand; Hartmann, Arndt; Claussen, Jing; Urich, Alexander; Atreya, Raja; Rascher, Wolfgang; Waldner, Maximilian (2017)
EVALuna2:33901

Multispectral optoacoustic tomography of the human intestine – temporal precision and the influence of postprandial gastrointestinal blood flow - Paulus, Lars-Philip; Wagner, Alexandra; Buehler, Adrian; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Günther, Josefine; Rother, Ulrich; Lang, Werner; Hörning, André; et al. (Photoacoustics, 2023)
Multispectral optoacoustic tomography (MSOT) holds great promise as a non-invasive diagnostic tool for inflammatory bowel diseases. Yet, reliability and the impact of physiological processes during fasting and after food intake on optoacoustic signals have not been studied. In the present investigator initiated trial (NCT05160077) the intestines of ten healthy subjects were examined by MSOT at eight timepoints on two days, one fasting and one after food intake. While within-timepoint and within-day reproducibility were good for single wavelength 800 nm and total hemoglobin (ICC 0.722–0.956), between-day reproducibility was inferior (ICC −0.137 to 0.438). However, temporal variability was smaller than variation between individuals (coefficients of variation 8.9%−33.7% vs. 17.0%−48.5%). After food intake and consecutive increased intestinal circulation, indicated by reduced resistance index of simultaneous Doppler ultrasound, optoacoustic signals did not alter significantly. In summary, this study demonstrates high reliability and temporal stability of MSOT for imaging the human intestine during fasting and after food intake.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Gut; Inflammatory bowel disease; Intestinal blood flow; Multispectral optoacoustic imaging; Optoacoustic; Photoacoustic; Postprandial; Reliability; Reproducibility

"Multisystem Inflammatory Syndrome in Children"-Like Disease after COVID-19 Vaccination (MIS-V) with Potential Significance of Functional Active Autoantibodies Targeting G-Protein-Coupled Receptors (GPCR-fAAb) for Pathophysiology and Therapy. - Schmidt, Marius; Hébert, Steven; Wallukat, Gerd; Ponader, Rolf; Krickau, Tobias; Galiano, Matthias; Reutter, Heiko Martin; Wölfle, Joachim; Agaimy, Abbas; Mardin, Christian; Hörning, André; Hohberger, Bettina (Children, 2023)
BACKGROUND: An infection with SARS-CoV-2 can trigger a systemic disorder by pathological autoimmune processes. A certain type of this dysregulation is known as Multisystemic inflammatory syndrome in children (MIS-C). However, similar symptoms may occur and have been described as Multisystemic inflammatory syndrome after SARS-CoV-2 Vaccination (MIS-V) following vaccination against SARS-CoV-2. We report the case of a 12-year-old boy who was identified with MIS-C symptoms without previous SARS-CoV-2 infection after receiving two doses of the Pfizer-BioNTech COVID-19 vaccine approximately one month prior to the onset of symptoms. He showed polyserositis, severe gastrointestinal symptoms and, consequently, a manifestation of a multiorgan failure. IgG antibodies against spike proteins of SARS-CoV-2 were detected, indicating a successful vaccination, while SARS-CoV-2 Nucleocapsid protein antibodies and SARS-CoV-2 PCR were not detected. Several functional, active autoantibodies against G-protein-coupled receptors (GPCR-fAAb), previously associated with Long COVID disease, were detected in a cardiomyocyte bioassay. Immunosuppression with steroids was initiated. Due to side effects, treatment with steroids and later interleukin 1 receptor antagonists had to be terminated. Instead, immunoadsorption was performed and continued with tacrolimus and mycophenolic acid therapy, leading to improvement and discharge after 79 days. GPCR-fAAb decreased during therapy and remained negative after clinical curing and under continued immunosuppressive therapy with tacrolimus and mycophenolic acid. Follow-up of the patient showed him in good condition after one year. CONCLUSIONS: Infection with SARS-CoV-2 shows a broad and severe variety of symptoms, partly due to autoimmune dysregulation, which, in some instances, can lead to multiorgan failure. Despite its rarity, post-vaccine MIS-C-like disease may develop into a serious condition triggered by autoimmune dysregulation. The evidence of circulating GPCR-fAAb and their disappearance after therapy suggests a link of GPCR-fAAb to the clinical manifestations. Thus, we hypothesize a potential role of GPCR-fAAb in pathophysiology and their potential importance for the therapy of MIS-C or MIS-V. However, this observation needs further investigation to prove a causative correlation.
EVALuna2:547545

“Multisystem Inflammatory Syndrome in Children” (MIS-C) after COVID-19 Infection in the Metropolitan Area of Nuremberg-Erlangen, Germany—Expectations and Results of a Two-Year Period - Hébert, Steven; Schmidt, Marius; Topf, Georg; Rieger, Daniel; Klinge, Jens; Vermehren, Jan; Fusch, Christoph; Grillhösl, Christian; Schroth, Michael; Toni, Irmgard; Reutter, Heiko Martin; Morhart, Patrick; et al. (Children, 2023)
Background: Multisystemic Inflammatory Syndrome in children (MIS-C) is a rare autoimmune disorder occurring after a latency period following acute SARS-CoV-2 infection. The therapeutic regime of MIS-C is adapted to the therapy of the Kawasaki disease, as clinical symptoms are similar. Since the Kawasaki disease can potentially result in severe symptoms, which may even affect long-term health, it is essential to gain further knowledge about MIS-C. Thus, we aimed to investigate the incidence, symptoms, therapeutical procedure and outcome of MIS-C patients in the metropolitan area of Nuremberg-Erlangen during the SARS-CoV2 pandemic. Material and Methods: Retrospective analysis of clinical charts of MIS-C patients was carried out at three children’s hospitals covering the medical care of the metropolitan area of Nuremberg-Erlangen in Germany. Demographic characteristics and symptoms at first visit, their clinical course, therapeutic regime and outcome were recorded within the time period January 2021–December 2022. Results: Analysis of 10 patients (5 male, 5 female) with MIS-C resulting in an incidence of 2.14/100.000 children. The median time between COVID-19 infection and admission to hospital was 5 weeks. The median age was 7 years. Symptoms comprised fever (100%), rash (70%), bilateral non-purulent conjunctivitis (70%) and urticaria (20%). At the time of presentation, diagnosis-defining inflammation parameters were increased and the range for C-reactive protein was 4.13 mg/dL to 28 mg/dL, with a median of 24.7 mg/dL. Procalcitonin was initially determined in six patients (1.92 ng/mL to 21.5 ng/mL) with a median value of 5.5 pg/mL. Two patients displayed leukocytosis and two displayed leukopenia. None of the patients presented coronary pathologies. Nine of the ten patients received intravenous immunoglobulin (IVIG) therapy. In addition, patients received intravenous steroids (80%) and acetylsalicylic acid (80%). Conclusion: SARS-CoV virus may rarely exert multiorgan manifestations due to hyperinflammatory immunological processes. Within two years of the COVID-19 pandemic, we identified ten patients with COVID-induced MIS-C in the metropolitan area Nuremberg-Erlangen. In the description of the patient collective, we can confirm that MIS-C is distinguished from the Kawasaki disease by the lack of coronary manifestations. Interestingly, although having monitored all pediatric facilities in the investigated area, we find lower incidences of MIS-C compared to findings in the literature. In conclusion, an overestimation of incidences in the upcoming MIS-C during the pandemic needs to be considered.
CRIS-Team Scopus Importer:2023-09-08
Keywords: COVID-19; intravenous immunoglobulins; IVIG; mAbs; MIS-C; monoclonal antibodies; Multisystem Inflammatory Syndrome in children

Mutational spectrum in 101 patients with hypohidrotic ectodermal dysplasia and breakpoint mapping in independent cases of rare genomic rearrangements - Wohlfart, Sigrun; Hammersen, Johanna; Schneider, Holm (Journal of Human Genetics, 2016)
Hypohidrotic ectodermal dysplasia (HED), a rare and heterogeneous hereditary disorder, is characterized by deficient development of multiple ectodermal structures including hair, sweat glands and teeth. If caused by mutations in the genes EDA, EDA1R or EDARADD, phenotypes are often very similar as the result of a common signaling pathway. Single-nucleotide polymorphisms (SNPs) affecting any gene product in this pathway may cause inter- and intrafamilial variability. In a cohort of 124 HED patients, genotyping was attempted by Sanger sequencing of EDA, EDA1R, EDARADD, TRAF6 and EDA2R and by multiplex ligation-dependent probe amplification (MLPA). Pathogenic mutations were detected in 101 subjects with HED, affecting EDA, EDA1R and EDARADD in 88%, 9% and 3% of the cases, respectively, and including 23 novel mutations. MLPA revealed exon copy-number variations in five unrelated HED families (two deletions and three duplications). In four of them, the genomic breakpoints could be localized. The EDA1R variant rs3827760 (p.Val370Ala), known to lessen HED-related symptoms, was found only in a single individual of Asian origin, but in none of the 123 European patients. Another SNP, rs1385699 (p.Arg57Lys) in EDA2R, however, appeared to have some impact on the hair phenotype of European subjects with EDA mutations.
EVALuna2:33878

Mutations in CFAP74 as a cause of primary ciliary dyskinesia (PCD) with normal nasal NO production rate and normal ciliary ultrastructure - Biebach, L.; Cindric, S.; Koenig, J.; Aprea,; Dougherty, G.; Raidt, J.; Bracht, D.; Ruppel, Renate; Schreiber, J.; Hieij, R.; Olbrich, H.; Omran, H. (KLINISCHE PADIATRIE, 2022)
Einleitung Die PCD ist eine seltene genetische Erkrankung deren respiratorischer Phänotyp langfristig durch eine destruktive, bronchiektasenbildende Lungenerkrankung charakterisiert ist. Mutationen in CFAP74 (Cilia and Flagella Associated Protein 74) wurden kürzlich als Ursache für MMAF (multiple morphological abnormalities of sperm flagella) bei zwei unfruchtbaren Männern veröffentlicht. Respiratorische Zilien wurden nicht untersucht, so dass CFAP74, welches ein central pair (CP)-assoziiertes Protein kodiert, als PCD-Ursache bislang nicht etabliert wurde. Methoden Patienten mit PCD-Verdacht wurden per genetischer Paneldiagnostik auf das Vorliegen von CFAP74-Mutationen untersucht und gefundene Mutationen mittels Sanger-Sequenzierung bestätigt. Neben Anamnese und klinischer Untersuchung erfolgten nasale NO-Messung, Hochfrequenz-Videomikroskopie-Analyse (HVMA), Immunfluoreszenz (IF) und Transmissions-Elektronenmikroskopie (TEM) als PCD-Diagnostik. Die mukoziläre Clearance wurde anhand von particle tracking auf ALI-Kulturen untersucht. Western Blot Analysen erfolgten zur Untersuchung der Proteinexpression. Ergebnisse Wir berichten über drei Betroffene aus zwei Familien mit biallelischen compound heterozygoten Loss-of-Function-Mutationen in CFAP74. Alle Patienten litten an rezidivierenden Atemwegsinfektionen. Interessanterweise waren sowohl die nasalen NO-Produktionsraten, als auch die Ultrastruktur in der TEM normal. Die HVMA wiederum identifizierte milde Anomalien des Zilienschlags. Die mukoziliäre Clearance war beeinträchtigt. Western-Blot-Analysen bewiesen die fehlende Expression von CFAP74. Schlussfolgerungen Mutationen in CFAP74 können PCD mit normaler NO-Produktionsrate, normaler Ultrastruktur und subtilem Zilienschlagdefekt verursachen. Um diese Patienten im diagnostischen Prozess dennoch identifizieren zu können, ist eine genetische Testung entscheidend. Wir empfehlen bei allen Patienten mit PCD-Verdacht eine genetische Untersuchung, die auch CFAP74 beinhalte
CRIS-Team WoS Importer:2023-01-27

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Neuromyelitis Optica Spectrum Disorder in a 6-Year-Old Boy - Kamawal, Ariana; Hörning, Susanne; Galiano, Matthias; Rompel, Oliver; Trollmann, Regina (Klinische Pädiatrie, 2019)
CRIS-Team Scopus Importer:2019-07-26

Myocarditis and sports in the young: data from a nationwide registry on myocarditis—“MYKKE-Sport” - Schöffl, Isabelle; Holler, Sophia; Dittrich, Sven; Pickardt, Thomas; Opgen-Rhein, Bernd; Boehne, Martin; Wannenmacher, Bardo; Reineke, Katja; Wiegand, Gesa; Hecht, Tobias; Kaestner, Michael; Messroghli, Daniel; et al. (Frontiers in Sports and Active Living, 2023)
Background: Myocarditis represents one of the most common causes of Sudden Cardiac Death in children. Myocardial involvement during a viral infection is believed to be higher as a consequence of intensive exertion. Recommendations for return to sports are based on cohort and case studies only. This study aims to investigate the relationship between physical activity and myocarditis in the young. Patient: Every patient in the MYKKE registry fulfilling criteria for suspicion of myocarditis was sent a questionnaire regarding the physical activity before, during and after the onset of myocarditis. Method: This study is a subproject within the MYKKE registry, a multicenter registry for children and adolescents with suspected myocarditis. The observation period for this analysis was 93 months (September 2013–June 2021). Anamnestic, cardiac magnetic resonance images, echocardiography, biopsy and laboratory records from every patient were retrieved from the MYKKE registry database. Results: 58 patients (mean age 14.6 years) were enrolled from 10 centers. Most patients participated in curricular physical activity and 36% in competitive sports before the onset of myocarditis. There was no significant difference of heart function at admission between the physically active and inactive subjects (ejection fraction of 51.8 ± 8.6% for the active group vs. 54.4 ± 7.7% for the inactive group). The recommendations regarding the return to sports varied widely and followed current guidelines in 45%. Most patients did not receive an exercise test before returning to sports. Conclusion: Sports before the onset of myocarditis was not associated with a more severe outcome. There is still a discrepancy between current literature and actual recommendations given by health care providers. The fact that most participants did not receive an exercise test before being cleared for sports represents a serious omission.
CRIS-Team Scopus Importer:2023-07-21
Keywords: cardiomyopathy; heart muscle infection; prevention; return to sports; sudden cardiac death

Nanoscale Topography of Anodic TiO2 Nanostructures Is Crucial for Cell-Surface Interactions - Park, Jung; Tesler, Alexander; Gongadze, Ekaterina; Iglič, Aleš; Schmuki, Patrik; Mazare, Anca Valentina (ACS Applied Materials and Interfaces, 2024)
Anodic titanium dioxide (TiO2) nanostructures, i.e., obtained by electrochemical anodization, have excellent control over the nanoscale morphology and have been extensively investigated in biomedical applications owing to their sub-100 nm nanoscale topography range and beneficial effects on biocompatibility and cell interactions. Herein, we obtain TiO2 nanopores (NPs) and nanotubes (NTs) with similar morphologies, namely, 15 nm diameter and 500 nm length, and investigate their characteristics and impact on stem cell adhesion. We show that the transition of TiO2 NPs to NTs occurs via a pore/wall splitting mechanism and the removal of the fluoride-rich layer. Furthermore, in contrast to the case of NPs, we observe increased cell adhesion and proliferation on nanotubes. The enhanced mesenchymal stem cell adhesion/proliferation seems to be related to a 3-fold increase in activated integrin clustering, as confirmed by immunogold labeling with β1 integrin antibody on the nanostructured layers. Moreover, computations of the electric field and surface charge density show increased values at the inner and outer sharp edges of the top surfaces of the NTs, which in turn can influence cell adhesion by increasing the bridging interactions mediated by proteins and molecules in the environment. Collectively, our results indicate that the nanoscale surface architecture of the lateral spacing topography can greatly influence stem cell adhesion on substrates for biomedical applications.
CRIS-Team Scopus Importer:2024-02-23
Keywords: anodization; integrin; stem cells; surface topography; TiO2 nanopores; TiO2 nanotubes

National survey of referrals for precocious puberty in Germany - Baehr, Sonja; Schnabel, Dirk; Wölfle, Joachim; Schreiner, Felix; Gohlke, Bettina (BMJ Paediatrics Open, 2023)
An unusual high number of girls were referred to our paediatric endocrine clinic with suspected precocious puberty (PP) since the beginning of the COVID-19 pandemic. We analysed our data and initiated a survey among German paediatric endocrinologists. At our centre, less than 10 patients were diagnosed of PP annually between 2015 and 2019. This increased to n=23 (2020) and n=30 (2021). A German survey confirmed this observation: Out of 44 centres which completed the questionnaire, 30/44 (68%) reported an increase of PP. Above this, 32/44 (72%) stated an increase in girls diagnosed with 'early normal puberty' since the beginning of the COVID-19 pandemic.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Adolescent Health; COVID-19; Endocrinology

National Survey on Training in Pediatric Cardiology by the "Junges Forum" of the DGPK - Horst, Jan Pit; Michel, Miriam; Kubicki, Rouven; Lang, Nora; Zschirnt, Martin; Moosmann, Julia (Thoracic and Cardiovascular Surgeon, 2020)
BACKGROUND: This is the first national survey of residents and fellows in pediatric cardiology in Germany evaluating training, research activity, and the general working environment. METHODS: An online questionnaire including 62 questions (SurveyMonkey) was developed by the "Junges Forum" of the German Society of Pediatric Cardiology. Fellows and residents during training and up to 3 years after completing their pediatric cardiology fellowship were invited to participate. RESULTS: A total of 102 pediatric cardiology fellows and residents completed the questionnaire. Many participants complained about their training as being unstructured (47%) and non-transparent (37%). The numbers of technical and catheter interventions required by the national medical board in Germany cannot be achieved, especially regarding invasive procedures. Sixty per cent work more than contractually agreed, usually in Germany it is 40 hours daytime work plus on calls, while 90% of all participants prefer less than 50 weekly working hours; 50% of the participants are engaged in research that is usually done during their spare time. More than 90% are satisfied with their professional relationships with colleagues and coworkers. Seventy-eight per cent describe their career perspectives as promising, and 84% would start a fellowship in pediatric cardiology again. CONCLUSION: The majority of pediatric cardiology fellows and residents are satisfied with their working environment and with their choice of a career in pediatric cardiology. Besides the heavy work load, we identified the urgent desire for better structured transparent clinical training concept including the teaching of manual skills, i.e., invasive procedures and catheterization.
CRIS-Team Scopus Importer:2020-03-13

Natural history and clinical outcome of junctional epidermolysis bullosa generalized intermediate due to a LAMA3 mutation - Reimer, A.; Schwieger-Briel, A.; He, Y.; Leppert, J.; Schauer, F.; Kiritsi, D.; Schneider, Holm; Ott, H.; Bruckner-Tuderman, L.; Has, C. (British Journal of Dermatology, 2018)
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Natural history of X-linked hypohidrotic ectodermal dysplasia: a 5-year follow-up study - Wohlfart, Sigrun; Meiller, Ralph; Hammersen, Johanna; Park, Jung; Menzel-Severing, Johannes; Melichar, Volker O.; Huttner, Kenneth; Johnson, Ramsey; Porte, Florence; Schneider, Holm (Orphanet Journal of Rare Diseases, 2020)
BACKGROUND: X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene EDA disrupting the prenatal development of ectodermal derivatives. Cardinal symptoms are hypotrichosis, lack of teeth, and hypo- or anhidrosis, but the disease may also evoke other clinical problems. This study aimed at investigating the clinical course of XLHED in early childhood as the basis for an evaluation of the efficacy of potential treatments. METHODS: 25 children (19 boys and 6 girls between 11 and 35 months of age) with genetically confirmed XLHED were enrolled in a long-term natural history study. Clinical data were collected both retrospectively using parent questionnaires and medical records (pregnancy, birth, infancy) and prospectively until the age of 60 months. General development, dentition, sweating ability, ocular, respiratory, and skin involvement were assessed by standardized clinical examination and yearly quantitative surveys. RESULTS: All male subjects suffered from persistent anhidrosis and heat intolerance, although a few sweat ducts were detected in some patients. Sweating ability of girls with XLHED ranged from strongly reduced to almost normal. In the male subjects, 1-12 deciduous teeth erupted and 0-8 tooth germs of the permanent dentition became detectable. Tooth numbers were higher but variable in the female group. Most affected boys had no more than three if any Meibomian glands per eyelid, most girls had fewer than 10. Many male subjects developed additional, sometimes severe health issues, such as obstructive airway conditions, chronic eczema, or dry eye disease. Adverse events included various XLHED-related infections, unexplained fever, allergic reactions, and retardation of psychomotor development. CONCLUSIONS: This first comprehensive study of the course of XLHED confirmed the early involvement of multiple organs, pointing to the need of early therapeutic intervention.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Dry eye; Ectodysplasin A; Heat intolerance; Hypohidrotic ectodermal dysplasia; Natural history; Oligodontia

Near final height in 62 twin pairs with twin-to-twin transfusion syndrome is not associated with the GHRd3 genotype - Schreiner, Felix; Schulte, Sandra; Kasner, Charlotte; Bartmann, Peter; Wölfle, Joachim; Gohlke, Bettina (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Neonatal Cholestasis - Differential Diagnoses, Current Diagnostic Procedures, and Treatment - Goetze, Thomas; Blessing, Holger; Grillhösl, Christian; Gerner, Patrick; Hoerning, Andre (Frontiers in Pediatrics, 2015)
Cholestatic jaundice in early infancy is a complex diagnostic problem. Misdiagnosis of cholestasis as physiologic jaundice delays the identification of severe liver diseases. In the majority of infants, prolonged physiologic jaundice represent benign cases of breast milk jaundice, but few among them are masked and caused by neonatal cholestasis (NC) that requires a prompt diagnosis and treatment. Therefore, a prolonged neonatal jaundice, longer than 2 weeks after birth, must always be investigated because an early diagnosis is essential for appropriate management. To rapidly identify the cases with cholestatic jaundice, the conjugated bilirubin needs to be determined in any infant presenting with prolonged jaundice at 14 days of age with or without depigmented stool. Once NC is confirmed, a systematic approach is the key to reliably achieve the diagnosis in order to promptly initiate the specific, and in many cases, life-saving therapy. This strategy is most important to promptly identify and treat infants with biliary atresia, the most common cause of NC, as this requires a hepatoportoenterostomy as soon as possible. Here, we provide a detailed work-up approach including initial treatment recommendations and a clinically oriented overview of possible differential diagnoses in order to facilitate the early recognition and a timely diagnosis of cholestasis. This approach warrants a broad spectrum of diagnostic procedures and investigations including new methods that are described in this review.
EVALuna2:18888

Neonatal nephron loss during active nephrogenesis - detrimental impact with long-term renal consequences - Menendez-Castro, Carlos; Nitz, Doerte; Cordasic, Nada; Jordan, Jutta; Bäuerle, Tobias; Fahlbusch, Fabian B.; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea (Scientific Reports, 2018)
Neonatal nephron loss may follow hypoxic-ischemic events or nephrotoxic medications. Its long-term effects on the kidney are still unclear. Unlike term infants, preterm neonates less than 36 weeks gestational age show ongoing nephrogenesis. We hypothesized that nephron loss during nephrogenesis leads to more severe renal sequelae than nephron loss shortly after the completion of nephrogenesis. Rats show nephrogenesis until day 10 of life resembling the situation of preterm infants. Animals were uninephrectomized at day 1 (UNX d1) resulting in nephron reduction during nephrogenesis and at day 14 of life (UNX d14) inducing nephron loss after the completion of nephrogenesis. 28 days after uninephrectomy the compensatory renal growth was higher in UNX d1 compared to UNX d14. Nephrin was reduced and collagen deposition increased in UNX d1. At 1 year of age, glomerulosclerosis and markers of tubulointerstitial damage were most prevalent in UNX d1. Moreover, the number of desmin-positive podocytes was higher and nephrin was reduced in UNX d1 indicating podocyte damage. Infiltration of inflammatory cells was heightened after UNX d1. Uninephrectomized animals showed no arterial hypertension. We conclude that neonatal nephron loss during active nephrogenesis leads to more severe glomerular and tubulointerstitial damage, which is not a consequence of compensatory arterial hypertension.
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Neonatal nephron loss during active nephrogenesis results in altered expression of renal developmental genes and markers of kidney injury - Raming, Roman; Cordasic, Nada; Kirchner, Philipp; Ekici, Arif Bülent; Fahlbusch, Fabian; Wölfle, Joachim; Hilgers, Karl Friedrich; Hartner, Andrea; Menendez-Castro, Carlos (Physiological Genomics, 2021)
Preterm neonates are at a high risk for nephron loss under adverse clinical conditions. Renal damage potentially collides with postnatal nephrogenesis. Recent animal studies suggest that nephron loss within this vulnerable phase leads to renal damage later in life. Nephrogenic pathways are commonly reactivated after kidney injury supporting renal regeneration. We hypothesized that nephron loss during nephrogenesis affects renal development, which, in turn, impairs tissue repair after secondary injury. Neonates prior to 36 wk of gestation show an active nephrogenesis. In rats, nephrogenesis is ongoing until day 10 after birth. Mimicking the situation of severe nephron loss during nephrogenesis, male pups were uninephrectomized at day 1 of life (UNXd1). A second group of males was uninephrectomized at postnatal day 14 (UNXd14), after terminated nephrogenesis. Agematched controls were sham operated. Three days after uninephrectomy transcriptional changes in the right kidney were analyzed by RNA-sequencing, followed by functional pathway analysis. In UNXd1, 1,182 genes were differentially regulated, but only 143 genes showed a regulation both in UNXd1 and UNXd14. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations. Reduced expression of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and injury (nephrin, podocin, Tgf-b 1) were detected. The downregulation of Bmp7 and Gdnf persisted until day 28. In UNXd14, Six2 was upregulated and Pax2 was downregulated. We conclude that nephron loss during nephrogenesis affects renal development and induces a specific regulation of genes that might hinder tissue repair after secondary kidney injury.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Neonatal nephron loss; Neonatal uninephrectomy; Nephrogenesis; Renal regeneration; RNA-sequencing

Nephroprotective treatment exemplified by Alport syndome - Gross, O.; Rascher, Wolfgang (Monatsschrift Kinderheilkunde, 2019)
In children with the hereditary kidney disease Alport syndrome, the extreme importance of clarification of (micro)hematuria in childhood in order to enable an early nephroprotective treatment can be shown. This not only decisively delays the kidney disease but also improves life expectancy. Children with Alport syndrome develop progressive renal fibrosis due to genetic variants in type IV collagen genes. In the past the symptomatic hematuria symptoms in heterozygous carrier patients was misclassified as familial benign hematuria; however, the disease process by these heterozygous carrier patients often does not have a benign course of the disease. Therefore, all homozygous and heterozygous patients are now summarized under the diagnosis Alport syndrome. If diagnosed early Alport syndrome can be well treated. Renal failure can be delayed by many years and life expectancy can be improved. Because of the available treatment options, the diagnosis should be made as soon as possible in every affected child by molecular genetic testing. Unfortunately, the diagnosis is often made too late at the age of early adolescence when the renal function is already severely impaired.
CRIS-Team WoS Importer:2019-06-18

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study - Thome, Ulrich H.; Genzel-Boroviczeny, Orsolya; Bohnhorst, Bettina; Schmid, Manuel; Fuchs, Hans; Rohde, Oliver; Avenarius, Stefan; Topf, Hans-Georg; Zimmermann, Andrea; Faas, Dirk; Timme, Katharina; Kleinlein, Barbara; et al. (Archives of Disease in Childhood-Fetal and Neonatal Edition, 2017)
BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743.
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Neurogenic bladder function disorders in patients with meningomyelocele: S2k guidelines on diagnostics and therapy - Stein, R.; Assion, C.; Beetz, R.; Buerst, M.; Cremer, R.; Ermert, A.; Goepel, M.; Kuwertz-Broeking, E.; Ludwikowski, B.; Michael, T.; Pannek, J.; Peters, H.; et al. (Urologe, 2015)
The treatment of children and adolescents with meningomyelocele has experienced a clear change in the last 30 years. The establishment of pharmacotherapy, clean intermittent catheterization (CIC) and infection prophylaxis have improved the prognosis for patients and have led to new therapeutic strategies. The interdisciplinary cooperation between neonatologists, neurosurgeons, pediatric neurologists, pediatric urologists, pediatric nephrologists, pediatric orthopedists and pediatric surgeons leads to optimization of individualized therapy. These guidelines present definitions and classifications, investigations and timing which are described in detail. The conservative and operative therapy options for neurogenic bladder function disorders are described and discussed with reference to the current literature. The brief overview provides in each case assistance for the treating physician in the care of this patient group and facilitates the interdisciplinary cooperatio
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Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence - Krinzinger, Helga; Hall, Charlotte L.; Groom, Madeleine J.; Ansari, Mohammed T.; Banaschewski, Tobias; Buitelaar, Jan K.; Carucci, Sara; Coghill, David; Danckaerts, Marina; Dittmann, Ralf W.; Falissard, Bruno; Garas, Peter; et al. (Neuroscience and Biobehavioral Reviews, 2019)
Methylphenidate (MPH), the most common medication for children with Attention Deficit/Hyperactivity Disorder (ADHD) in many countries, is often prescribed for long periods of time. Any long-term psychotropic treatment in childhood raises concerns about possible adverse neurological and psychiatric outcomes. We aimed to map current evidence regarding neurological and psychiatric outcomes, adverse or beneficial, of long-term MPH (> 1 year) treatment in ADHD. We coded studies using a “traffic light” system: Green: safe/favours MPH; Amber: warrants caution; Red: not safe/not well-tolerated. Un-categorisable study findings were coded as “Unclear”. Although some evidence suggests an elevated risk of psychosis and tics, case reports describe remission on discontinuation. Several studies suggest that long-term MPH may reduce depression and suicide in ADHD. Evidence suggests caution in specific groups including pre-school children, those with tics, and adolescents at risk for substance misuse. We identified a need for more studies that make use of large longitudinal databases, focus on specific neuropsychiatric outcomes, and compare outcomes from long-term MPH treatment with outcomes following shorter or no pharmacological intervention.
CRIS-Team Scopus Importer:2019-11-19
Keywords: ADHD; Adverse neuropsychiatric events; Anxiety; Bipolar; Long-term methylphenidate treatment; Mood; Psychosis; Seizures; Sleep disorders; Substance use disorder; Suicidal ideation; Tics

Neurological outcome at 24 months corrected age of prematurely born infants after preterm premature rupture of membranes (PPROM) of at least 7 days: a two-center experience in Germany - Müller, Hanna; Storbeck, Tobias; Katzer, David; Bruns, Nora; Wössner-Stegmann, Gaby; Ai, Maria; Köninger, Angela; Müller, Andreas; Felderhoff-Müser, Ursula; Bagci, Soyhan (Journal of Maternal-Fetal & Neonatal Medicine, 2018)
OBJECTIVE: Preterm premature rupture of membranes (PPROM) is a risk factor for chorioamnionitis (CA) and injury to the fetal brain. However, prolongation of gestation prevents morbidity and decreases complications of prematurity. The current investigation is to define risk factors for the adverse neurological outcome from the influence of PPROM of at least 7 days. METHODS: A case-control study included three groups of preterm infants born at the University Hospitals Bonn and Essen, Germany. The first group consisted of infants with PPROM of at least 7 days and no chorioamnionitis (CA) (PPROM group), the second included preterm infants with CA (CA group), and the third group consisted of infants without PPROM and CA (control group). The outcome was assessed using Bayley Scales of Infant Development at a corrected age of 24 months. Each group consisted of 20 corresponding infants with an identical birth weight and gestational age at birth. RESULTS: There was no significant difference between the mental development index (MDI) and psychomotor development index (PDI) scores (mean ± SD): the MDI score was 101 ± 14 in the PPROM group, 98 ± 12 in the CA group and 96 ± 17 in the control group; the PDI score 96 ± 10, 89 ± 16, and 90 ± 17, respectively. Multiple regression analysis revealed no significant influence of PPROM and CA on neurological outcome. CONCLUSIONS: PPROM of at least 7 days has no influence on neurodevelopmental outcome at a corrected age of 24 months when birth is initiated in the case of beginning CA.
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Neuromonitoring in Neonatal-Onset Epileptic Encephalopathies - Trollmann, Regina (Frontiers in Neurology, 2021)
Considering the wide spectrum of etiologies of neonatal-onset epileptic encephalopathies (EE) and their unfavorable consequences for neurodevelopmental prognoses, neuromonitoring at-risk neonates is increasingly important. EEG is highly sensitive for early identification of electrographic seizures and abnormal background activity. Amplitude-integrated EEG (aEEG) is recommended as a useful bedside monitoring method but as a complementary tool because of methodical limitations. It is of special significance in monitoring neonates with acute symptomatic as well as structural, metabolic and genetic neonatal-onset EE, being at high risk of electrographic-only and prolonged seizures. EEG/aEEG monitoring is established as an adjunctive tool to confirm perinatal hypoxic-ischemic encephalopathy (HIE). In neonates with HIE undergoing therapeutic hypothermia, burst suppression pattern is associated with good outcomes in about 40% of the patients. The prognostic specificity of EEG/aEEG is lower compared to cMRI. As infants with HIE may develop seizures after cessation of hypothermia, recording for at least 24 h after the last seizure is recommended. Progress in the identification of genetic etiology of neonatal EE constantly increases. However, presently, no specific EEG changes indicative of a genetic variant have been characterized, except for individual variants associated with typical EEG patterns (e.g., KCNQ2, KCNT1). Long-term monitoring studies are necessary to define and classify electro-clinical patterns of neonatal-onset EE.
CRIS-Team Scopus Importer:2021-03-05
Keywords: electroencephalopgraphy; genetic epilepsy; metabolic epilepsy; neonatal brain; suppression burst

Neuromonitoring in neonatal seizures-significance and challenges Neuromonitoring bei zerebralen Anfällen im Neugeborenenalter-Chancen und Herausforderungen - Trollmann, Regina (Klinische Neurophysiologie, 2021)
Neonatal EEG-monitoring including amplitude-integrated EEG (aEEG) is a valuable bedside tool for diagnosis of epileptic seizures and neonatal epileptic encephalopathies, as well as for continuous treatment monitoring. Because of methodical limitations of aEEG monitoring, the combinatory use of aEEG and conventional EEG is recommended as the gold standard. Especially physiological EEG maturation patterns and epileptic discharges (e. g. discharges<10 s, electrographic seizures in very preterm neonates) are exclusively identified by conventional EEG. Long-term EEG/aEEG monitoring is of special significance in neonates at risk of electrographic-only or subtle seizures. EEG/aEEG is an important additional tool for monitoring neonates with HIE undergoing therapeutic hypothermia. Rarely, typical EEG changes indicative of a genetic variant have been characterized. Further studies are necessary on the role of EEG/aEEG as biomarker of neurodevelopmental outcome in neonates with seizures of various etiology.
CRIS-Team Scopus Importer:2021-09-24
Keywords: amplitude-integrated EEG; genetic early-onset epileptic encephalopathy; hypoxic-ischemic encephalopathy; KCNQ2; KCNT1; maturational patterns; neonatal stroke

Neuropathy in paediatric type 1 diabetes mellitus - Clinical characterization and analysis of risk factors in the diabetes prospective follow-up registry DPV (Diabetes-Patienten-Verlaufsdokumentation)-registry - Pappa, Angeliki; Haeusler, Martin G.; Tittel, Sascha R.; Boettcher, Claudia; Hilgard, Doerte; Knauer-Fischer, Sabine; Pavel, Marianne Ellen; Wölfle, Joachim; Holl, Reinhard W. (Journal of Pediatric Endocrinology & Metabolism, 2023)
Objectives: Data on the prevalence, clinical features and risk factors associated with paediatric diabetic neuropathy (DN) are scarce. Methods: We retrospectively analysed data from the DPV registry, including patients under 20years of age, treated for type 1 diabetes mellitus (T1D) between 2005 and 2021. Patients with non-diabetic neuropathy were excluded. Data came from centres in Austria, Germany, Luxembourg and Switzerland. Results: 1,121 of the 84,390 patients included had been diagnosed with DN. Univariate analysis showed patients with DN to be older and predominantly female, with a longer duration of T1D, higher insulin dosages per kg and day, lower rates of insulin pump therapy, higher postprandial glucose-, higher HbA1c-and higher cholesterol levels, and higher diastolic and systolic blood pressure values. There was also a larger proportion of smokers and higher prevalence of diabetic retinopathy. Median duration of diabetes at diagnosis of DN was 8.3years. Multivariable analysis, adjusted for demographics revealed an increased risk for DN among female patients and those who were older, underweight (BMI-SDS), smoked cigarettes or had a longer duration of T1D or higher levels of HbA1c and postprandial blood glucose. The presence of retinopathy and higher cholesterol levels were also linked to increased risk while not-using insulin pump therapy was not. Conclusions: DN can develop after just a short duration of T1D. Prevention may be achieved by a lowering of HbA1c-and postprandial glucose levels through improved glycaemic control. This warrants further investigation. The slight female predominance suggests further hormonal and genetic etiological factors.
CRIS-Team Scopus Importer:2023-07-07
Keywords: autonomic dysfunction; childhood diabetes; diabetic neuropathy; DPV; small fiber neuropathy; type 1 diabetes mellitus

Neutrophil Extracellular Traps Initiate Gallstone Formation - Munoz, Luis Enrique; Boeltz, Sebastian; Bilyy, Rostyslav; Schauer, Christine; Mahajan, Aparna; Widulin, Navena; Grüneboom, Anika; Herrmann, Irmgard; Boada, Edgyda; Rauh, Manfred; Krenn, Veit; Biermann, Mona H.C.; et al. (Immunity, 2019)
The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.
CRIS-Team Scopus Importer:2019-09-17
Keywords: calcium carbonate crystals; cholesterol crystals; gallstone growth; gallstones; lisosomal leakage; lithogenic diet; neutrophil extracellular traps; neutrophils; NOX2; PADi4

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratio in Univentricular Patients From Birth to Follow-Up After Fontan-Predicting Lymphatic Abnormalities - Moosmann, Julia; Schroeder, Christian; Cesnjevar, Robert; Rottermann, Kathrin; Weigelt, Annika; Dittrich, Sven (Frontiers in Pediatrics, 2021)
Background: Reliable laboratory parameters identifying complications after Fontan surgery including the lymphatic abnormalities and the development of protein-losing enteropathy (PLE) are rare. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocte ratio (PLR) are inflammatory markers and have been studied to predict outcome and prognosis in various diseases. The aim of this study was to investigate NLR and PLR from birth to follow-up after Fontan and evaluate their use as prognostic parameters for single ventricle patients regarding the development of lymphatic malformations during follow-up.Materials and Methods: Sixty-six univentricular patients who underwent Fontan surgery and had 6-month follow-up magnetic resonance imaging (MRI) with T2 weighted lymphatic imaging after total cavopulmonary connection (TCPC) surgery were included in the study. NLR and PLR were determined at specific time points, from neonatal age to follow-up after Fontan operation and correlated to data from the MRI 6 months after Fontan.Results: NLR and PLR increase significantly over time from the first surgery during infancy to the follow-up after Fontan (both p < 0.0001), with a significant increase after the Glenn surgery for both ratios (each p < 0.0001). Higher NLR (p = 0.002) and higher PLR (p = 0.004) correlated with higher-grade classification of lymphatic abnormalities in T2-weighted imaging 6 months after Fontan surgery and higher NLR correlated with higher transpulmonary gradient prior to Fontan surgery (p = 0.035) Both ratios showed a significant correlation to total protein at follow-up (NLR p = 0.0038; PLR<0.0001).Conclusion: Increased NLR and PLR correlate with higher degree lymphatic malformations after TCPC and therefore might contribute as valuable additional biomarker during follow-up after TCPC. NLR and PLR are simple, inexpensive and easily available parameters to complement diagnostics after TCPC.
CRIS-Team WoS Importer:2021-12-31

Newborn screening and disease variants predict neurological outcome in isovaleric aciduria - Muetze, Ulrike; Henze, Lucy; Gleich, Florian; Lindner, Martin; Gruenert, Sarah C.; Spiekerkoetter, Ute; Santer, Rene; Blessing, Holger; Thimm, Eva; Ensenauer, Regina; Weigel, Johannes; Beblo, Skadi; et al. (Journal of Inherited Metabolic Disease, 2021)
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P =.0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P =.01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.
CRIS-Team Scopus Importer:2021-03-05
Keywords: isovaleric acidemia; isovaleric aciduria; long-term outcome; neonatal screening; newborn screening

Newbornscreening SMA - From Pilot Project to Nationwide Screening in Germany - Müller-Felber, Wolfgang; Blaschek, Astrid; Schwartz, Oliver; Gläser, Dieter; Nennstiel, Uta; Brockow, Inken; Wirth, Brunhilde; Burggraf, Siegfried; Röschinger, Wulf; Becker, Marc; Durner, Jürgen; Eggermann, Katja; et al. (Journal of Neuromuscular Diseases, 2023)
Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.
CRIS-Team Scopus Importer:2023-01-20
Keywords: 5q-SMA; newborn screening; SMA treatment; Spinal muscular atrophy

New kids on the CPET: age-appropriate outdoor cardiopulmonary exercise testing in preschoolers - Rottermann, Kathrin; Weigelt, Annika; Staebler, Tim; Ehrlich, Benedikt; Dittrich, Sven; Schöffl, Isabelle (European Journal of Applied Physiology, 2022)
Purpose: Cardiopulmonary exercise testing (CPET) in preschoolers (4–6 years) represents a challenge. Most studies investigating CPET have been limited to older children (> 8 year). However, knowledge of the performance of small children is essential for evaluating their cardiorespiratory fitness. This study strives to compare a modified Bruce protocol with a new age-appropriate incremental CPET during natural movement running outdoors, using a mobile device. Methods: A group of 22 4–6-year-old healthy children was tested indoor on a treadmill (TM) using the modified Bruce protocol. The results were compared with a self-paced incremental running test, using a mobile CPET device in an outdoor park. The speeds were described as (1) slow walking, (2) slow running, (3) regular running, and (4) running with full speed as long as possible. Results: Mean exercise time outdoors (6,57 min) was significantly shorter than on the treadmill (11,20 min), V˙ O2peak (51.1 ml/min/kg vs. 40.1 ml/min/kg), RER (1.1 vs. 0.98) and important CPET parameters such as V˙ Emax, O2pulse, heart rate and breath rate were significantly higher outdoors. The submaximal parameter OUES was comparable between both the tests. Conclusions: Testing very young children with a mobile device is a new alternative to treadmill testing. With a significantly shorter test duration, significantly higher values for almost all cardiopulmonary variables can be achieved without losing the ability to determine VT1 and VT2. It avoids common treadmill problems and allows for individualized exercise testing. The aim is to standardize exercise times with individual protocols instead of standardizing protocols with individual exercise times, allowing for better comparability.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Age-appropriate; Cardiopulmonary exercise test; CPET; Outdoor; Pediatric; Preschooler

NEXT-GENERATION REFERENCE INTERVALS FOR PEDIATRIC HEMATOLOGY - Zierk, Jakob; Hirschmann, J.; Toddenroth, Dennis; Arzideh, F.; Streichert, T.; Haeckel, R.; Prokosch, Hans-Ulrich; Rauh, Manfred; Metzler, Markus (2017)
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Next-generation reference intervals for pediatric hematology - Zierk, Jakob; Hirschmann, Johannes; Toddenroth, Dennis; Arzideh, Farhad; Haeckel, Rainer; Bertram, Alexander; Cario, Holger; Frühwald, Michael C.; Groß, Hans Jürgen; Groening, Arndt; Grützner, Stefanie; Gscheidmeier, Thomas; et al. (Clinical Chemistry and Laboratory Medicine, 2019)
Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions. We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905-1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases. We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases. The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.
CRIS-Team Scopus Importer:2019-05-09
Keywords: hematology; laboratory test result display; pediatric reference intervals

No benefit of HIF prolyl hydroxylase inhibition for hypertensive renal damage in renovascular hypertensive rats - Hartner, Andrea; Dambietz, Thomas; Cordasic, Nada; Willam, Carsten; Burzlaff, Nicolai; Brötsch, Martin; Daniel, Christoph; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Schley, Gunnar; Hilgers, Karl Friedrich (Frontiers in Physiology, 2023)
Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified “preconditioning” approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.
CRIS-Team Scopus Importer:2023-07-21
Keywords: capillarization; HIF stabilization; malignant hypertension; renovascular; vascular lesions

Noduläre Schilddrüsenbefunde bei zwei Patienten im Alter von 6 und 13 Jahren - Wowra, T.; Deeg, K. H. (Pädiatrische Praxis, 2020)
Patientin 1 Im vierten Lebensjahr war das Mädchen an einer akuten lymphoblastischen Leukämie ohne ZNS- Beteiligung erkrankt. Im fünften Lebensjahr kam es zu einem ZNS-negativen Acute Lymphoblastic Leukemia-(ALL-)Rezidiv. Es wurde keine Radiatio durchgeführt. Im selben Jahr folgte eine Stammzelltransplantation. Bis zum 12. Lebensjahr verliefen die Nachsorgetermine unauffällig. Patient 2 Ein seit Geburt gesunder, aktuell 6-jähriger Junge wurde mit seit wenigen Monaten nicht mehr abklingenden Halsschmerzen und Schluck-beschwerden vorgestellt. Sein Allgemein- und Ernährungszustand waren deutlich reduziert. Es bestanden eine Dyspnoe in Form jugulärer Einziehungen und einem leisen Stridor. Der Junge konnte lediglich kurze Sätze sprechen, dabei bestand Heiserkeit.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Noduläre Schilddrüsenbefunde; Punktförmige Echogenitätsvermehrungen

No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia - Körber, Laura; Schneider, Holm; Fleischer, Nicole; Maier-Wohlfart, Sigrun (Orphanet Journal of Rare Diseases, 2021)
Background: X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns. Methods: Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features. Results: The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes. Conclusions: We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Ectodysplasin A; Female carriers; Genotype–phenotype correlation; X-chromosome inactivation; X-linked hypohidrotic ectodermal dysplasia

No evidence of the unfolded protein response in the placenta of two rodent models of preeclampsia and intrauterine growth restriction - Denkl, Barbara; Cordasic, Nada; Hübner, Hanna; Menendez-Castro, Carlos; Schmidt, Marius; Mocker, Alexander; Wölfle, Joachim; Hartner, Andrea; Fahlbusch, Fabian (Biology of Reproduction, 2021)
In humans, intrauterine growth restriction (IUGR) and preeclampsia (PE) are associated with induction of the unfolded protein response (UPR) and increased placental endoplasmic reticulum (ER) stress. Especially in PE, oxidative stress occurs relative to the severity of maternal vascular underperfusion (MVU) of the placental bed. On the premise that understanding the mechanisms of placental dysfunction could lead to targeted therapeutic options for human IUGR and PE, we investigated the roles of the placental UPR and oxidative stress in two rodent models of these human gestational pathologies. We employed a rat IUGR model of gestational maternal protein restriction, as well as an endothelial nitric oxide synthase knockout mouse model (eNOS-/-) of PE/IUGR. Placental expression of UPR members was analyzed via qRT-PCR (Grp78, Calnexin, Perk, Chop, Atf6, and Ern1), immunohistochemistry, and Western blotting (Calnexin, ATF6, GRP78, CHOP, phospho-eIF2α, and phospho-IRE1). Oxidative stress was determined via Western blotting (3-nitrotyrosine and 4-hydroxy-2-nonenal). Both animal models showed a significant reduction of fetal and placental weight. These effects did not induce placental UPR. In contrast to human data, results from our rodent models suggest retention of placental plasticity in the setting of ER stress under an adverse gestational environment. Oxidative stress was significantly increased only in female IUGR rat placentas, suggesting a sexually dimorphic response to maternal malnutrition. Our study advances understanding of the involvement of the placental UPR in IUGR and PE. Moreover, it emphasizes the appropriate choice of animal models researching various aspects of these pregnancy complications.
CRIS-Team Scopus Importer:2021-08-27
Keywords: eNOS; ER stress; IUGR; oxidative stress; placenta; preeclampsia

No juvenile arterial hypertension in sheep multiples despite reduced nephron numbers - Muehle, Anja; Mühle, Christiane; Amann, Kerstin Ute; Dötsch, Jörg; Nuesken, Kai-Dietrich; Boltze, Johannes; Schneider, Holm (Pediatric Nephrology, 2010)
Low birth weight is associated with an increased risk of metabolic dysfunction and arterial hypertension in later life. Because of their reduced birth weight twins have been used repeatedly as a natural model to investigate prenatal programming of hypertension. To reveal an early impact of lower nephron endowment on blood pressure, we performed a longitudinal study on lambs from single, twin and triplet pregnancies. The lambs were studied from birth until adulthood, including regular blood analyses, measurements of body weight and blood pressure and post-mortem estimation of glomerular numbers. Relative weight differences between multiples and singletons at birth were -28% for twins and -44% for triplets, respectively. Some lambs showed rapid catch-up growth. Total nephron number of twins and triplets was reduced by 21 and 37% with respect to that of singletons (p∈<∈0.01). However, multiples did not show increased blood pressure within the time frame of this study. No gender-specific effect was observed. Plasma concentrations of creatinine, urea, electrolytes or osmolality also did not differ. Our data indicate that the previously reported postnatal blood pressure differences between sheep multiples and singletons are a time-limited phenomenon. During infancy and adolescence, a reduced nephron number in sheep multiples is neither associated with increased blood pressure nor reflected by plasma parameters. © 2010 IPNA.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Blood pressure; Nephron number; Prenatal programming

Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: the GABA-1 trial-a study protocol. - Kaguelidou, Florentia; Le Roux, Enora; Mangiarini, Laura; Lundin, Rebecca; De Leeuw, Thomas G.; Della Pasqua, Oscar; Felisi, Mariagrazia; Bonifazi, Donato; Tibboel, Dick; Ceci, Adriana; De Wildt, Saskia N.; Alberti, Corinne; et al. (BMJ Open, 2019)
INTRODUCTION: Gabapentin is currently used 'off-label' in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking. OBJECTIVES: The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population. METHODS AND ANALYSIS: The trial is a multicentre, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial. Participants aged from 3 months to <18 years of age with moderate to severe (≥4/10 in age-appropriate pain scales) chronic neuropathic or mixed pain will be recruited in 14 clinical sites in eight European countries. A total of 94 subjects will be randomised to receive gabapentin and tramadol placebo or tramadol and gabapentin placebo throughout 16-19 weeks (including 3 weeks of titration [optimisation period], 12 weeks of treatment at a stable dose [maintenance period] and 1-4 weeks of tapering [discontinuation period]). The primary objective is to assess the efficacy of gabapentin relative to tramadol for the treatment of moderate to severe chronic neuropathic or mixed pain by comparing the difference in average pain scores (assessed by age-appropriate pain scales) between intervention arms after 15 weeks of treatment. Secondary objectives include the assessment of the safety, quality of life and global satisfaction with treatment and the description of the pharmacokinetic-pharmacodynamic relationship of gabapentin liquid formulation and tramadol oral drops to validate the recommended paediatric doses. Only rescue pain medication by paracetamol and/or ibuprofen is allowed during the trial. ETHICS AND DISSEMINATION: Ethic approval was obtained in the eight participating countries. Results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. TRIAL REGISTRATION NUMBERS: 2014-004851-30 and NCT02722603. TRIAL STATUS: Ongoing research study, currently recruiting.
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NON-INVASIVE IN VIVO METABOLIC PROFILING OF INFLAMMATION IN JOINTS AND ENTHESES BY OPTOACOUSTIC IMAGING - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, F.; Krönke, Gerhard; Bohr, D.; Ramming, Andreas; Hartmann, F.; Klett, Daniel; Federle, Anna; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, Florian; Krönke, Gerhard; Bohr, Daniela; Ramming, Andreas; Hartmann, Fabian; Klett, Daniel; Federle, Anna; et al. (Rheumatology, 2022)
Objective To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. Methods We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. Results We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. Conclusion MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.
CRIS-Team WoS Importer:2022-07-22

Noninvasive Prenatal Diagnosis of Hypohidrotic Ectodermal Dysplasia by Tooth Germ Sonography - Wuensche, S.; Juengert, J.; Faschingbauer, Florian; Mommsen, H.; Goecke, T.; Schwanitz, K.; Stepan, H.; Schneider, Holm (Ultraschall in der Medizin, 2015)
Hypohidrotic ectodermal dysplasia, a potentially life-threatening heritable disorder, may be recognized already in utero by characteristic features such as oligodontia and mandibular hypoplasia. As therapeutic options and prognosis depend on the time point of diagnosis, early recognition was attempted during routine prenatal ultrasound examinations.Fetuses of nine pregnant women (one triplet and eight singleton pregnancies) with family histories of hypohidrotic ectodermal dysplasia were investigated by sonography between the 20th and 24th week of gestation.In 4 male and 2 female fetuses reduced amounts of tooth germs were detected, whereas 5 fetal subjects showed the normal amount. Three-dimensional ultrasound evaluation revealed mandibular hypoplasia in 5 of the 6 fetuses with oligodontia. Molecular genetic analysis and/or clinical findings after birth confirmed the prenatal sonographic diagnosis in each subject.In subjects with a family history of hypohidrotic ectodermal dysplasia, the diagnosis of this rare condition can be established noninvasively by sonography in the second trimester of pregnancy. Early recognition of the disorder may help to prevent dangerous hyperthermic episodes in infancy and may allow timely therapeutic intervention
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Noninvasive Sacral Neuromodulation in Children and Adolescents: A Case-Control Study of Patients With Chronic Refractory Constipation - Diez, Sonja; Kirchgatter, Annemarie; Adam, Dana; Füldner, Arne; Müller, Hanna; Matzel, Klaus; Besendörfer, Manuel (Neuromodulation, 2022)
Objectives: In adult patients with chronic refractory constipation, invasive sacral neuromodulation (SNM) has been applied successfully. There is a need for less invasive solutions while providing comparable therapeutic effects in children and adolescents. We present a prospective, interventional case-control study on the application of noninvasive SNM. Materials and Methods: Patients with chronic constipation refractory to conservative treatment were prospectively included in the study from 2018 to 2021 and randomized to either SNM (SNM group: single current stimulation for 24 h/d, frequency 15 Hz, pulse width 210 μs, intensity 1–10 mA) or conventional treatment (controls: full range of pharmacologic and nonpharmacologic options). Treatment was conducted for 12 weeks. Treatment effects were collected with specialized questionnaires and quality-of-life analysis (KINDLR). Outcome variables were defecation frequency, stool consistency, fecal incontinence (FI) episodes, and abdominal pain. Results: Analysis was conducted in 28 patients with SNM and 31 controls (median age 7.0, range 3–16 years). Overall responsiveness to treatment was 86% of the SNM group and 39% of the control group (p < 0.001). All outcome variables were positively influenced by SNM treatment. Defecation frequency improved in 46% of patients with SNM and in 19% of controls (p = 0.026), as did stool consistency in 57% of patients with SNM and in 26% of controls (p = 0.014). Fecal incontinence was significantly reduced in 76% of patients with SNM (n = 16/21 vs 42% of controls [n = 11/26], p = 0.042). Quality of life improved significantly during SNM treatment (71.32 [baseline] vs 85.00 [after 12 weeks], p < 0.001) and confirmed a positive influence of SNM treatment compared with the control group (85.00 [SNM after 12 weeks] vs 79.29 [controls after 12 weeks], p = 0.047). Conclusions: Outcome of noninvasive SNM treatment in patients with chronic refractory constipation is better than conventional treatment.
CRIS-Team Scopus Importer:2022-11-18
Keywords: Fecal incontinence; functional constipation; Hirschsprung disease; sacral nerve stimulation; sacral neuromodulation

Nonlinear fibre distribution in a finite element model of a human left ventricle for sparse and non-constant data sets - Holz, David; Duong, Minh Tuan; Kim, Myoungsic; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (Proceedings of the 8th GACM Colloquium on Computational Mechanics, 2019)

Nonlinear fibre distribution in cardiac modelling - Holz, David; Duong, Minh Tuan; Kim, Myoungsic; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (25th Congress of the European Society of Biomechanics, 2019)

Nonurgent Visits to the Pediatric Emergency Department before and during the First Peak of the COVID-19 Pandemic - Guckert, Laura; Reutter, Heiko Martin; Saleh, Nadia; Ganschow, Rainer; Müller, Andreas; Ebach, Fabian (International Journal of Pediatrics, 2022)
Background. Nonurgent visits in pediatric Emergency Departments are a growing burden. In order to find predictors for those nonurgent visits, we performed a retrospective analysis of unscheduled visits at the Pediatric Emergency Department of the University Hospital of Bonn, Germany, in the year 2017. Additionally, we compared these findings to unscheduled visits during the first peak of the worldwide pandemic of the Coronavirus disease 2019, to see if there would be an effect on nonurgent pediatric Emergency Department attendances. Methods. For our retrospective cohort study, we analyzed more than 5.000 visits at the pediatric Emergency Department of the University Hospital of Bonn, Germany, before and during the first peak of the ongoing worldwide pandemic of the Coronavirus disease 2019, particularly with regard to their urgency. Data included gender, age, zip code, urgency, and preexisting conditions. Results. Our study shows that more than half of unscheduled pediatric Emergency Department visits (69%) at the University Hospital in Bonn are for nonurgent reasons, with short living distance being a factor to present children to a pediatric Emergency Department, even with minor complaints. During the first peak of the pandemic of the Coronavirus disease 2019, nonurgent visits decreased significantly, potentially due to hesitation to attend a pediatric Emergency Department with minor issues, fearing an infection with SARS-CoV-2 at the hospital. Conclusion. Many people use pediatric Emergency Departments for nonemergency complaints. In order to address the reasons for nonurgent visits to pediatric Emergency Departments and to prevent parents from doing so, further studies and targeted education concepts for parents are needed.
CRIS-Team Scopus Importer:2022-04-01

Normal values of the pulmonary artery acceleration time (PAAT) and the right ventricular ejection time (RVET) in children and adolescents and the impact of the PAAT/RVET-index in the assessment of pulmonary hypertension - Habash, Sheeraz; Laser, Kai Thorsten; Moosmann, Julia; Reif, Roland; Adler, Werner; Glöckler, Martin; Kececioglu, Deniz; Dittrich, Sven (International Journal of Cardiovascular Imaging, 2019)
New echocardiographic modalities including pulmonary artery acceleration time (PAAT) and right ventricular ejection time (RVET) are evolving to facilitate an early non-invasive diagnosis for pulmonary hypertension (PH) in adults. In children, PAAT depends on age, body surface area (BSA) and heart rate (HR) and is used to predict PH. Normal values of RVET and their role to predict PH in children are still missing. PAAT/RVET-index correlates negatively with PH. We hypothesized that this index is a good predictor for PH in children and adolescents independent of age, BSA and HR and RVET is significantly reduced in PH. PAAT and RVET of 401 healthy children and 30 PH-patients were measured using pulsed-wave-Doppler. PH was diagnosed in PH-group invasively. PAAT/RVET-index for both groups was calculated. Sensitivity and specificity in prediction of PH of PAAT, PAAT z-score and PAAT/RVET-index were compared. We demonstrated normal values of RVET in children. In the healthy group, PAAT and RVET correlated significant positive to age (p<0.001), and BSA (p<0.001) and negative to HR (p<0.001). PAAT/RVET-index correlated weakly to age, BSA and HR (p<0.001). Mean pulmonary artery pressure (PAPM) ranged in the PH-group from 27 to 82mmHg (mean 44mmHg). In predicting PH, RVET is significantly reduced (p<0.001). Comparing area under the curve (AUC), the difference between sensitivity and specificity of PAAT/RVET-index<0.29 and calculated PAAT cut-off-point (87ms) was significant (p<0.001). Equally, AUC comparison between PAAT/RVET-index <0.29 and PAAT z-score of -1.33 was significant (p=0.008). PAAT/RVET-index<0.29 represents a good predictor of PH with a 100% sensitivity and a 95.8% specificity. PAAT/RVET-index is a simple tool and facilitates prediction of PH independent from z-scores.
CRIS-Team WoS Importer:2019-04-09

Novel loci for non-syndromic coarctation of the aorta in sporadic and familial cases - Moosmann, Julia; Uebe, Steffen; Dittrich, Sven; Rueffer, Andre; Ekici, Arif Bülent; Toka, Okan (PLoS ONE, 2015)
Coarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA.We performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification.We identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 ( 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members.Of all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance.
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Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1) - Sandor, Mate; Thiel, Franziska G.; Schmid, Margit; Demcsak, Alexandra; Granda, Nataly C. Morales; Nemeth, Balazs Csaba; Vajda, Sandor; Hörning, André; Sahin-Toth, Miklos (International Journal of Molecular Sciences, 2022)
Inborn mutations in the digestive protease carboxypeptidase A1 (CPA1) gene may be associated with hereditary and idiopathic chronic pancreatitis (CP). Pathogenic mutations, such as p.N256K, cause intracellular retention and reduced secretion of CPA1, accompanied by endoplasmic reticulum (ER) stress, suggesting that mutation-induced misfolding underlies the phenotype. Here, we report the novel p.G250A CPA1 mutation found in a young patient with CP. Functional properties of the p.G250A mutation were identical to those of the p.N256K mutation, confirming its pathogenic nature. We noted that both mutations are in a catalytically important loop of CPA1 that is stabilized by the Cys248-Cys271 disulfide bond. Mutation of either or both Cys residues to Ala resulted in misfolding, as judged by the loss of CPA1 secretion and intracellular retention. We re-analyzed seven previously reported CPA1 mutations that affect this loop and found that all exhibited reduced secretion and caused ER stress of varying degrees. The magnitude of ER stress was proportional to the secretion defect. Replacing the naturally occurring mutations with Ala (e.g., p.V251A for p.V251M) restored secretion, with the notable exception of p.N256A. We conclude that the disulfide-stabilized loop of CPA1 is prone to mutation-induced misfolding, in most cases due to the disruptive nature of the newly introduced side chain. We propose that disease-causing CPA1 mutations exhibit abolished or markedly reduced secretion with pronounced ER stress, whereas CPA1 mutations with milder misfolding phenotypes may be associated with lower disease risk or may not be pathogenic at all.
CRIS-Team WoS Importer:2023-01-20
Keywords: pancreatitis; misfolding; endoplasmic reticulum stress; carboxypeptidase; genetic risk

Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis - Fan, Zheng; Wirth, A-K; Chen, Daishi; Wruck, C. J.; Rauh, Manfred; Buchfelder, Michael; Savaskan, Nicolai (Oncogenesis, 2017)
Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc-) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles' heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics.
EVALuna2:34244

Numerical simulation of cardiac muscles in a rat biventricular model - Duong, Minh Tuan; Ach, Theresa; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (6th European Conference on Computational Mechanics (ECCM 6) and 7th European Conference on Computational Fluid Dynamics (ECFD 7), 2018)

Objective perimetry using a four-channel multifocal VEP system: correlation with conventional perimetry and thickness of the retinal nerve fibre layer - Horn, Folkert; Kaltwasser, Christoph; Jünemann, Anselm; Kremers, Jan; Tornow, Ralf-Peter (British Journal of Ophthalmology, 2012)
There is evidence that multifocal visual evoked potentials (VEPs) can be used as an objective tool to detect visual field loss. The aim of this study was to correlate multifocal VEP amplitudes with standard perimetry data and retinal nerve fibre layer (RNFL) thickness.Multifocal VEP recordings were performed with a four-channel electrode array using 58 stimulus fields (pattern reversal dartboard). For each field, the recording from the channel with maximal signal-to-noise ratio (SNR) was retained, resulting in an SNR optimised virtual recording. Correlation with RNFL thickness, measured with spectral domain optical coherence tomography and with standard perimetry, was performed for nerve fibre bundle related areas.The mean amplitudes in nerve fibre related areas were smaller in glaucoma patients than in normal subjects. The differences between both groups were most significant in mid-peripheral areas. Amplitudes in these areas were significantly correlated with corresponding RNFL thickness (Spearman R=0.76) and with standard perimetry (R=0.71).The multifocal VEP amplitude was correlated with perimetric visual field data and the RNFL thickness of the corresponding regions. This method of SNR optimisation is useful for extracting data from recordings and may be appropriate for objective assessment of visual function at different locations.This study has been registered at http://www.clinicaltrials.gov (NCT00494923).
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„Off-label“-Anwendung in der Klinik – Welche Folgen hat ein Urteil des Bundessozialgerichts für die Pädiatrie? - Rascher, Wolfgang; Wimmer, Stefan; Neubert, Antje; Berner, Reinhard; Boos, Joachim; Erdlenbruch, Bernhard; Kaufmann, Jost; Mentzer, Dirk; Pabel, Helmut; Scherer, Sabine; Schwab, Matthias; Wagner, Norbert; et al. (Monatsschrift Kinderheilkunde, 2020)
The off-label prescription of medicines is becoming increasingly more problematic in pediatric and adolescent medicine. A legally binding judgment of the Federal Social Court (BSG) in 2016 has determined under which prerequisites statutory health insurance companies (GKV) can reimburse off-label prescription in inpatient care. It is to be expected that in future the medical service of the health insurance companies (MDK) will inspect the off-label prescription of expensive drugs for which an additional fee is paid and consequently the hospitals face the risk that reimbursement will be denied. The judgement of the BSG also has consequences for the development of guidelines. The aim of the article is the presentation of five supreme court judgments of German courts (1990–2016) on off-label use and the consequences and possible solution approaches for pediatrics. Although most court decisions involve adult medicine, the judgments affect the prescription of medicines for children.
CRIS-Team Scopus Importer:2020-02-28
Keywords: Approval; Children; Court; Guidelines; Medication; Off label use

Off-label-Anwendung – Wie kommen wir zur Evidenz? - Rascher, Wolfgang (Monatsschrift Kinderheilkunde, 2020)
CRIS-Team Scopus Importer:2020-06-02

Off-label use of drugs in pediatric (specialized) outpatient clinics-What has changed between 2009 and 2019? - Toni, Irmgard; Hupfer, Jutta; Gerber, Christine; Rascher, Wolfgang; Neubert, Antje (PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2022)
CRIS-Team WoS Importer:2022-10-28

Oligoclonal bands predict multiple sclerosis in children with optic neuritis - Heussinger, Nicole; Kontopantelis, Evangelos; Gburek-Augustat, Janina; Jenke, Andreas; Vollrath, Gesa; Korinthenberg, Rudolf; Hofstetter, Peter; Meyer, Sascha; Brecht, Isabel; Kornek, Barbara; Herkenrath, Peter; Schimmel, Mareike; et al. (Annals of Neurology, 2015)
We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Multiple Cox proportional-hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39-10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32-5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02-1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84-fold higher HR for developing MS compared to double negativity (95% CI = 12.26-58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON.
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O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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On the interdisciplinary S3 guidelines for the treatment of chronic idiopathic tinnitus - Zenner, H. -P.; Delb, W.; Kroener-Herwig, B.; Jaeger, B.; Peroz, I.; Hesse, G.; Mazurek, B.; Goebel, G.; Gerloff, C.; Trollmann, Regina; Biesinger, E.; Seidler, H.; et al. (HNO, 2015)
Tinnitus is a frequent symptom, which, particularly in combination with comorbidities, can result in a severe disease-related burden. Chronic idiopathic tinnitus (CIT) is the most frequent type of tinnitus. A considerable number of treatment strategies are used to treat CIT-for many of which there is no evidence of efficacy. In order to enable scientific evidence-based treatment of CIT, German interdisciplinary S3 guidelines have recently been constructed for the first time. Here we present a short form of these S3 guidelines.The guidelines were constructed based on a meta-analysis of the treatment of chronic tinnitus performed by the authors. Additionally, a systematic literature search was performed in the PubMed and Cochrane Library databases. Furthermore, a systematic search for international guidelines was performed in Google, as well as in the Guidelines International Network and National Guideline Clearinghouse (USA) database. Evidence was classified according to the Oxford Centre for Evidence-Based Medicine system.According to the guidelines, alongside counselling, manualized structured tinnitus-specific cognitive behavioral therapy (tCBT) with a validated treatment manual is available as evidence-based therapy. In addition, the guidelines recommend concurrent treatment of comorbidities, including drug-based treatment, where appropriate. Particularly important is treatment of anxiety and depression. Where a psychic or psychiatric comorbidity is suspected, further diagnosis and treatment should be performed by an appropriately qualified specialist (psychiatrist, neurologist, psychosomatic medicine consultant) or psychological psychotherapist. In cases accompanied by deafness or hearing loss bordering on deafness, cochlear implants may be indicated.No recommendations can be made for drug-based treatment of CIT, audiotherapy, transcranial magnetic or electrical stimulation, specific forms of acoustic stimulation or music therapy; or such recommendations must remain open due to the lack of available evidence. Polypragmatic tinnitus treatment with therapeutic strategies for which there is no evidence of efficacy from controlled studies is to be refused.
EVALuna2:18924

Open Field Exercise Testing in Pediatric Congenital Heart Disease Patients: A Subsumption of Cardiovascular Parameters - Rückert, J.; Michaelis, A.; Markel, F.; Kalden, P.; Löffelbein, F.; Klehs, S.; Dähnert, I.; Schöffl, Isabelle; Rottermann, Kathrin; Paech, C. (Pediatric Cardiology, 2023)
Heart failure is a common phenomenon in congenital heart disease patients. Cardiopulmonary exercise testing is used for a reliable assessment of heart failure but is still challenging, especially for young children. Implementing mobile cardiopulmonary exercise testing (CPET) can close that diagnostic gap. While average values for healthy children have already been published, this study aims to describe typical ranges of cardiovascular performance parameters of young children with congenital heart disease performing an 8-min running cardiopulmonary exercise test. Children aged 4–8 years with common congenital heart defects after corrective surgery (Tetralogy of Fallot; transposition of the great arteries and univentricular hearts after palliation) were included. The outdoor running protocol consisted of slow walking, slow jogging, fast jogging, and maximum speed running. Each exercise was performed for 2 min, except the last, in which children were instructed to keep up maximal speed as long as possible. A total of 78 children (45 male/33 female, mean age 6,24) with congenital heart disease participated in the study, of which 97% completed the CPET successfully. A detailed description of participating patients, including data on cardiac function and subjective fitness levels, is given to help physicians use this method to classify their patients. This study presents a typical range for cardiovascular performance parameters in a population of 4–8-year-old children with congenital heart disease tested in a newly developed outdoor running protocol for CPET.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Children; Congenital heart disease; CPET; Exercise testing

Open field stress testing: finally an optimal method in young children? Reference values for mobile cardiopulmonary exercise testing in healthy children aged 4-8 years - Kalden, Philipp; Schöffl, Isabelle; Rottermann, Kathrin; Loeffelbein, Florian; Michaelis, Anna; Markel, Franziska; Brosig, Susann; Gebauer, Roman Antonin; Daehnert, Ingo; Paech, Christian (Cardiology in the Young, 2021)
Introduction: Cardiopulmonary exercise testing represents the diagnostic tool for determining cardiopulmonary function. Especially in small children, exercise testing is extremely challenging. To address this problem, field testing has been implemented using small mobile devices. This study aims at using this protocol for developing normal values for cardiopulmonary exercise testing in very young children. Material and methods: Healthy children aged 4-8 years were recruited. All children were tested according to an outdoor protocol, in which they were instructed to walk, then run slowly, then a little harder and at last run at full speed. Each step lasted for 2 minutes, except the last step, in which the children were instructed to maintain as long as possible. Results: A total of 104 children (64 female/35 male, mean age 6.6 years) performed outdoor cardiopulmonary exercise testing using a mobile device. Almost all tests were completed successfully (95%). Despite a predominance of female study subjects, anthropometric values did not differ between boys and girls. V?O (2) peak/kg, respiratory exchange ratio, VT1, heart rate at VT1, and time of exercise were also comparable between sexes. Generally, a tendency of higher maximal oxygen uptake could be observed in older children. Conclusion: Open field mobile cardiopulmonary exercise testing represents a novel approach in very young children. In this study, we were able to determine normal values of maximal oxygen uptake and OUES/kg for 4-8-year-old children. The method is easy to achieve and safe.
CRIS-Team WoS Importer:2021-12-17

Optoacoustic Imaging in Inflammation - Regensburger, Adrian; Brown, Emma; Krönke, Gerhard; Waldner, Maximilian; Knieling, Ferdinand (Biomedicines, 2021)
Optoacoustic or photoacoustic imaging (OAI/PAI) is a technology which enables non-invasive visualization of laser-illuminated tissue by the detection of acoustic signals. The combination of "light in" and "sound out" offers unprecedented scalability with a high penetration depth and resolution. The wide range of biomedical applications makes this technology a versatile tool for preclinical and clinical research. Particularly when imaging inflammation, the technology offers advantages over current clinical methods to diagnose, stage, and monitor physiological and pathophysiological processes. This review discusses the clinical perspective of using OAI in the context of imaging inflammation as well as in current and emerging translational applications.
CRIS-Team WoS Importer:2021-06-04

Oral Presentation: Drug-Related Hospital Admissions in Paediatrics-Is There Potential for Prevention? - Toni, Irmgard; Ahne, G.; Marek, Ines; Moritz, Katrin; Schulze, Christopher; Schreeck, F.; Makosi, D. M.; Rascher, Wolfgang; Neubert, Antje (DRUG SAFETY, 2022)
CRIS-Team WoS Importer:2022-10-07

Orofacial clefts alter early life oral microbiome maturation towards higher levels of potentially pathogenic species: A prospective observational study - Seidel, Corinna L.; Strobel, Karin; Weider, Matthias; Tschaftari, Marco; Unertl, Christoph; Willershausen, Ines; Weber, Manuel; Hörning, André; Morhart, Patrick; Schneider, Michael; Beckmann, Matthias; Bogdan, Christian; et al. (Journal of Oral Microbiology, 2023)
Orofacial clefts (OFC) present different phenotypes with a postnatal challenge for oral microbiota development. In order to investigate the impact of OFC on oral microbiota, smear samples from 15 neonates with OFC and 17 neonates without OFC were collected from two oral niches (tongue, cheek) at two time points, i.e. after birth (T0: Ø3d OFC group; Ø2d control group) and 4–5 weeks later (T1: Ø32d OFC group; Ø31d control group). Subsequently, the samples were analyzed using next-generation sequencing. We detected a significant increase of alpha diversity and anaerobic and Gram-negative species from T0 to T1 in both groups. Further, we found that at T1 OFC neonates presented a significantly lower alpha diversity (lowest values for high cleft severity) and significantly higher levels of Enterobacteriaceae (Citrobacter, Enterobacter, Escherichia-Shigella, Klebsiella), Enterococcus, Bifidobacterium, Corynebacterium, Lactocaseibacillus, Staphylococcus, Acinetobacter and Lawsonella compared to controls. Notably, neonates with unilateral and bilateral cleft lip and palate (UCLP/BCLP) presented similarities in beta diversity and a mixture with skin microbiota. However, significant differences were seen in neonates with cleft palate only compared to UCLP/BCLP with higher levels of anaerobic species. Our findings revealed an influence of OFC as well as cleft phenotype and severity on postnatal oral microbiota maturation.
CRIS-Team Scopus Importer:2023-01-20
Keywords: early life dysbiosis; microbiome maturation; neonates; oral microbiome; Orofacial clefts

Orthotic Care Based on the Ferrari Concept for Children and Adults with Meningomyelocele - Schmid, Tim; Strehl, Elisabeth; Trollmann, Regina; Forst, Raimund; Fujak, Albert (Zeitschrift für Orthopädie und Unfallchirurgie, 2019)
Background Even today, myelomeningocele (MMC) is still encountered in clinical medicine and its incidence has not decreased over the last 20 years despite a known reduction in risk due to the use of folic acid supplements. The spectrum of clinical symptoms is extremely broad and, depending on the level of the defect, varies from mild to severe. Subject to the degree of paralysis, patients are reliant on the use of orthopaedic aids and orthoses for the treatment of primary contractures and deformities and the prevention of secondary ones. This forms the basis for attaining or maintaining mobility in many patients. The objective of the study was to determine the practical application of the proposed Ferrari concept for the provision of orthoses for children and adults. Patients and Material The retrospective study comprised medical records of 180 patients (97 m) with an average age of 19.44 years (3-52 years, SD 9.3) at the time of investigation. The average duration of treatment was 15.34 years (1-38 years, SD 8.96). Data relating to deformities of the vertebral column and lower limbs, provision of hydrocephalus shunts and orthoses, and patient mobility was evaluated. Results Most patients were given systematic treatment with orthoses at an early stage. In 58,9% of cases, it was possible to implement the proposed concept for providing patients with dynamic orthoses, whereby the treatment concept was more difficult to implement with high lumbar lesions than with lower lesions. Moreover, a decrease in the patients' mobility with increasing age was noticeable. Some 42.3% of adult patients were able to walk with marked variations in mobility in relation to the different levels of lesions. Conclusion Taking into consideration the complexity of both the clinical picture and therefore the provision of orthopaedic devices, the result of the implementation of the proposed orthotic concept can be considered positive. Similarly, early commencement of provision of orthoses and hence the possibility of achieving a positive influence on later mobility can be considered a success. The need for individual concepts and further development in order to increase mobility particularly in the case of patients with thoracic or high lumbar lesions is evident. A more comprehensive provision of information to patients regarding orthotic treatment options and their consequences for prophylaxis and quality of life should be an important component of interdisciplinary long-term patient care.
CRIS-Team Scopus Importer:2019-12-13
Keywords: MMC; mobility; orthopaedic treatment concept; orthotics

Osteosarcoma and causes of death: A report of 1520 deceased patients from the Cooperative Osteosarcoma Study Group (COSS) - Bielack, Stefan S.; Blattmann, Claudia; Borkhardt, Arndt; Csóka, Monika; Hassenpflug, Wolf; Kabíčková, Edita; Kager, Leo; Kessler, Thorsten; Kratz, Christian; Kühne, Thomas; Kevric, Matthias; Lehrnbecher, Thomas; et al. (European Journal of Cancer, 2022)
Purpose: Most aspects of osteosarcoma have been addressed in detail, but there is no comprehensive analysis of deceased patients and causes of death. Methods: The database of the Cooperative Osteosarcoma Study Group COSS (1980-03/31/2021; 4475 registered high-grade central osteosarcoma patients) was searched deaths from any cause. Affected patients were analyzed for demographic and baseline variables and disease-status at the time of demise. Deaths from causes other than osteosarcoma were analyzed in detail. Results: A total of 1520 deceased patients were identified (median age (range) at osteosarcoma diagnosis 16 (2–78) years; 908 (59.7%) male, 612 (40.3%) female; primary tumor: extremities 1263 (83.1%), trunk 208 (13.7%), craniofacial 47 (3.1%) (site unknown 2); metastases at registration: absent 1.051 (69.1%), present 466 (30.7%) (3 no data). The median time from diagnosis to death was 2.22 (0.08–32.02) years. 1286 (84.6%) patients succumbed to osteosarcoma (370 without achieving complete remission, 488 first, 428 more than one recurrences), 146 (9.6%) to other, 88 (5.8%) to unknown causes. Chemotherapy-related infections (40), secondary malignancies (39), and perioperative complications (19) were among the most frequent potentially treatment-related causes, and high-dose methotrexate (19), doxorubicin (17), and ifosfamide (15) were the drugs most commonly held responsible. Patients with unknown causes of death had an unusually long median follow-up. Conclusion: The major cause of death of patients after osteosarcoma is this malignancy, mostly from one of its multiple relapses. However, almost 10% of fatalities are due to other documented causes. Some of these deaths may be preventable with the knowledge gained from comprehensive analyses such as this.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Adolescent; Adult; Child; Osteosarcoma; Survival

Outdoor Uphill Exercise Testing for Trail Runners, a More Suitable Method? - Schöffl, Isabelle; Jasinski, Dominik; Ehrlich, Benedikt; Dittrich, Sven; Schoeffl, Volker (Journal of Human Kinetics, 2021)
There is extensive knowledge about uphill running on a treadmill, although paucity regarding the influence of uphill trail running on exercise capacity in runners. The purpose of this study was to compare an uphill field test with a treadmill test with 1% inclination especially considering cardiopulmonary exercise variables. The difference in those tests between a group of trail runners and a group of road runners was tested for establishing a test specifically for trail runners. Ten male endurance road runners and ten male trail runners performed one maximal incremental treadmill test with 1% inclination and a maximal incremental field test on a hill at 16% inclination which they were instructed to run up four times for three minutes, each time with a higher pace. A mobile cardiopulmonary exercise testing unit was used to measure ventilation. There were no significant differences between trail runners and road runners. The equivalence factor was comparable between both groups. VO2peak was comparable for both test protocols. However, there was a significant difference between the two test protocols regarding lactate concentration, the respiratory exchange ratio, running cost, heart rate, Breathing reserve, and O-2pulse. The greater lactate concentration and running cost recorded uphill indicate a higher energy demand during trail running than level road running.
CRIS-Team WoS Importer:2021-08-13

Ovarian Sertoli Leydig cell tumours in children and adolescents: an analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) - Schneider, Dominik T; Orbach, Daniel; Cecchetto, Giovanni; Stachowicz-Stencel, Teresa; Brummel, Bastian; Brecht, Ines B; Bisogno, Gianni; Ferrari, Andrea; Reguerre, Yves; Godzinski, Jan; Bien, Ewa; Calaminus, Gabriele; et al. (European Journal of Cancer, 2015)
To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification.Forty-four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies (n=23), French TGM protocols (n=10), Italian Rare Tumour Project (TREP) registry (n=6), and the Polish Pediatric Rare Tumour Study group (n=5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO).Median age was 13.9 (0.5-17.4) years. All patients underwent resection by tumour enucleation (n=8), ovariectomy (n=17), adenectomy isolated (n=18) or with hysterectomy (n=1). FIGO-stage: Ia 24pts., Ic 17pts., II/III 3pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic-III), eight relapsed, and five patients died. Eleven patients were initially treated with two to sixcycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70±0.07, relapse-free survival 0.81±0.06 and overall survival 0.87±0.05.Prognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.
EVALuna2:18936

Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development - Jung, Susan; Boie, Gudrun; Dörr, Helmuth-Günther; Trollmann, Regina (American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2017)
Perinatal hypoxia severely disrupts metabolic and somatotrophic development, as well as cerebral maturational programs. Hypoxia-inducible transcription factors (HIFs) represent the most important endogenous adaptive mechanisms to hypoxia, activating a broad spectrum of growth factors that contribute to cell survival and energy homeostasis. To analyze effects of systemic hypoxia and growth hormone (GH) therapy (rhGH) on HIF-dependent growth factors during early postnatal development, we compared protein (using ELISA) and mRNA (using quantitative RT PCR) levels of growth factors in plasma and brain between normoxic and hypoxic mice (8% O2, 6 h; postnatal day 7, P7) at P14. Exposure to hypoxia led to reduced body weight (P < 0.001) and length (P < 0.04) compared with controls and was associated with significantly reduced plasma levels of mouse GH (P < 0.01) and IGF-1 (P < 0.01). RhGH abrogated these hypoxia-induced changes of the GH/IGF-1 axis associated with normalization of weight and length gain until P14 compared with controls. In addition, rhGH treatment increased cerebral IGF-1, IGF-2, IGFBP-2, and erythropoietin mRNA levels, resulting in significantly reduced apoptotic cell death in the hypoxic, developing mouse brain. These data indicate that rhGH may functionally restore hypoxia-induced systemic dysregulation of the GH/IGF-1 axis and induce upregulation of neuroprotective, HIF-dependent growth factors in the hypoxic developing brain.
EVALuna2:34028

p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction - Kohli, Shrey; Hoffmann, Juliane; Lochmann, Franziska; Markmeyer, Paulina; Hübner, Hanna; Fahlbusch, Fabian B.; Al-Dabet, Moh'D Mohanad; Gadi, Ihsan; Manoharan, Jayakumar; Loettge, Michael; Zenclussen, Ana C.; Aharon, Anat; et al. (Cell Death & Disease, 2017)
Placental insufficiency jeopardizes prenatal development, potentially leading to intrauterine growth restriction (IUGR) and stillbirth. Surviving fetuses are at an increased risk for chronic diseases later in life. IUGR is closely linked with altered trophoblast and placental differentiation. However, due to a paucity of mechanistic insights, suitable biomarkers and specific therapies for IUGR are lacking. The transcription factor p45 NF-E2 (nuclear factor erythroid derived 2) has been recently found to regulate trophoblast differentiation in mice. The absence of p45 NF-E2 in trophoblast cells causes IUGR and placental insufficiency in mice, but mechanistic insights are incomplete and the relevance of p45 NF-E2 for human syncytiotrophoblast differentiation remains unknown. Here we show that p45 NF-E2 negatively regulates human syncytiotrophoblast differentiation and is associated with IUGR in humans. Expression of p45 NF-E2 is reduced in human placentae complicated with IUGR compared with healthy controls. Reduced p45 NF-E2 expression is associated with increased syncytiotrophoblast differentiation, enhanced glial cells missing-1 (GCM1) acetylation and GCM1 desumoylation in IUGR placentae. Induction of syncytiotrophoblast differentiation in BeWo and primary villous trophoblast cells with 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP) reduces p45 NF-E2 expression. Of note, p45 NF-E2 knockdown is sufficient to increase syncytiotrophoblast differentiation and GCM1 expression. Loss of p45 NF-E2 using either approach resulted in CBP-mediated GCM1 acetylation and SENP-mediated GCM1 desumoylation, demonstrating that p45 NF-E2 regulates post-translational modifications of GCM1. Functionally, reduced p45 NF-E2 expression is associated with increased cell death and caspase-3 activation in vitro and in placental tissues samples. Overexpression of p45 NF-E2 is sufficient to repress GCM1 expression, acetylation and desumoylation, even in 8-Br-cAMP exposed BeWo cells. These results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. These studies identify a new pathomechanism related to IUGR in humans and thus provide new impetus for future studies aiming to identify new biomarkers and/or therapies of IUGR.
EVALuna2:34008

Pädiatrische epileptische Enzephalopathien mit Manifestation oberhalb des Neugeborenenalters: ein Up-date - Trollmann, Regina; Borggräfe, Ingo; Müller-Felber, Wolfgang; Brandl, Ulrich (Klinische Neurophysiologie, 2021)
Developmental and epileptic encephalopathies represent complex and neurodegenerative disorders characterized by onset of refractory seizures usually in the first year of life and associated with motor and intellectual disability. The new ILAE classification of seizures and epilepsies proposed a revised definition of epileptic encephalopathies including electro-clinical phenotype as well as etiological spectrum and associated comorbidities. Modern genetic techniques led to the identification of a precise genotype in several electro-clinical syndromes such as West syndrome and Dravet syndrome. EEG continues to play a specific role as an additional tool in diagnosis and management of epileptic encephalopathies with special focus on the diagnosis of complications such as subclinical seizures and status epilepticus as well as treatment monitoring. This article reviews current aspects of complex pediatric epileptic encephalopathies and the significance of EEG monitoring.
CRIS-Team Scopus Importer:2021-09-24
Keywords: CSWS; Dravet syndrome; Landau-Kleffner syndrome; Lennox-Gastaut syndrome; West syndrome

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern - Haller, Florian; Knopf, Jasmin; Ackermann, Andreas; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E.; Giedl, Josef; Carbon, Roman; et al. (Journal of Pathology, 2016)
Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged.
EVALuna2:6792

Paediatric chronic myeloid leukaemia presenting in de novo or secondary blast phase - a comparison of clinical and genetic characteristics - Sembill, Stephanie; Goehring, Gudrun; Schirmer, Elke; Lutterloh, Friederike; Suttorp, Meinolf; Metzler, Markus; Karow, Axel (British Journal of Haematology, 2021)
Additional data on blast phase (BP) chronic myeloid leukaemia (CML) in children and adolescents is essential for improving diagnostic and therapeutic approaches of this rare but serious condition. Here, we describe distinct clinical and genetic characteristics of 18 paediatric patients with de novo (n = 10) and secondary (n = 8) BP CML enrolled in the CML-PAED-II trial and registry. Our findings suggest that paediatric patients exhibit a diverse cytogenetic profile compared to adults with BP CML. In addition, patients with de novo BP CML in this cohort presented at a younger age, whereas patients with secondary BP CML more often harboured complex karyotypes.
CRIS-Team Scopus Importer:2021-03-19
Keywords: ABL1 kinase domain mutations; blast phase; chemotherapy regimen; Chronic myeloid leukemia; cytogenetic aberrations; hematopoietic stem cell transplantation; pediatric chronic myeloid leukemia; tyrosine kinase inhibitor

Papilledema and Echographically Detectable Retro-orbital Dilatation of the Sub-arachnoidal Space with open Fontanelle - Six Case Reports - Gusek-Schneider, G. C.; Mardin, Christian Y.; Trollmann, Regina; Eyüpoglu, Ilker Yasin; Ganslandt, Oliver Thomas (Klinische Monatsblätter für Augenheilkunde, 2011)
This paper analyses the case reports for three children in which a papilledema occurred before the age of one year. Furthermore, an analysis is also given of three further case reports for children aged less than one year in which, in spite of open fontanelle, no papilledema was found, however, a dilatation of the sub-arachnoidal space was demonstrated echographically. Even in children less than one year of age in which an open fontanelle still exists and in whom a neuro-paediatric clarification of internal hydrocepalus is made, in spite of opththalmoscopically inconspicuous findings for the papilla an echography is indispensable for the evaluation of the sub-arachnoidal space. Here, the early recognition of a dilatation of the retro-bulbar sub-arachnoidal space can possibly prevent the occurrence of a consecutive optic atrophy. At the present time, the data available do not allow the recommendation of an upper age limit for an echographic examination.
EVALuna2:21040

Parecoxib does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis - Nögel, Stephanie; Chada, Martin; Schmidt, Ariana; Bosselmann, Stephan; Kandler, Michael; Schweer, Horst; Watzer, Bernhard; Schneider, Holm; Gessner, André; Rascher, Wolfgang (Prostaglandins & Other Lipid Mediators, 2009)
Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity. © 2009 Elsevier Inc. All rights reserved.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Group b streptococcal sepsis; Parecoxib; Thromboxane

Partial homonymous hemianopia of traumatic origin after riding a high-speed amusement ride - Hohberger, B.; Trollmann, Regina; Rompel, O.; Gölitz, Philipp; Gusek-Schneider, G. C. (Ophthalmologe, 2016)
Amusement park injuries have become more common in recent years. Especially neurological symptoms dominate clinical findings. In this article, the case of a 15-year-old child with homonymous hemianopia due to an atypical intracranial bleeding with subdural hematoma after a giant swing ride is described for the first time.
EVALuna2:21326

Particularities of Crohn's disease in pediatric patients: current status and perspectives regarding imaging modalities - Schreiber-Dietrich, Dagmar; Chiorean, Liliana; Cui, Xin-Wu; Braden, Barbara; Kucharzik, Torsten; Juengert, Joerg; Kosiak, Wojciech; Stenzel, Martin; Dietrich, Christoph F. (Expert Review of Gastroenterology and Hepatology, 2015)
A consensus on the best imaging modality evaluating inflammatory bowel disease in the pediatric population is lacking and it is often unclear which modality to choose in specific clinical circumstances. Children with inflammatory bowel disease are exposed to ionizing radiation from multiple imaging studies performed at initial diagnosis, throughout treatment and during the follow-up period. This paper discusses the value of different imaging techniques in pediatric patients with inflammatory bowel disease and gives a review of the literature. In addition, particular features of inflammatory bowel disease in children including the predilection of affected segments in the gastrointestinal tract are highlighted. Based on current literature knowledge, we encourage an integrative approach to the interpretation of clinical and imaging data for diagnosis and follow-up in daily clinical settings.
EVALuna2:18921

Passive mechanical properties in healthy and infarcted rat left ventricle characterised via a mixture model - Martonová, Denisa; Alkassar, Muhannad; Seufert, Julia; Holz, David; Duong, Minh Tuan; Reischl, Barbara; Friedrich, Oliver; Leyendecker, Sigrid (Journal of the Mechanical Behavior of Biomedical Materials, 2021)
During the cardiac cycle, electrical excitation is coupled with mechanical response of the myocardium. Besides the active contraction, passive mechanics plays an important role, and its behaviour differs in healthy and diseased hearts as well as among different animal species. The aim of this study is the characterisation of passive mechanical properties in healthy and infarcted rat myocardium by means of mechanical testing and subsequent parameter fitting. Elasticity assessments via uniaxial extension tests are performed on healthy and infarcted tissue samples from left ventricular rat myocardium. In order to fully characterise the orthotropic cardiac tissue, our experimental data are combined with other previously published tests in rats – shear tests on healthy myocardium and equibiaxial tests on infarcted tissue. In a first step, we calibrate the Holzapfel-Ogden strain energy function in the healthy case. Sa far, this orthotropic constitutive law for the passive myocardium has been fitted to experimental data in several species, however there is a lack of an appropriate parameter set for the rat. With our determined parameters, a finite element simulation of the end-diastolic filling is performed. In a second step, we propose a model for the infarcted tissue. It is represented as a mixture of intact myocardium and a transversely isotropic scar structure. In our mechanical experiments, the tissue after myocardial infarction shows significantly stiffer behaviour than in the healthy case, and the stiffness correlates with the amount of fibrosis. A similar relationship is observed in the computational simulation of the end-diastolic filling. We conclude that our new proposed material model can capture the behaviour of two kinds of tissues – healthy and infarcted rat myocardium, and its calibration with the fitted parameters represents the experimental data well.<br
CRIS-Team Scopus Importer:2021-04-09
Keywords: Fibrosis; Holzapfel-Ogden strain energy; Incompressibility; Myocardial infarction; Parameter fitting; Passive mechanics; Rat left ventricle

Pathway to assess severe primary IGF-1 deficiency diagnosis in a real-life setting: data from the Global Increlex (R) Registry - Bang, Peter; Polak, Michel; Bossowski, Artur; De Schepper, Jean; Sert, Caroline; Perrot, Valerie; Wölfle, Joachim (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Patient preference for therapies in hypertension: a cross-sectional survey of German patients - Schmieder, Roland; Högerl, Karin; Jung, Susan; Bramlage, Peter; Veelken, Roland; Ott, Christian (Clinical Research in Cardiology, 2019)
BACKGROUND: Hypertension is poorly controlled in numerous patients despite effective medication being available. Catheter-based renal denervation (RDN) has emerged as an alternative treatment option. We aimed to assess how likely patients with elevated blood pressure (BP) are to accept RDN as treatment option. METHODS: A questionnaire-based cross-sectional survey was performed in patients with elevated BP in Germany. Data on patient demographics, clinical characteristics and treatment preferences were collected, anonymized and analyzed. RESULTS: One thousand and eleven patients completed the survey. Mean age was 66 years (55% male). If not already on medication (n = 172), 38.2% of patients would prefer RDN. Of those already on drug therapy (n = 839), 28.2% would opt for RDN. Patients who were pro-RDN were younger (p < 0.0001) and more often male (p < 0.0001). Nineteen percent would choose RDN if it lowered systolic BP by at least 20 mmHg, more than 40% if they did not have to take any more pills thereafter, and 30% if it would lower BP by at least 10 mmHg. Experiences of side effects and drug adherence were identified as determinants of patient preference. Physicians were the main source of information regarding medical problems (95.5%) and influence patients' decision regarding therapies (98%). CONCLUSIONS: This survey found that a significant proportion of patients would choose catheter-based RDN over lifelong pharmacotherapy. These patients were younger and more likely to be male but their expectation of the extent of BP decrease with RDN was high. Physicians are key mediators for treatment selection. They need to incorporate patient preferences into shared decision making.
EVALuna2:118640

Patient-reported health-related quality of life (HRQOL) following allogeneic stem cell transplantation (SCT) performed early after diagnosis of pediatric chronic myeloid leukemia (CML) - Schleicher, O.; Horndasch, A.; Krumbholz, Manuela; Sembill, S.; Karow, A.; Bremensdorfer, C.; Grabow, D.; Metzler, Markus; Suttorp, M. (BONE MARROW TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-11-25

Patient-reported long-term outcome following allogeneic hematopoietic stem cell transplantation in pediatric chronic myeloid leukemia - Schleicher, Oliver; Horndasch, Annkathrin; Krumbholz, Manuela; Sembill, Stephanie; Bremensdorfer, Claudia; Grabow, Desiree; Erdmann, Friederike; Karow, Axel; Metzler, Markus; Suttorp, Meinolf (Frontiers in Oncology, 2022)
BackgroundPediatric CML is very rare. Before the introduction of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (HSCT) from a donor -if available- was the standard cure attempt. Data on the long-term outcome and health-related quality of life (HRQOL) in former pediatric CML patients undergoing HSCT are lacking. Study questionWe investigated long-term survivors' self-reporting to a questionnaire sent out to patients formerly enrolled in pediatric CML-HSCT trials. MethodsIndividuals with CML transplanted at age <18 years were identified from the German Childhood Cancer Registry database. Long-term survivors received a questionnaire based on the SF-36 and FACT-BMT asking them to self-report HRQOL issues. (Ethical vote #541_20 B, Medical Faculty, University of Erlangen-Nurnberg). Results111/171 (64.9%) individuals survived HSCT long-term and 86/111 (77.5%) fulfilled all inclusion criteria and received the questionnaire. 37/86 (43%) participants (24 female, 13 male, median age at HSCT 12 years [range 2-18], median age at the time of the survey 29 years [range 18-43]) responded after a median follow-up period of 19 years (range 4-27) after HSCT. 10/37 (27%) participants underwent no regular medical follow-up examinations. Self-reported symptoms like chronic graft-versus-host disease (cGvHD)-associated organ impairments and conditioning regimen consequences could causatively not sharply be separated in each case. Complains comprised hypothyroidism (N=11, 30%), infertility (N=9, 24%), lung problems, dry eyes (each N=7, 19%), skin alterations (N=6, 17%), hair problems (N=4, 11%), and sexual dysfunction (N=3, 9%). 10 (27%) participants experienced 13 CML relapses after a median interval from HSCT of 31 months (range 2-93). Only one patient underwent 2nd SCT after failure of relapse treatment with TKIs. Six secondary malignancies (dysplastic melanocytic nevus and ALL, basal cell carcinoma (N=2), rhabdomyosarcoma, and thyroid carcinoma developed in 5 (13%) participants. As assessed by the SF-36 questionnaire, impaired physical health was mainly associated with cGvHD. The mental component summary score showed that also participants without cGvHD scored significantly lower than the general population. When assessed by the FACT-BMT, participants with cGvHD scored significantly lower while participants without cGvHD scored even 5 points higher than the data from controls. 18 (49%) participants considered the sequelae of HSCT an obstacle to education. Out of the total cohort, N=20 (54%), N=7 (19%), N=5 (14%), and N=4 (11%) participants worked full time, part-time, were unemployed, or had not yet finalized their education, respectively. 20 (54%) participants lived as singles, 8 (22%) lived in a partnership, 6 (16%) were married, and 3 (8%) had been divorced. Four (11%) participants reported a total number of 7 children. ConclusionThis first assessment of HRQOL in former pediatric patients with CML surviving HSCT for more than two decades demonstrates self-reported satisfactory well-being only in the absence of cGvHD. Research-based on self-reported outcomes sheds light on former patients' perspectives and provides an additional layer of valuable knowledge for pediatric and adult hematologists. Regular follow-up examinations are mandatory helping to avoid that late secondary neoplasias, CML-relapse, and disorders forming the broad range of possible long-term consequences of HSCT are not detected too late.
CRIS-Team WoS Importer:2022-11-04

Pediatric Buried Bumper Syndrome: Diagnostic Validity of Transabdominal Ultrasound and Artificial Intelligence - Aguilar, Caroline; Regensburger, Adrian; Knieling, Ferdinand; Wagner, Alexandra; Siebenlist, Gregor; Wölfle, Joachim; Koehler, Henrik; Hörning, André; Jüngert, Jörg M. (Ultraschall in der Medizin, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-06-04

Pediatric cardiac MRI: automated left-ventricular volumes and function analysis and effects of manual adjustments - Hammon, Matthias; Janka, Rolf Matthias; Dankerl, Peter; Glöckler, Martin; Kammerer, Ferdinand J.; Dittrich, Sven; Uder, Michael; Rompel, Oliver (Pediatric Radiology, 2015)
Cardiac MRI is an accurate and reproducible technique for the assessment of left ventricular volumes and function. The accuracy of automated segmentation and the effects of manual adjustments have not been determined in children.To evaluate automated segmentation and the effects of manual adjustments for left ventricular parameter quantification in pediatric cardiac MR images.Left ventricular parameters were evaluated in 45 children with suspected myocarditis (age 13.4 ± 3.5 years, range 4-17 years) who underwent cardiac MRI. Dedicated software was used to automatically segment and adjust the parameters. Results of end-diastolic volume, end-systolic volume, stroke volume, myocardial mass, and ejection fraction were documented before and after apex/base adjustment and after apex/base/myocardial contour adjustment.The software successfully detected the left ventricle in 42 of 45 (93.3%) children; failures occurred in the smallest and youngest children. Of those 42 children, automatically segmented end-diastolic volume (EDV) was 151 ± 47 ml, and after apex/base adjustment it was 146 ± 45 ml, after apex/base/myocardial contour adjustment 146 ± 45 ml. The corresponding results for end-systolic volume (ESV) were 66 ± 32 ml, 63 ± 29 ml and 64 ± 28 ml; for stroke volume (SV) they were 85 ± 25 ml, 83 ± 23 ml and 83 ± 23 ml; for ejection fracture (EF) they were 57 ± 10%, 58 ± 9% and 58 ± 9%, and for myocardial mass (MM) they were 104 ± 31 g, 95 ± 31 g and 94 ± 30 g. Statistically significant differences were found when comparing the EDV/ESV/MM results, the EF results after apex/base adjustment and after apex/base/myocardial contour adjustment and the SV results (except for comparing the SVs after apex/base adjustment and after apex/base/myocardial contour adjustment).Automated segmentation for the evaluation of left ventricular parameters in pediatric MR images proved to be feasible. Automated segmentation + apex/base adjustment provided clinically acceptable parameters for the majority of cases.
EVALuna2:14344

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach - Hijiya, Nobuko; Schultz, Kirk R.; Metzler, Markus; Millot, Frederic; Suttorp, Meinolf (Blood, 2016)
Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.
EVALuna2:33877

Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes - Weber, Marie; Schneider, Dominik T.; Offenmüller, Sonja; Kaatsch, Peter; Einsiedel, Hagen Graf; Benesch, Martin; Claviez, Alexander; Ebinger, Martin; Kramm, Christof; Kratz, Christian; Lawlor, Jennifer; Leuschner, Ivo; et al. (Pediatric Blood & Cancer, 2016)
Colorectal carcinoma (CRC) is the second most common adult cancer in Germany, however, it is extremely rare in children and adolescents. In these patients, previous literature describes aggressive behavior and diagnosis at advanced stage.Thirty-one patients with CRC age <= 18 years and treated between 1990 and 2012 have been identified through the structures and registries of the German Society for Pediatric Oncology and Hematology.The age range was 9-18 years (median 13.5 years); the median follow-up time was 43.9 months (range 1-124 months). Twenty-six patients (84%) were tested for a genetic tumor syndrome (GTS); of these, 11 patients (35% of all patients) tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, two patients with constitutional mismatch repair deficiency). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) in 68% of carcinoma (n = 21). Overall survival (OS) and event-free survival at 5 years was 52.0% and 65.6%, respectively. Five-year survival according to stage was 100% in stage II (n = 2), 100% in stage III (n = 13), and 12.9% in stage IV (n = 15; P < 0.001). Five-year OS in patients with and without a defined GTS was 100% and 36.5% (P = 0.019), respectively.Children and adolescents with CRC are frequently diagnosed in advanced stages and have an unfavorable prognosis. In this study, a high percentage of pediatric CRC patients presented with a tumor predisposition syndrome and showed an especially favorable OS.
EVALuna2:15175

Pediatric Cullen gangrene: Case report of postoperative pyoderma gangrenosum in a preterm infant with a complex gastrointestinal malformation - Diez, Sonja; Syed, Julia; Müller, Hanna; Besendörfer, Manuel; Schellerer, Vera (International Journal of Surgery Case Reports, 2020)
Introduction: Pyoderma gangrenosum (PG) is a rare condition in infants, children and adolescents. The postoperative variant of this rapidly progressive ulceration is known as Cullen gangrene. Only a few case reports of pediatric Cullen gangrene have been published. Presentation of case: We present a male infant (gestational age 31 + 6 weeks) with gastroschisis and intrauterine volvulus. After multiple operations due to his complex gastrointestinal malformation, the patient showed classical symptoms of postoperative PG (PPG) 4 weeks after birth. Diagnosis could be made early in an interdisciplinary approach, differentiating intraabdominal infection (vancomycin resistant enterococcus (VRE), candida albicans) from epifascial occurrence. Treatment with high-dose steroids and immunoglobulins was initiated immediately and led to rapid recovery. Discussion: The unusual combination of a complex gastrointestinal malformation and an intraabdominal infection with VRE and candida albicans made the diagnosis difficult. However, early diagnosis is crucial in the treatment of Cullen gangrene. Conclusion: This is the first case report of Cullen gangrene presenting in an infant (at 4 weeks of age).
CRIS-Team Scopus Importer:2020-01-21
Keywords: Cullen gangrene; Gastroschisis; Pediatric surgery; Pyoderma gangrenosum

Pediatric Extracorporeal Life Support Using a Third Generation Diagonal Pump - Speth, Marlene; Münch, Frank; Purbojo, Ariawan; Glöckler, Martin; Toka, Okan; Cesnjevar, Robert; Rueffer, Andre (Asaio Journal, 2016)
This study reports a single-centre experience of the Medos Deltastream diagonal-pump (DP3) for extracorporeal cardiac, pulmonary, or combined support in a single-center pediatric cohort. Twenty-seven consecutive patients with 28 runs of the DP3 between January 2013 and June 2014 were included for analysis. Median patient age, weight, and duration of support were 278 days (range: 0 days-14.2 years), 7.2 kg (range: 2.5-39 kg), and 8 days (range: 2-69 days). Midline sternotomy (n = 20, 71.4%) or cervical approaches (n = 8, 28.6%) were used for cannulation. The DP3 was employed for either veno-arterial extracorporeal life support (ECLS, n = 16), veno-venous extracorporeal membrane oxygenation (ECMO, n = 5), or ventricular assist devices (right ventricular assist device [RVAD], n = 1; left ventricular assist device [LVAD], n = 1; and univentricular assist device [UNIVAD], n = 5). Three patients initially supported with ECLS were switched to UNIVAD and one patient with UNIVAD was changed to ECLS. Required flow for neonates (n = 8) ranged between 0.2 and 0.75 L/min. Irreversible pump damage occurred in one patient during deairing after air block. Successful weaning, 30 day and hospital survival were 89.3% (n = 25), 85.7% (n = 24), and 71.4% (n = 20). All patients on UNIVAD, who did not require further extracorporeal respiratory assist, survived. In conclusion, the DP3 can be used for individual patient demands and adapted to their most suitable method of support. Meticulous flow adjustments render this pump highly effective for extracorporeal support particularly in pediatric patients.
EVALuna2:25117

Pediatric Mesothelioma Tumors: The European Expert Group Contribution - Orbach, D.; Andre, N.; Brecht, I.; Lopez Almaraz, R.; Ben Ami, T.; Wermersch, S.; Carton, M.; Virgone, C.; Bisogno, G.; Schneider, D.; Bajciova, V.; Reguerre, Y.; et al. (PEDIATRIC BLOOD & CANCER, 2020)
CRIS-Team WoS Importer:2020-12-04

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases - Argani, Pedram; Lian, Derrick W.Q.; Agaimy, Abbas; Metzler, Markus; Wobker, Sara E.; Matoso, Andres; Epstein, Jonathan I.; Sung, Yun Shao; Zhang, Lei; Antonescu, Cristina R. (American Journal of Surgical Pathology, 2021)
Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.
CRIS-Team Scopus Importer:2021-04-23

Pediatric multi-drug-resistant tuberculosis in Germany – diagnostic and therapeutic challenges of an “orphan disease” - Schäfer, Hannah Lena; Barker, Michael; Follmann, Peter; Günther, Annette; Hörning, André; Kaiser-Labusch, Petra; Kerzel, Sebastian; Maier, Christoph; Roth, Samra; Schmidt, Christian; Schütz, Katharina; Stehling, Florian; et al. (European Journal of Pediatrics, 2023)
Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case–control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). Conclusions: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. Trial Registration: Deutsches Register Klinischer Studien (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817), DRKS00023817, 2020–09-08. What is Known: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. What is New: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.
CRIS-Team Scopus Importer:2023-09-22
Keywords: Children; Germany; Multicenter; Multidrug resistance (MDR); Tuberculosis

Pediatric reference intervals for alkaline phosphatase - Zierk, Jakob; Arzideh, Farhad; Haeckel, Rainer; Cario, Holger; Fruehwald, Michael C.; Gross, Hans-Juergen; Gscheidmeier, Thomas; Hoffmann, Reinhard; Krebs, Alexander; Lichtinghagen, Ralf; Neumann, Michael; Ruf, Hans-Georg; et al. (Clinical Chemistry and Laboratory Medicine, 2017)
BACKGROUND: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. METHODS: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method. RESULTS: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. CONCLUSIONS: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.
EVALuna2:34216

Performance of epimyocardial leads in patients with a single ventricle circulation - Zartner, Peter A.; Mini, Nathalie; Vergnat, Mathieu; Momcilovic, Diana; Schneider, Martin B.; Dittrich, Sven (Pace-Pacing and Clinical Electrophysiology, 2021)
Background Cardiac pacing can be challenging after a Fontan operation, and limited data exist regarding strategies to plan these epimyocardial systems while minimizing the number of surgical procedures.
CRIS-Team WoS Importer:2021-04-02

Performance of stented biological valves for right ventricular outflow tract reconstruction - Buchholz, Christian; Mayr, Andreas; Purbojo, Ariawan; Glöckler, Martin; Toka, Okan; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2016)
This retrospective single-centre review presents mid- and long-term results of stented biological valves (SBVs) in the pulmonary position.Fifty-two SBVs (17 Carpentier-Edwards Supraannular; 13 Carpentier-Edwards Perimount; 12 St. Jude Medical Trifecta; 4 Sorin Mitroflow; 4 Sorin Soprano; 2 Sorin More) were implanted between 2000 and 2015. The median valve size, patient age and weight were 23 mm (range 19-27), 22.8 years (range 5-77) and 62.0 kg (range 14-110), respectively. The main cardiac diagnosis was tetralogy of Fallot in 26 patients (50%). Forty-four patients (85%) had previous cardiac surgery; 12 patients (23%) had previous conduit or biological valve replacement. Valve degeneration was defined as a valvular peak pressure gradient >50 mmHg or pulmonary valve regurgitation more than moderate.The mean follow-up was 7.9 ± 5.5 years. Two patients died after 5.8 and 6.1 years of causes not related to SBVs. Eleven SBVs (21%) had to be replaced surgically (n = 6) or interventionally (n = 5) after 9.0 ± 4.1 years due to valve degeneration (n = 8), endocarditis (n = 2) or right ventricular dysfunction (n = 1). The rates of freedom from valve replacement were 100%, 92% [95% confidence interval (CI) 79-97], 81% (CI 64-91) and 60% (CI 40-78) after 1, 5, 10 and 15 years, respectively. Successful interventional valve-in-valve implantation resulted in 100% freedom from surgical valve replacement in all patients older than 19.1 years. Multivariate analysis identified patient age <19.1 years (P = 0.007) as a risk factor for earlier valve degeneration.SBVs in the pulmonary position showed encouraging long-term results in mature patients. The design of SBVs enables interventional valve implantation, postponing the need for reoperation.
EVALuna2:25813

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial - Thome, Ulrich H.; Genzel-Boroviczeny, Orsolya; Bohnhorst, Bettina; Schmid, Manuel; Fuchs, Hans; Rohde, Oliver; Avenarius, Stefan; Topf, Hans-Georg; Zimmermann, Andrea; Faas, Dirk; Timme, Katharina; Kleinlein, Barbara; et al. (The Lancet Respiratory Medicine, 2015)
Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death.In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743.Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36).Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection.Deutsche Forschungsgemeinschaft.
EVALuna2:18882

Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia - Gebhard, Anna; Lilienthal, Patrick; Metzler, Markus; Rauh, Manfred; Sager, Sebastian; Schmiegelow, Kjeld; Toksvang, Linea Natalie; Zierk, Jakob (Scientific Reports, 2023)
In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic–pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.
CRIS-Team Scopus Importer:2023-09-08

Pharmacologic stabilization of hypoxia-inducible transcription factors protects developing mouse brain from hypoxia-induced apoptotic cell death - Trollmann, Regina; Richter, Markus; Jung, Susan; Walkinshaw, G.; Brackmann, Florian (Neuroscience, 2014)
Accumulation of hypoxia-inducible transcription factors (HIFs) by prolyl-4-hydroxylase inhibitors (PHI) has been suggested to induce neuroprotection in the ischemic rodent brain. We aimed to investigate in vivo effects of a novel PHI on HIF-regulated neurotrophic and pro-apoptotic factors in the developing normoxic and hypoxic mouse brain.Neonatal mice (P7) were treated with PHI FG-4497 (30-100mg/kg, i.p.) followed by exposure to systemic hypoxia (8% O2, 6h) 4h later. Cerebral expression of HIF?-subunits, specific neurotrophic and vasoactive target genes (vascular endothelial growth factor (VEGF), adrenomedullin (ADM), erythropoietin (EPO), inducible nitric oxide synthase (iNOS)) as well as pro-apoptotic (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 gene (BNIP3), immediate early response 3 (IER3)) and migratory factors (chemokine receptor 4 (CXCR4), stromal cell-derived factor 1 (SDF-1)) was determined (quantitative real-time (RT)., Western blot analysis) in comparison to controls. Apoptotic cell death was analyzed by terminal desoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and cleaved caspase 3 (CC3) staining.Under normoxic conditions, FG-4497 treatment significantly induced the accumulation of both HIF-1? and HIF-2? isoforms in developing mouse brain. In addition, there was a significant up-regulation of HIF target genes (VEGF, ADM, EPO, CXCR4, p<0.01) with FG-4497 treatment compared to controls supporting functional activation of the HIF proteins. Under hypoxia, differential target gene activation was observed in the developing brain including additive effects of FG-4497 and hypoxia on mRNA expression of VEGF and ADM as well as a dose-dependent down-regulation of iNOS. BNIP3 but not IER3 mRNA levels significantly increased in hypoxic brains pre-treated with high-dose FG-4497 compared to controls. Of special interest, FG-4497 treatment significantly diminished apoptotic cell death, quantified by TUNEL and CC3-positive cells, in hypoxic developing brains compared to controls.PHI treatment modulates neurotrophic factors known to be crucially involved in hypoxia-induced cerebral adaptive mechanisms as well as early brain maturation. Pre-treatment with FG-4497 seems to protect the developing brain from hypoxia-induced apoptosis. Present observations provide basic information for further evaluation of neuroprotective properties of PHI treatment in hypoxic injury of the developing brain. However, potential effects on maturational processes need special attention in experimental research targeting HIF-dependent neuroprotective interventions during the very early stage of brain development.
EVALuna2:18900

Pharmacology and pharmacokinetics of imatinib in pediatric patients - Suttorp, Meinolf; Bornhaeuser, Martin; Metzler, Markus; Schleyer, Eberhard; Millot, Frederic (Expert Review of Clinical Pharmacology, 2018)
INTRODUCTION: The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug-drug/food-drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically. Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.
EVALuna2:34299

PHENOCOPIESOF CLINICALLY DIAGNOSED ARPKD REVEALED IN CHILDREN - Halawi, Abdul; Burgmaier, Kathrin; Buescher, Anja; Dursun, Ismail; Galiano, Matthias; Gessner, Michaela; Gokce, Ibrahim; Kowalewska, Claudia; Mekahli, Djalila; Mir, Sevgi; Shroff, Rukshana; Stabouli, Stella; et al. (PEDIATRIC NEPHROLOGY, 2021)
CRIS-Team WoS Importer:2021-10-01

Phosphate Intoxication after Application of Enema - a Life-threatening Iatrogenic Complication - Marek, I.; Benz, Kerstin; Kusnik, Stefan; Morhart, P.; Botzenhardt, S.; Toni, I.; Rascher, Wolfgang (Klinische Pädiatrie, 2015)
Enemas are used in pediatric patients with constipation. Retention of phosphate containing enemas with prolonged resorption or reduced renal elimination of phosphate can result in life-threatening hyperphosphatemia with subsequent lethal hypocalcemia and acidosis.We report the case of a 6-month-old child who received phosphate-containing enema to treat acute aggravation of constipation. The used enema here was not licensed for this age group. Phosphate intoxication resulted (phosphate 19.87 mmol/l) and presented like a sepsis. Hyperphosphatemia was treated by hemodialysis. A non-diagnosed Hirschsprung disease had led to prolonged resorption of phosphate containing enema and to an ileus and toxic megacolon that had to be operated.Insufficient elimination of phosphate containing enema can result in lethal or life threatening hyperphosphatemia, hypocalcemia and metabolic acidosis. These can be treated efficaciously by hemodialysis. Because of the high risk of intoxication in using enemas containing phosphate in infants or in patients with gastrointestinal or renal comorbidities, physicians treating constipation should choose enemas without phosphate but with ingredients with lower risk like glycerol or sorbitol in this age group.
EVALuna2:18933

PKD1L1 Is Involved in Congenital Chylothorax - Whitchurch, Jonathan B.; Schneider, Sophia; Hilger, Alina Christine; Köllges, Ricarda; Stegmann, Jil D.; Waffenschmidt, Lea; Dyer, Laura; Thiele, Holger; Dhabhai, Bhanupriya; Dakal, Tikam Chand; Müller, Andreas; Norris, Dominic P.; et al. (Cells, 2024)
Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in PKD1L1 in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of Pkd1l1 mutant mouse embryos revealed about 20% of Pkd1l1-/- embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in Pkd1l1-/- embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of PKD1L1 in congenital lymphatic anomalies, including CCTs.
CRIS-Team Scopus Importer:2024-02-02
Keywords: chylothorax; congenital; PKD1L1; pleural effusion

Plasma concentrations of the amyloid-? peptides in young volunteers: the influence of the APOE genotype - Zimmermann, Rüdiger; Huber, Ellen; Schamber, Christine; Lelental, Natalia; Mroczko, Barbara; Brandner, Sebastian; Maler, Juan Manuel; Oberstein, Timo; Szmitkowski, Maciej; Rauh, Manfred; Kornhuber, Johannes; Lewczuk, Piotr (Journal of Alzheimer's Disease, 2014)
Changes in the concentrations of amyloid-? (A?) in the body fluids are the earliest alterations observed in Alzheimer's disease (AD), however, there is a lack of data about how early these alterations occur, before the onset of the clinical symptoms. APOE genotype is the most recognized genetic risk/protective factor of AD, meaning that a group of non-demented persons carrying ?4 allele is enriched in the subjects who will develop AD, compared to the group of non-carriers. Therefore, we studied the plasma concentrations of A? peptides (A?1-42, A?1-40, A?x-42, and A?x-40), and the APOE genotype in 173 young volunteers (average age, 28 ± 7.6 years) without memory deficits, in order to see whether the non-demented group of subjects at risk already characterize with A? changes three-to-four decades before the age at which dementia usually occurs. We did not find statistically significant differences among the groups of ?4 carriers, ?3 homozygotes, and ?2 carriers. We conclude that the APOE genotype does not influence the metabolism of the A? peptides in young persons without memory deficits.
EVALuna2:18883

Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors - März, Juliane; Kurlbaum, Max; Roche-Lancaster, Oisin; Deutschbein, Timo; Peitzsch, Mirko; Prehn, Cornelia; Weismann, Dirk; Robledo, Mercedes; Adamski, Jerzy; Fassnacht, Martin; Kunz, Meik; Kroiss, Matthias (Frontiers in Endocrinology, 2021)
Context: Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet. Objective: Evaluation of quantitative metabolomics as a diagnostic tool for PPGL. Design: Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study. Patients: Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded. Results: Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines. By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling. Conclusions: The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability.
CRIS-Team Scopus Importer:2021-10-01
Keywords: adrenal; catecholamines; feature selection; machine learning; mass spectronomy; paraganglioma; pheochromocytoma; targeted metabolomics

Pleiotropic effects under combined therapy with empagliflozin and linagliptin compared to metformin and insulin glargine in patients with type 2 diabetes - Jung, Susan; Ott, Christian; Kannenkeril, D.; Bosch, Agnes; Karg, M.; Striepe, Kristina; Bramlage, P.; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

Point of Care detection of anti-infliximab antibodies in inflammatory bowel disease patients treated with the biosimilar SB2: performance comparison with ELISA - Atreya, Raja; Schmitt, H.; Fischer, Sven Moritz; Neurath, Markus; Rekalde, X.; Nagore, D.; Ametzazurra, A. (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Postoperative pain in small-for-gestational age infants after hernia repair, orchidopexy and urethral reconstruction surgery: A pilot study - Schüssler, Stephanie C.; Kußmann, Franziska; Fahlbusch, Fabian B.; Münster, Tino; Hirsch, Karin; Carbon, Roman; Albrecht, Sven; Dötsch, Jörg; Rascher, Wolfgang (Early Human Development, 2019)
Background: Small-for-gestational-age (SGA) birth bears an enhanced risk of developing hypertension, obesity, insulin resistance and mental health disorders in later life as a consequence of adaptive processes in utero. Only a small number of studies on pain perception in SGA infants exist. These are indicative of a blunted stress response to pain in SGA newborns. Aim: We initiated a pilot study investigating differences in postoperative pain perception between SGA and appropriate-for-gestational-age (AGA) infants. Methods: Pain and alertness levels of 10 formerly SGA and 14 AGA infants at the age 0.5–2 years were evaluated by the FLACC scale, Steward and Aldrete Scores following hernia repair, reconstructive surgery of hypospadia and orchidopexy. In addition, the postoperative consumption of non-steroidal anti-inflammatory drugs was compared between SGA and AGA. Results: Postoperative pain and alertness levels were not significantly different in SGA and AGA children. We did not observe significant group differences regarding the consumption of non-steroidal anti-inflammatory drugs. Conclusion: While previous studies were suggestive of a suppressed stress response to pain in SGA newborns, these findings did not fully translate into an altered response to pain beyond the newborn age. Further studies in a larger cohort seem necessary to verify this finding.
CRIS-Team Scopus Importer:2019-07-16

Potential for Radiation Dose Reduction in Dual-Source Computed Tomography of the Lung in the Pediatric and Adolescent Population Compared to Digital Radiography - Wetzl, Matthias; May, Matthias; Weinmann, Daniel; Hammon, Matthias; Kopp, Markus; Ruppel, Renate; Trollmann, Regina; Wölfle, Joachim; Uder, Michael; Rompel, Oliver (Diagnostics, 2021)
Low-dose dual-source computed tomography (DSCT) protocols for the evaluation of lung diseases in children and adolescents are of importance since this age group is particularly prone to radiation damage. The aim of this study was to evaluate image quality of low-dose DSCT of the lung and to assess the potential of radiation dose reduction compared to digital radiographs (DR). Three groups, each consisting of 19 patients, were examined with different DSCT protocols using tin prefiltration (Sn96/64/32 ref. mAs at 100 kV). Different strengths of iterative reconstruction were applied (ADMIRE 2/3/4). DSCT groups were compared to 19 matched patients examined with posterior-anterior DR. Diagnostic confidence, detectability of anatomical structures and small lung lesions were evaluated on a 4-point Likert scale (LS 1 = unacceptable, 4 = fully acceptable; a value >= 3 was considered acceptable). Effective dose (ED) was 31-/21-/9-fold higher in Sn96/Sn64/Sn32 compared to DR. Diagnostic confidence was sufficient in Sn96/Sn64 (LS 3.4/3.2), reduced in Sn32 (LS 2.7) and the worst in DR (LS 2.4). In DSCT, detectability of small anatomical structures was always superior to DR (p < 0.05). Mean lesion size ranged from 5.1-7 mm; detectability was acceptable in all DSCT groups (LS 3.0-3.4) and superior to DR (LS 1.9; p < 0.05). Substantial dose lowering in DSCT of the pediatric lung enables acceptable detectability of small lung lesions with a radiation dose being about 10-fold higher compared to DR.
CRIS-Team WoS Importer:2021-03-12

Precise variant interpretation, phenotype ascertainment, and genotype–phenotype correlation of children in the EARLY PRO-TECT Alport trial - Boeckhaus, Jan; Hoefele, Julia; Riedhammer, Korbinian M.; Tönshoff, Burkhard; Ehren, Rasmus; Pape, Lars; Latta, Kay; Fehrenbach, Henry; Lange-Sperandio, Baerbel; Kettwig, Matthias; Hoyer, Peter; Staude, Hagen; et al. (Clinical Genetics, 2020)
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype–phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
CRIS-Team Scopus Importer:2020-10-30
Keywords: Alport syndrome; COL4A3; COL4A4; COL4A5; hereditary kidney disease

Precision of handheld multispectral optoacoustic tomography for muscle imaging - Wagner, Anna; Danko, Vera; Federle, Anna; Klett, Daniel; Simon, David; Heiß, Rafael; Jüngert, Jörg M.; Uder, Michael; Schett, Georg; Neurath, Markus; Wölfle, Joachim; Waldner, Maximilian; et al. (Photoacoustics, 2021)
Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm–1210 nm and five MSOT-parameters (deoxygenated/oxygenated/total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82–0.92; MSOT-parameter: 0.72−0.92) and interrater reproducibility (SWL: 0.79−0.87; MSOT-parameter: 0.78−0.86), with the exception for MSOT-parameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation.
CRIS-Team Scopus Importer:2020-12-25
Keywords: MSOT; Multispectral optoacoustic tomography; Muscle imaging; Optoacoustics; Photoacoustics

Preconceptual Counseling, Prenatal Care and peripartum Management of Female Patients with Ullrich-Turner Syndrome and a High-risk cardiovascular Profile - Pontones, Constanza; Lubrich, Hannah; Schwenke, E.; Cupisti, Susanne; Dittrich, Ralf; Kehl, Sven; Beckmann, Matthias; Fahlbusch, C.; Oppelt, Patricia (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Prediction of High Bell Stages of Necrotizing Enterocolitis Using a Mathematic Formula for Risk Determination - Diez, Sonja; Bell, Lea Emilia; Moosmann, Julia; Weiss, Christel; Müller, Hanna; Besendörfer, Manuel (Children, 2022)
Necrotizing enterocolitis (NEC) continues to cause high morbidity and mortality. Identifying early predictors for severe NEC is essential to improve therapy and optimize timing for surgical intervention. We present a retrospective study of patients with NEC, treated between 2010 and 2020, trying to identify factors influencing the severity of NEC. Within the study period, 88 affected infants with NEC or NEC-like symptoms are analyzed. A multiple logistic regression analysis reveals the following three independent predictors for NEC in Bell stage III: red blood cell transfusion (p = 0.027 with odds ratio (OR) = 3.298), sonographic findings (p = 0.037; OR = 6.496 for patients with positive vs. patients without pathological findings) and cardiac anatomy (p = 0.015; OR = 1.922 for patients with patent ductus arteriosus (PDA) vs. patients with congenital heart disease (CHD); OR = 5.478/OR = 2.850 for patients with CHD/PDA vs. patients without cardiac disease). Results are summarized in a clinical score for daily application in clinical routine. The score is easy to apply and combines clinically established parameters, helping to determine the timing of surgical intervention.
CRIS-Team Scopus Importer:2022-05-13
Keywords: Bell stage; clinical score; congenital heart disease; fulminant NEC; NEC; necrotizing enterocolitis

Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”) - Matejek, Nicola; Tittel, Sascha R.; Haberland, Holger; Rohrer, Tilman; Busemann, Eva-Maria; Jorch, Norbert; Schwab, Karl-Otfried; Wölfle, Joachim; Holl, Reinhard W.; Bettendorf, Markus (European Journal of Pediatrics, 2021)
Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry “HypoDok” for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of l-thyroxine (l-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cutoffs predicting TCH by screening TSH concentrations and l-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cutoff screening TSH concentration was 73 mU/L. The cutoff daily l-T4 dosage at 1 year was 3.1 μg/kg (90% sensitivity, 63% specificity; 36 μg/day) and at 2 years of age 2.95 μg/kg (91% sensitivity, 59% specificity; 40 μg/day). At 2 years of age, specificity (71%) increased when both of these parameters were considered together. Conclusion: The decision to continue or cease l-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual l-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided; and affected families reassured.What is Known:• The course of congenital primary hypothyroidism may be transient, causing potential overtreatment.• The dose ofl-thyroxine at 1 or 2 years of age may predict a transient course of primary congenital hypothyroidism.What is New:• TSH screening concentration andl-thyroxine dosages at 1 and 2 years of age represent reliable predictors for transient congenital primary hypothyroidism with higher sensitivity and specificity when considered together in order to select eligible patients who qualify for treatment withdrawal.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Congenital primary hypothyroidism; Permanent congenital primary hypothyroidism; Prediction; Transient congenital primary hypothyroidism

Premature birth associated with a favorable course in gestational alloimmune liver disease (GALD): A case report - Mulzer, Linda-Marie; Reutter, Heiko Martin; Jüngert, Jörg M.; Knisely, A. S.; Schmid, Margit; Hörning, André; Morhart, Patrick (Frontiers in Pediatrics, 2023)
Gestational alloimmune liver disease (GALD) is a rare neonatal disorder with high mortality and morbidity. The patients come to caregivers' attention aged a few hours or days. The disease manifests as acute liver failure with or without siderosis. The differential diagnosis of neonatal acute liver failure (NALF) is broad, including mainly immunologic, infectious, metabolic and toxic disorders. The most common cause, however, is GALD followed by herpes simplex virus (HSV) infection. The best suited pathophysiological paradigm of GALD is that of a maternofetal alloimmune disorder. State of the art treatment combines intravenously administered immunoglobulin (IVIG) with exchange transfusion (ET). We report an infant born at 35 + 2 weeks' gestation in whom GALD had a favorable course, of interest because premature birth in our patient may have exerted protective aspects and lessened morbidity in that intrauterine exposure to maternal complement-fixing antibodies was shortened. The diagnosis of GALD was challenging and difficult. We suggest a modified diagnostic algorithm combining clinical findings with histopathologic findings in liver and lip mucosa and, if available, on abdominal magnetic resonance imaging-study focusing on the liver, spleen, and pancreas. This diagnostic workup must be followed by ET and subsequent administration of IVIG without delay.
CRIS-Team WoS Importer:2023-04-14

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia - Schneider, Holm; Faschingbauer, Florian; Schuepbach-Mallepell, Sonia; Koerber, Iris; Wohlfart, Sigrun; Dick, Angela; Wahlbuhl, Mandy; Kowalczyk-Quintas, Christine; Vigolo, Michele; Kirby, Neil; Tannert, Corinna; Rompel, Oliver; et al. (New England Journal of Medicine, 2018)
Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).
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Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe - Nowotny, Hanna; Neumann, Uta; Tardy-Guidollet, Veronique; Faisal Ahmed, S.; Baronio, Federico; Battelino, Tadej; Bertherat, Jerome; Blankenstein, Oliver; Bonomi, Marco; Bouvattier, Claire; De la Perrière, Aude Brac; Brucker, Sara; et al. (European Journal of Endocrinology, 2022)
Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase defic iency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed ce ntres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 μg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
CRIS-Team Scopus Importer:2022-04-29

Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome? - Vasileiou, Georgia; Hoyer, Juliane; Thiel, Christian; Schaefer, Jan Thomas; Zapke, Maren; Krumbiegel, Mandy; Kraus, Cornelia; Zweier, Markus; Uebe, Steffen; Ekici, Arif Bülent; Schneider, Michael; Wiesener, Michael; et al. (Prenatal Diagnosis, 2019)
Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.
CRIS-Team WoS Importer:2019-11-08

Prenatal therapy in developmental disorders: drug targeting via intra-amniotic injection to treat X-linked hypohidrotic ectodermal dysplasia - Hermes, Katharina; Schneider, Pascal; Krieg, Peter; Anh Thu Dang,; Huttner, Kenneth; Schneider, Holm (Journal of Investigative Dermatology, 2014)
EVALuna2:18898

Prenatal treatment of X-linked hypohidrotic ectodermal dysplasia using recombinant ectodysplasin in a canine model - Margolis, Carol A.; Schneider, Pascal; Huttner, Kenneth; Kirby, Neil; Houser, Timothy P.; Wildman, Lee; Grove, Gary L.; Schneider, Holm; Casal, Margret L. (Journal of Pharmacology and Experimental Therapeutics, 2019)
X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.
CRIS-Team Scopus Importer:2019-09-17

Preoperative assessment of the aortic arch in children younger than 1 year with congenital heart disease: utility of low-dose high-pitch dual-source computed tomography. A single-centre, retrospective analysis of 62 cases - Glöckler, Martin; Halbfass, Julia; Koch, Andreas; Dittrich, Sven; Achenbach, Stephan; Rueffer, Andre; Ihlenburg, Katharina Susanne; Cesnjevar, Robert; May, Matthias; Uder, Michael; Rompel, Oliver (European Journal of Cardio-Thoracic Surgery, 2014)
To evaluate the feasibility, image quality and impact of 3D imaging in low-dose high-pitch dual-source computed tomography (DSCT) to assess arbitrary anatomical malformations of the aortic arch in children <1 year of age with congenital heart disease (CHD).Between January 2010 and May 2013, DSCT was performed to assess the aortic arch anatomy in a total of 62 consecutive patients with CHD (aged 0-348 days). DSCT was used whenever conventional echocardiography was not sufficient to display the complex anatomy entirely. Image data acquisition was realized within a single cardiac cycle using prospective ECG triggering. 3D reconstruction for surgical planning was performed. Image quality was assessed retrospectively, using a 4-point scale from '1 = no artefacts' to '4 = uninterpretable'. The accuracy and impact of the 3D reconstructions was compared with intraoperative findings using a 5-point scale (from '1 = essential' to '5 = misleading'). Administered radiation exposure was evaluated.Imaging was successful in all patients, image quality was rated 1.34 on the 4-point scale and the impact of the 3D reconstructions for surgical planning was 2.05 on the 5-point scale. Mean dose-length product was 6.8 ± 2.6 mGy cm, and the effective dose was 0.45 ± 0.13 mSv (0.21-0.74).DSCT is a fast and appropriate imaging modality in the preoperative assessment of the aortic arch for surgical planning in CHD.
EVALuna2:11864

Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature - Strzelczyk, Adam; Grau, Janina; Bast, Thomas; Bertsche, Astrid; Bettendorf, Ulrich; Hahn, Andreas; Hartmann, Hans; Hertzberg, Christoph; Hornemann, Frauke; Immisch, Ilka; Jacobs, Julia; Klotz, Kerstin A.; et al. (Expert Review of Clinical Pharmacology, 2021)
Objective Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC. Methods We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence. Results TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs. Conclusions The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.
CRIS-Team WoS Importer:2021-06-11

Preterm small-for-gestational age children: Predictive role of gestational age for mental development at the age of 2 years - Nögel, Stephanie; Deiters, Ludger; Stemmler, Mark; Rascher, Wolfgang; Trollmann, Regina (Brain & Development, 2015)
AIM: The aim of the study was to compare the cognitive development of very low birth weight (VLBW) preterm SGA children and preterm AGA children at the age of 2 years. The hypothesis was that SGA children are at an additional risk for deficits in cognitive function. Additionally, the impact of neonatal risk factors and the parents' profession on the early cognitive development was analysed. METHODS: Cognitive function of 107 preterm infants with a gestational age of 24-35 weeks was assessed with the Mental Bayley Scales of Infant Development at the age of 2 years (mean±SEM). The results of SGA (n=38) and AGA (n=69) children were compared as well as neonatal risk factors and parental education. RESULTS: There was a linear regression between the Mental Bayley Scales result and gestational age for preterm infants with a gestational age of 24-32 weeks. SGA and AGA children did not differ significantly in their cognitive function at the age of 2 years. A strong association was found between the parents' profession and cognitive development. Among the neonatal risk factors, bronchopulmonary dysplasia was a strong predictor of mental development. INTERPRETATION: Cognitive development of two-year-old preterm children with a gestational age of 24-32 weeks was mainly related to their gestational age. Being born preterm and small for gestational age was not additionally associated with cognitive deficits at the age of 2 years. The parents' profession had a significant impact on the cognitive development. The role of the parents' profession on the early development of preterm infants should be elucidated in further studies. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Gestational age; Mental development; Parental profession; Preterm infants

Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy - Blueschke, Gert; Nuesken, Kai-Dietrich; Schneider, Holm (Early Human Development, 2010)
Objective: To re-evaluate the mortality of hypohidrotic ectodermal dysplasia (HED) and the prevalence of hyperpyrexia and possible neurological sequelae in affected infants. Study design: A cross-sectional postal survey was conducted among parents of 100 children with ectodermal dysplasia who had been registered with the German-Swiss-Austrian patient support group at any time point within the past 10. years. Detailed questionnaires referring to the first year of life were evaluated statistically. Results: 63% of parents returned completed surveys, identifying 57% of children as patients with X-linked HED and 20% as patients with autosomal HED or HED of unknown origin. Of those two groups, 17 infants had been placed in an incubator after birth, where body temperature recording proved to be of utmost importance. In 94% of all HED patients, episodes of unexplained fever were observed during the first year of life. X-linked HED was associated with frequent airway infections. Febrile seizures occurred in 5.9% of infants with X-linked HED and in 17% of the other HED patients. Developmental retardation was reported for 15% and 25%, respectively. Prognosis depended on the type of genetic defect and the time point of diagnosis. Except for one all patients survived infancy. Early recognition of the disease was aided by vigilant neonatal care and consulting a dermatologist or geneticist. Adequate instruction of the parents and networking with patient support groups also reduced the risks associated with HED. Conclusions: Today, mortality of HED and the risk of hyperthermic brain damage are still increased, but lower than reported previously. © 2010 Elsevier Ltd.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Ectodermal dysplasia; Febrile seizure; Hyperthermia; Sudden infant death

Prevalence of chronic drug use in pediatrics: Comprehensive overview based on German claims data - Scholle, Oliver; Neubert, Antje; Riedel, Oliver; Toni, Irmgard; Haug, Ulrike (PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2020)
CRIS-Team WoS Importer:2020-11-13

Prevalence of metastases within the hypothalamic-pituitary area in patients with brain metastases - Janssen, Stefan; Mehta, Preena; Bartscht, Tobias; Schmid, Sebastian M.; Fahlbusch, Fabian; Rades, Dirk (Radiation Oncology, 2019)
Aim To quantify the prevalence of brain metastases involving the hypothalamic-pituitary (HT-P) area. Introduction Cognitive impairment and fatigue are common side effects of whole brain irradiation (WBI) comprising the quality of life (QoL) for survivors. While the former is related to radiation-induced hippocampal injury, the latter could be secondary to hormonal disbalance as a consequence of radiation of the HT-P area. Thus, sparing both regions from higher irradiation doses could reduce these sequelae. Methods T1 contrast medium enhanced magnetic resonance imaging (MRI) scans of 865 patients with brain metastases (4,280 metastases) were reviewed. HT-P area was individually contoured with a margin of 5 mm in order to evaluate the prevalence of brain metastases in this region. Results Involvement of the hypothalamic region was found in 26 patients (involvement rate of 3% for patients and 1% for metastases), involvement of the pituitary gland in 9 patients (1% for patients and < 1% for metastases). Binary logistical regression analysis revealed the presence of > 10 brain metastases as the only factor associated with hypothalamic involvement while no distinct factor was associated with an involvement of the pituitary gland. Conclusion The low prevalence of metastases within the HT-P area in patients with brain metastases calls for further studies examining whether sparing of this region might improve patients QoL.
CRIS-Team WoS Importer:2019-09-10

Prevalence of SARS-CoV-2 in Pregnant Women Assessed by RT-PCR in Franconia, Germany: First Results of the SCENARIO Study (SARS-CoV-2 prEvalence in pregNAncy and at biRth In FrancOnia) - Hein, Alexander; Kehl, Sven; Häberle, Lothar; Tiemann, Carsten; Peuker, Rebecca; Mereutanu, Denise; Stumpfe, Florian; Faschingbauer, Florian; Meyer-Schlinkmann, Kirstin; Koch, Martin C.; Kainer, Franz; Dammer, Ulf; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Purpose Detection of SARS-CoV-2-infected pregnant women admitted to maternity units during a pandemic is crucial. In addition to the fact that pregnancy is a risk factor for severe COVID-19 and that medical surveillance has to be adjusted in infected women and their offspring, knowledge about infection status can provide the opportunity to protect other patients and healthcare workers against virus transmission. The aim of this prospective observational study was to determine the prevalence of SARS-CoV-2 infection among pregnant women in the hospital setting. Material and Methods All eligible pregnant women admitted to the nine participating hospitals in Franconia, Germany, from 2 June 2020 to 24 January 2021 were included. COVID-19-related symptoms, secondary diseases and pregnancy abnormalities were documented. SARS-CoV-2 RNA was detected by RT-PCR from nasopharyngeal swabs. The prevalence of acute SARS-CoV-2 infection was estimated by correcting the positive rate using the Rogan-Gladen method. The risk of infection for healthcare workers during delivery was estimated using a risk calculator. Results Of 2414 recruited pregnant women, six were newly diagnosed RT-PCR positive for SARS-CoV-2, which yielded a prevalence of SARS-CoV-2 infection of 0.26% (95% CI, 0.10-0.57%). Combining active room ventilation and wearing FFP2 masks showed an estimated reduction of risk of infection for healthcare workers in the delivery room to < 1%. Conclusions The prevalence of newly diagnosed SARS-CoV-2 infection during pregnancy in this study is low. Nevertheless, a systematic screening in maternity units during pandemic situations is important to adjust hygienic and medical management. An adequate hygienic setting can minimise the calculated infection risk for medical healthcare workers during patients' labour.
CRIS-Team Scopus Importer:2022-02-25
Keywords: COVID-19; infection; pregnancy; prevalence; SARS-CoV-2

Preventing maternal phenylketonuria (PKU) syndrome: important factors to achieve good metabolic control throughout pregnancy - Rohde, Carmen; Thiele, Alena Gerlinde; Baerwald, Christoph; Ascherl, Rudolf Georg; Lier, Dinah; Och, Ulrike; Heller, Christina; Jung, Alexandra; Schoenherr, Kathrin; Joerg-Streller, Monika; Luttat, Simone; Matzgen, Sabine; et al. (Orphanet Journal of Rare Diseases, 2021)
Background Insufficient metabolic control during pregnancy of mothers with phenylketonuria (PKU) leads to maternal PKU syndrome, a severe embryo-/fetopathy. Since maintaining or reintroducing the strict phenylalanine (Phe) limited diet in adults with PKU is challenging, we evaluated the most important dietary and psychosocial factors to gain and sustain good metabolic control in phenylketonuric women throughout pregnancy by a questionnaire survey with 38 questions concerning therapy feasibility. Among them, the key questions covered 5 essential items of PKU care as follows: General information about maternal PKU, PKU training, diet implementation, individual metabolic care, personal support. In addition, all participating PKU mothers were asked to estimate the quality of their personal metabolic control of the concluded pregnancies. 54 PKU mothers with 81 pregnancies were approached at 12 metabolic centers in Germany and Austria were included. According to metabolic control, pregnancies of PKU women were divided in two groups: group "ideal" (not more than 5% of all blood Phe concentrations during pregnancy > 360 mu mol/l; n = 23) and group "suboptimal" (all others; n = 51). Results The demand for support was equally distributed among groups, concerning both amount and content. Personal support by the direct social environment (partner, family and friends) ("suboptimal" 71% vs "ideal" 78%) as well as individual metabolic care by the specialized metabolic center (both groups around 60%) were rated as most important factors. The groups differed significantly with respect to the estimation of the quality of their metabolic situation (p < 0.001). Group "ideal" presented a 100% realistic self-assessment. In contrast, group "suboptimal" overestimated their metabolic control in 53% of the pregnancies. Offspring of group "suboptimal" showed clinical signs of maternal PKU-syndrome in 27%. Conclusion The development of training programs by specialized metabolic centers for females with PKU in child bearing age is crucial, especially since those mothers at risk of giving birth to a child with maternal PKU syndrome are not aware of their suboptimal metabolic control. Such programs should provide specific awareness training for the own metabolic situation and should include partners and families.
CRIS-Team WoS Importer:2021-12-03

Previous diabetic ketoacidosis as a risk factor for recurrence in a large prospective contemporary pediatric cohort: Results from the DPV initiative - Hammersen, Johanna; Tittel, Sascha R.; Warncke, Katharina; Fritsch, Maria; Placzek, Kerstin; Pacaud, Danièle; Karges, Beate; Wölfle, Joachim; Holl, Reinhard W. (Pediatric Diabetes, 2021)
Objective: To assess the role of previous episodes of diabetic ketoacidosis (DKA) and their time-lag as risk factors for recurring DKA in youth with type 1 diabetes (T1D). Research Design and Methods: In a population-based analysis, data from 29,325 children and adolescents with T1D and at least 5 years of continuous follow-up were retrieved from the “Diabetes Prospective Follow-up” (DPV) multi-center registry in March 2020. Statistical analyses included unadjusted comparisons, logistic and negative binomial regression models. Results: Among 29,325 patients with T1D, 86.0% (n = 25,219) reported no DKA, 9.7% (n = 2,833) one, and 4.3% (n = 1,273) more than one episode, corresponding to a DKA rate of 4.4 [95% CI: 4.3–4.6] per 100 patient-years. Female sex, migratory background, higher HbA1c values, higher daily insulin doses, a lower glucose monitoring frequency, and less CGM usage were associated with DKA. In patients with a previous episode, the DKA rate in the most recent year was significantly higher than in patients with no DKA (17.6 [15.9–19.5] vs. 2.8 [2.7–3.1] per 100 patient-years; p < 0.001). Multiple DKAs further increased the recurrence rate. The risk for DKA in the most recent year was higher in patients with an episode in the preceding year than in patients with no previous DKA (OR: 10.0 [95% CI: 8.6–11.8]), and remained significantly elevated 4 years after an episode (OR: 2.3 [1.6–3.1]; p < 0.001). Conclusions: Each episode of DKA is an independent risk factor for recurrence, even 4 years after an event, underlining the importance of a close follow-up after each episode.
CRIS-Team Scopus Importer:2021-03-05

Priapism at Diagnosis of Pediatric Chronic Myeloid Leukemia: Data Derived from a Large Cohort of Children and Teenagers and a Narrative Review on Priapism Management - Suttorp, Meinolf; Sembill, Stephanie; Kalwak, Krzysztof; Metzler, Markus; Millot, Frederic (Journal of Clinical Medicine, 2023)
Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However, clinical signs of leukostasis are observed at diagnosis in only approximately 10% of all cases and among these, priapism is infrequent. Here, we analyze data from pediatric CML registries on the occurrence of priapism heralding diagnosis of CML in 16/491 (3.2%) boys (median age 13.5 years, range 4–18) with pediatric CML. In the cohort investigated, duration of priapism resulting in a diagnosis of CML was not reported in 5 patients, and in the remaining 11 patients, occurred as stuttering priapism over 3 months (n = 1), over 6 weeks (n = 1), over 1–2 weeks (n = 2), over several days (n = 2), or 24 h (n = 1), while the remaining 4 boys reported continuous erection lasting over 11–12 h. All patients exhibited splenomegaly and massive leukocytosis (median WBC 470,000/µL, range 236,700–899,000). Interventions to treat priapism were unknown in 5 patients, and in the remaining cohort, comprised intravenous fluids ± heparin (n = 2), penile puncture (n = 5) ± injection of sympathomimetics (n = 4) ± intracavernous shunt operation (n = 1) paralleled by leukocyte-reductive measures. Management without penile puncture by leukapheresis or exchange transfusion was performed in 3 boys. In total, 7 out 15 (47%) long-term survivors (median age 20 years, range 19–25) responded to a questionnaire. All had maintained full erectile function; however, 5/7 had presented with stuttering priapism while in the remaining 2 patients priapism had lasted <12 h until intervention. At its extreme, low-flow priapism lasting for longer than 24 h may result in partial or total impotence by erectile dysfunction. This physical disability can exert a large psychological impact on patients’ lives. In a narrative review fashion, we analyzed the literature on priapism in boys with CML which is by categorization stuttering or persisting as mostly painful, ischemic (low-flow) priapism. Details on the pathophysiology are discussed on the background of the different blood rheology of hyperleukocytosis in acute and chronic leukemias. In addition to the data collected, instructive case vignettes demonstrate the diagnostic and treatment approaches and the outcome of boys presenting with priapism. An algorithm for management of priapism in a stepwise fashion is presented. All approaches must be performed in parallel with cytoreductive treatment of leukostasis in CML which comprises leukapheresis and exchange transfusions ± cytotoxic chemotherapy.
CRIS-Team Scopus Importer:2023-08-11
Keywords: chronic myeloid leukemia; exchange transfusion; hyperleukocytosis; leukapheresis; leukostasis; pediatric CML; pediatric CML registry; penile puncture; priapism

Primary Periphyseal Stress Injuries of the Fingers in Adolescent Climbers: A Critical Review - Jones, Gareth; Johnson, Rowena; Schöffl, Volker Rainer; Schöffl, Isabelle; Lutter, Chris; Johnson, Mark; Halsey, Tim (Current Sports Medicine Reports, 2022)
The worldwide rise in popularity of climbing and development of climbing as a competitive sport is reflected by its debut at the 2021 Summer Olympic Games in Tokyo. Digital primary periphyseal stress injuries in adolescent climbers may pose a significant risk to long-term skeletal health. The aim of this article is to critically review research on the diagnosis and management of primary periphyseal stress injuries of the fingers in adolescent climbers. We adopted a systematic approach to searching for relevant literature. Articles were identified after searches of the following electronic databases: Discover, Academic Search Complete, PubMed, Embase, SPORTDiscus, and ScienceDirect. Conclusive evidence suggests digital primary periphyseal stress injuries are a consequence of repetitive microtrauma. Pain reported by adolescent climbers on the dorsal aspect of the proximal interphalangeal joint should be investigated promptly to avoid serious negative consequences. Clinicians should be aware of the efficacy of imaging techniques to inform a clinical diagnosis. A conservative management approach is preferred but in rare cases surgical intervention may be necessary. A diagnostic and therapeutic algorithm for digital primary periphyseal stress injuries is presented.
CRIS-Team WoS Importer:2023-01-13

Problems of drug therapy in pediatrics - Wimmer, Stefan; Rascher, Wolfgang (Kinderkrankenschwester, 2016)
EVALuna2:33998

Prognostic value of cta-derived left ventricular mass in neonates with congenital heart disease - Ellmann, Stephan; Nickel, Julie-Marie; Heiß, Rafael; El Amrani, Nouhayla; Wüst, Wolfgang; Rompel, Oliver; Rueffer, Andre; Cesnjevar, Robert; Dittrich, Sven; Uder, Michael; May, Matthias (Diagnostics, 2021)
For therapeutic decisions regarding uni-or biventricular surgical repair in congenital heart disease (CHD), left ventricular mass (LVM) is an important factor. The aim of this retrospective study was to determine the LVM of infants with CHD in thoracic computed tomography angiographies (CTAs) and to evaluate its usefulness as a prognostic parameter, with special attention paid to hypoplastic left heart (HLH) patients. Manual segmentation of the left ventricular endo-and epicardial volumes was performed in CTAs of 132 infants. LVMs were determined from these volumes and normalized to body surface area. LVMs of patients with different types of CHD were compared to each other using analyses of variances (ANOVA). An LVM cutoff for discrimination between uni-and biventricular repair was determined using receiver operating characteristics. Survival rates were calculated using Kaplan–Meier statistics. Patients with a clinical diagnosis of an HLH had significantly lower mean LVM (21.88 g/m2) compared to patients without applicable disease (50.22 g/m2; p < 0.0001) and compared to other CHDs, including persistent truncus arteriosus, left ventricular outflow tract obstruction, transposition of the great arteries, pulmonary artery stenosis or atresia, and double-outlet right ventricle (all, p < 0.05). The LVM cutoff for uni-vs. biventricular surgery was 33.9 g/m2 (sensitivity: 82.3%; specificity: 73.7%; PPV: 94.9%). In a subanalysis of HLH patients, a sensitivity of 50.0%, specificity of 100%, PPV of 100%, and NPV of 83.3% was determined. Patient survival was not significantly different between the surgical approaches or between patients with LVM above or below the cutoff. LVM can be measured in chest CTA of newborns with CHD and can be used as a prognostic factor.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Cardiac computed tomography; Computed tomography angiography; Congenital heart disease; Heart imaging; Heart surgery; Hypoplastic left heart

Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API) - Speckmann, Carsten; Nennstiel, Uta; Hoenig, Manfred; Albert, Michael H.; Ghosh, Sujal; Schuetz, Catharina; Brockow, Inken; Hoerster, Friederike; Niehues, Tim; Ehl, Stephan; Wahn, Volker; Borte, Stephan; et al. (Journal of Clinical Immunology, 2023)
Background: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. Methods: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. Results: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. Conclusion: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.
CRIS-Team Scopus Importer:2023-05-19
Keywords: Hematopoietic stem cell transplantation; HSCT; NBS; Newborn screening; SCID; Severe combined immunodeficiency; T cell receptor excision circles; Thymus transplantation; TREC

Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study - Inglis, S. K.; Carucci, S.; Garas, P.; Haege, A.; Banaschewski, T.; Buitelaar, J. K.; Dittmann, R. W.; Falissard, B.; Hollis, Chris; Kovshoff, Hanna; Liddle, Elizabeth; Mccarthy, S.; et al. (BMJ Open, 2016)
INTRODUCTION: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. METHODS AND ANALYSIS: 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. TRIAL REGISTRATION NUMBER: NCT01470261.
EVALuna2:34017

Prospective, randomized, double-blind, placebo-controlled phase IIa clinical trial on the effects of an estrogen-progestin combination as add-on to inpatient psychotherapy in adult female patients suffering from anorexia nervosa - Paslakis, Georgios; Maas, Stefanie; Gebhardt, Bernd; Mayr, Andreas; Rauh, Manfred; Erim, Yesim (BMC Psychiatry, 2018)

Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia - Schneider, Holm; Hadj-Rabia, Smail; Faschingbauer, Florian; Bodemer, Christine; Grange, Dorothy K.; Norton, Mary E.; Cavalli, Riccardo; Tadini, Gianluca; Stepan, Holger; Clarke, Angus; Guillén-Navarro, Encarna; Maier-Wohlfart, Sigrun; et al. (Genes, 2023)
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.
CRIS-Team Scopus Importer:2023-02-24
Keywords: anhidrosis; clinical trial; ectodermal dysplasia; ectodysplasin A; fetal therapy; protein replacement; sweat glands

PTEN hamartoma tumor syndrome in childhood and adolescence-a comprehensive review and presentation of the German pediatric guideline. - Plamper, Michaela; Gohlke, Bettina; Wölfle, Joachim (Molecular and Cellular Pediatrics, 2022)
BACKGROUND: The PTEN hamartoma tumor syndrome (PHTS) encompasses several different syndromes, which are linked to an autosomal-dominant mutation of the tumor suppressor PTEN gene on chromosome 10. Loss of PTEN activity leads to an increased phosphorylation of different cell proteins, which may have an influence on growth, migration, and apoptosis. Excessive activity of the PI3K/AKT/mTOR pathway due to PTEN deficiency may lead to the development of benign and malignant tumors and overgrowth. Diagnosis of PHTS in childhood can be even more challenging than in adulthood because of a lack of well-defined diagnostic criteria. So far, there are no official recommendations for cancer surveillance in affected children and adolescents. MAIN BODY: All individuals with PHTS are at high risk for tumor development and thus might benefit from cancer surveillance strategies. In childhood, macrocephaly may be the only evident symptom, but developmental delay, behavioral problems, dermatological features (e.g., penile freckling), vascular anomalies, lipoma, or enlarged perivascular spaces in cerebral magnetic resonance imaging (cMRI) may help to establish the diagnosis. Regular psychomotor assessment and assistance in subjects with neurological impairment play an important role in the management of affected children. Already in early childhood, affected patients bear a high risk to develop thyroid pathologies. For that reason, monitoring of thyroid morphology and function should be established right after diagnosis. We present a detailed description of affected organ systems, tools for initiation of molecular diagnostic and screening recommendations for patients < 18 years of age. CONCLUSION: Affected families frequently experience a long way until the correct diagnosis for their child's peculiarity is made. Even after diagnosis, it is not easy to find a physician who is familiar with this rare group of diseases. Because of a still-limited database, it is not easy to establish evidence-based (cancer) surveillance recommendations. The presented screening recommendation should thus be revised regularly according to the current state of knowledge.
EVALuna2:519679

Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex® Growth Forum Database Registry - Bang, Peter; Polak, Michel; Perrot, Valérie; Sert, Caroline; Shaikh, Haris; Wölfle, Joachim (Frontiers in Endocrinology, 2022)
Background: Puberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex® Growth Forum Database (Eu-IGFD) Registry (NCT00903110). Methods: The Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. Results: This analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3–13.0) cm/year in boys and 6.8 (1.3–9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. Conclusion: Children and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Eu-IGFD Registry; growth retardation; mecasermin; puberty; severe primary insulin-like growth factor-1 deficiency

Pulmonary Dysfunction after Pediatric COVID-19 - Heiß, Rafael; Tan, Lina; Schmidt, Sandy; Regensburger, Adrian; Ewert, Franziska; Mammadova, Dilbar; Bühler, Adrian; Vogel-Claussen, Jens; Voskrebenzev, Andreas; Rauh, Manfred; Rompel, Oliver; Nagel, Armin Michael; et al. (Radiology, 2022)
Background Long COVID occurs in lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field MRI may identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma on low-field MRI in children and adolescents with post COVID-19 compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional, prospective clinical trial using low-field MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes on MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive RT-PCR test and serological parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants and with long COVID. Results A total of 54 participants post COVID-19 infection (mean age, 11 years ±3 [SD], 56 males) and 9 healthy controls (mean age, 10 years ±3 [SD], 70 males) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (V/Q match) was reduced from 81±6.1% in healthy controls to 62±19% (P =.006) in the recovered group and 60±20% (P=.003) in the long COVID group. V/Q match was lower in post COVID patients with infection less than 180 days (63±20%, P=.03), 180 to 360 days (63±18%, P=0.03) and 360 days ago (41±12%, P<.001) as compared with the never-infected healthy controls (81±6.1%). Conclusion Low-field MRI showed persistent pulmonary dysfunction in both children and adolescents recovered from COVID-19 and with long COVI

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry - Kaemmerer, Harald; Gorenflo, Matthias; Huscher, Dorte; Pittrow, David; Apitz, Christian; Baumgartner, Helmut; Berger, Felix; Bruch, Leonhard; Brunnemer, Eva; Budts, Werner; Claussen, Martin; Coghlan, Gerry; et al. (Journal of Clinical Medicine, 2020)
Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients' median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naive. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.
CRIS-Team WoS Importer:2020-06-26

Pulmonary valve prostheses: patient's lifetime procedure load and durability. Evaluation of the German National Register for Congenital Heart Defects - Boethig, Dietmar; Avsar, Murat; Bauer, Ulrike M. M.; Sarikouch, Samir; Beerbaum, Philipp; Berger, Felix; Cesnjevar, Robert; Daehnert, Ingo; Dittrich, Sven; Ewert, Peter; Haverich, Axel; Hoerer, Juergen; et al. (Interactive Cardiovascular and Thoracic Surgery, 2022)
OBJECTIVES: We evaluated 4384 procedures performed between 1957 and 2018, collected in the National Register for Congenital Heart Defects, conducted on 997 patients with 1823 pulmonary valve replacements (PVRs), including 226 implanted via catheter [transcatheter valve (TCV)]. Main study targets are as follows: TCV benefit, valve type durability, decade-wise treatment changes and procedure frequencies over the lifetime of a PVR patient. METHODS: We studied TCV impact on surgical valve replacement (via Kaplan-Meier); pulmonary valve type-specific performance (Kaplan-Meier and Cox regressions with age group as stratification or ordinary variable); procedure interval changes over the decades (Kaplan-Meier); procedure load, i.e. frequency of any procedure/surgical PVR/interventional or surgical PVR by patient age (multistate analyses). RESULTS: TCV performance was equivalent to surgical PVRs and extended durability significantly. Homografts were most durable; Contegras lasted comparably less in older; and Hancock devices lasted less in younger patients. Matrix P-valves showed poorer performance. Age group stratification improves the precision of valve-specific explantation hazard estimations. The current median interval between procedures is 2.6 years; it became significantly shorter in most age groups below 40 years. At 30 years, 80% of patients had undergone ≥3 procedures, 20% ≥3 surgical PVRs and 42% ≥3 surgical or interventional PVRs. CONCLUSIONS: TCVs doubled freedom from explantation of conventional valves. Homografts' age group-specific explantation hazard ratio was lowest; Matrix P's hazard ratio was highest. Age-stratified Cox regressions improve the precision of prosthesis durability evaluations. The median time between procedures for PVR patients shortened significantly to 2.6 years. At 30 years, 42% had ≥3 PVRs.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Congenital heart disease; Long-term follow-up; Procedure load; Pulmonary valve prosthesis; Transcatheter pulmonary valve replacement

Pupillometry in the follow-up of patients undergoing EVT - prediction of space-occupying hemispheric infarction - Kossel, Clara-Sophie; Kobus, Franca; Borutta, Matthias; Kärtner, Maximilian; Kuramatsu, Joji; Engelhorn, Tobias; Schwab, Stefan; Köhn, Julia (Journal of Neurology, 2023)
Background: Despite benefits of endovascular treatment (EVT) for large vessel occlusion (LVO) ischemic stroke, space-occupying brain edema (BE) represents a detrimental complication. In critical-care settings, CT-imaging is needed for monitoring these patients. Yet, bed-side techniques with the potential to predict whether patients develop BE or not would facilitate a time- and cost-efficient patient care. We assessed clinical significance of automated pupillometry in the follow-up of patients undergoing EVT. Methods: From 10/2018 to 10/2021, neurocritical-care-unit patients were retrospectively enrolled after EVT of anterior circulation LVO. We monitored parameters of pupillary reactivity [light-reflex-latency (Lat), constriction- and redilation-velocities (CV, DV), percentage-change-of-apertures (per-change); NeurOptics-pupilometer®] up to every hour on day 1–3 of ICU stay. BE was defined as midline shift ≥ 5 mm on follow-up imaging 3–5 days after EVT. We calculated mean values of intra-individual differences between successive pairs of parameters (mean-deltas), determined best discriminative cut-off values for BE development (ROC-analyses), and evaluated prognostic performance of pupillometry for BE development (sensitivity/specificity/positive-/negative-predictive-values). Results: 3241 pupillary assessments of 122 patients [67 women, 73 years (61.0–85.0)] were included. 13/122 patients developed BE. Patients with BE had significantly lower CVs, DVs, and smaller per-changes than patients without BE. On day 1 after EVT mean-deltas of CV, DV, and per-changes were significantly lower in patients with than without BE. Positive-predictive-values of calculated thresholds to discriminate both groups were considerably low, yet, we found high negative-predictive-values for CV, DV, per-changes, and mean-deltas (max.: 98.4%). Conclusion: Our data suggest associations between noninvasively detected changes in pupillary reactivity and BE early after LVO-EVT. Pupillometry may identify patients who are unlikely to develop BE and may not need repetitive follow-up-imaging or rescue-therapy.
CRIS-Team Scopus Importer:2023-06-30
Keywords: Automated pupillometry; Endovascular treatment; Ischemic stroke; Large vessel occlusion; Pupillary reactivity

Qualitätssicherungsrichtlinie Früh- und Reifgeborene des Gemeinsamen Bundesausschusses als Qualitätsrisiko? Analyse zu Erfüllungsgrad und Konsequenzen in der Versorgung weiterer intensivpflichtiger Patienten sowie drohender Frühgeburten am Beispiel eines regionalen Verbund-Perinatalzentrums - Kleeberg, Markus; Beckmann, Matthias; Fusch, Christoph; Hanf, Volker; Kainer, Franz; Klinge, Jens; Koehler, Wolfgang; Morhart, Patrick; Schroth, Michael Andreas (Zeitschrift für Geburtshilfe und Neonatologie, 2020)
Background The quality guideline for care delivery to preterm and mature infants (QFR-RL) places high demands on perinatal centers. In this analysis, the degree of fulfillment was determined. Additionally, care delivery to further patient groups and sufficient nursing staff capacity for caredelivery to imminent preterm infants (FG) were evaluated. Methods A network of 4 perinatal centers (level 1) with about 10,000 births per year supplied the data on the ratio of 1:1/1:2-care infants,patients per nurse, and nursing staff capacity. This data was statistically evaluated by center, shift, and week day over a period of 5 months for compliance with QFR-RL and DGPM recommendations. Furthermore, imminent preterm infants were recorded and compared with available nursing staff capacity. Results In total, the QFR-RL was fulfilled in 88% of shifts (n=1,584). Only one center reached the required 95. The degree of fulfillment and the number of staff nurses declined from late to night shifts (p<0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p<0.001). Only 14.1 of imminent preterm infants could have been attended in accordance with the QFR-RL. Conclusion 1:1 care as well as lower nurse staffing in late and night shifts lead to non-fulfillment of requirements and poorer care delivery to other intensive care patients. This was also reflected in the lower degree of fulfillment of DGPM recommendations. Sufficient nursing staff capacity was rare with the consequence that it was almost impossible to deliver care to imminent preterm infants per the guideline.
CRIS-Team Scopus Importer:2020-11-06
Keywords: 1:1-Care; preterm infants care; quality guideline of care delivery of preterm and mature infants; quality of care; staffing ratio

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project - Hanning, Sara M.; Gul, Mine Orlu; Winslade, Jackie; Baarslag, Manuel A.; Neubert, Antje; Tuleu, Catherine (International Journal of Pharmaceutics, 2016)
A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project.
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Quality of life of short-statured children born small for gestational age or idiopathic growth hormone deficiency within one year of growth hormone treatment - Quitmann, Julia; Bloemeke, Janika; Silva, Neuza; Bullinger, Monika; Witt, Stefanie; Akkurt, Ilker; Dunstheimer, Desirée; Vogel, Christian; Böttcher, Volker; Krahl, Ursula Kuhnle; Bettendorf, Markus; Schönau, Eckhard; et al. (Frontiers in Pediatrics, 2019)
Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency (n = 65), born small for gestational age (n = 58) and idiopathic short stature (n = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Growth hormone treatment; Health-related quality of life; IGHD; ISS; QoLISSY; Short stature

Quality of life of young adults after a growth hormone therapy with childhood onset - Quitmann, J. H.; Rohenkohl, A. C.; Kammerer, U.; Schöfl, Christof; Bullinger, M.; Dörr, Helmuth-Günther (Deutsche Medizinische Wochenschrift, 2014)
Little is known about the health-related quality of life of young adults with childhood onset idiopathic growth hormone deficiency or neurosecretory dysfunction of growth hormone secretion, who have been treated with recombinant human growth hormone (GH).Patients were diagnosed and treated with human growth hormone at the University Children´s Hospital in Erlangen (n=85). The data of both groups were merged for analysis, because no difference between idiopathic growth hormone deficiency and neurosecretory dysfunction of growth hormone secretion in auxological. Data were found. Health-related quality of life was cross- sectionally assessed after the end of growth hormone therapy with the Short Form-36 Health Survey and the Nottingham Health Profiles for which population based norm data are available.At the time of the survey, the patients (53 m, 32 f) were 23.5 ± 4.6 years old. At start of GH therapy, age was 10.5 ± 2.8 and at the end 16.3 ± 1,4 years. At start, height SDS was -3.20 ± 1.06. GH dose was 0,026 ± 0,012 mg/kg/d (daily s. c.-injections). The increase in height SDS after the end of GH therapy was 1.69 ± 1.22. Compared to the reference population, patients reported significantly lower scores on the scales energy level, vitality, social functioning, indicating a greater social isolation, a stronger emotional reaction, an increased loss of mobility and a worse psychological state.Young adults report specific impairments after completion of GH therapy.
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Quality of Pediatric Palliative Care Crisis Intervention - A Retrospective Survey - Berkmueller, Magdalena; Gravou-Apostolatou, Chara; Rascher, Wolfgang (Klinische Pädiatrie, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-10-01

Quality of Survival and Growth in Children and Young Adults in the PNET4 European Controlled Trial of Hyperfractionated Versus Conventional Radiation Therapy for Standard-Risk Medulloblastoma - Kennedy, Colin; Bull, Kim; Chevignard, Mathilde; Culliford, David; Dörr, Helmuth-Günther; Doz, Francois; Kortmann, Rolf-Dieter; Lannering, Birgitta; Massimino, Maura; Navajas Gutierrez, Aurora; Rutkowski, Stefan; Spoudeas, Helen A.; et al. (International Journal of Radiation Oncology Biology Physics, 2014)
To compare quality of survival in "standard-risk" medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial.Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded.Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011).Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.
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Quantification of translocation-specific ctDNA provides an integrating parameter for early assessment of treatment response and risk stratification in ewing sarcoma - Krumbholz, Manuela; Eiblwieser, Johanna; Ranft, Andreas; Zierk, Jakob; Schmidkonz, Christian; Stuetz, Adrian M.; Peneder, Peter; Tomazou, Eleni M.; Agaimy, Abbas; Bäuerle, Tobias; Hartmann, Wolfgang; Dirksen, Uta; et al. (Clinical Cancer Research, 2021)
Purpose: We evaluated the predictive and prognostic value of circulating tumor DNA (ctDNA) in patients with Ewing sarcoma (EWS) treated in the EWING2008 trial. Experimental Design: Plasma samples from 102 patients with EWS enrolled in the EWING2008 trial were obtained before and during induction chemotherapy. Genomic EWSR1 fusion sequence spanning primers and probes were used for highly specific and sensitive quantification of the levels of ctDNA by digital droplet PCR. ctDNA levels were correlated to established clinical risk factors and outcome parameters. Results: Pretreatment ctDNA copy numbers were correlated with event-free and overall survival. The reduction in ctDNA levels below the detection limit was observed in most cases after only two blocks of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy. The persistence of ctDNA after two VIDE blocks was a strong predictor of poor outcomes. ctDNA levels correlated well with most established clinical risk factors; an inverse correlation was found only for the histologic response to induction therapy. ctDNA levels did not provide simple representations of tumor volume, but integrated information from various tumor characteristics represented an independent EWS tumor marker with predictive and prognostic value. Conclusions: ctDNA copy number in the plasma of patients with EWS is a quantifiable parameter for early risk stratification and can be used as a dynamic noninvasive biomarker for early prediction of treatment response and outcome of patients.
CRIS-Team Scopus Importer:2021-11-26

Radiotherapy for prostate cancer: DISCERN quality assessment of patient-oriented websites in 2018 - Janssen, S.; Fahlbusch, F. B.; Kaesmann, L.; Rades, D.; Vordermark, D. (BMC Urology, 2019)
Background: Prostate cancer is the most commonly diagnosed cancer in men. Radiotherapy represents one major treatment option in different therapeutic settings. As patients increasingly rely on internet-based medical information, we examined the quality of information on radiotherapy and prostate cancer in websites used by laypersons. Methods: An Internet search from a patients' perspective was carried out using different search engines (Google, Yahoo and Bing, search terms: "prostate cancer" and "radiotherapy"). The quality of search results was analyzed with regard to the DISCERN score, HON code certification, the JAMA criteria and the ALEXA traffic rank. Results: In general, websites were of good quality. The highest quality was found for websites operated by charity organizations. No significant differences in results obtained via the above-mentioned tools were seen for the examined search engines, but Google revealed the most stable search results in terms of temporal changes. Conclusion: Patients with prostate cancer can sufficiently inform themselves on general treatment options including radiotherapy on websites directed at laypersons. However, no simple strategy could identify high quality websites in general. For treating physicians, it is important to support patients in interpreting and ranking the vast quantity of information.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Health-related information; Internet; Online information; Prostate cancer; Radiotherapy

Rare intronic mutation between Exon 62 and 63 (c.9225–285A>G) of the dystrophin gene associated with atypical BMD phenotype - Schüssler, S. C.; Gerhalter, T.; Abicht, A.; Müller-Felber, W.; Nagel, Armin Michael; Trollmann, Regina (Neuromuscular Disorders, 2020)
Dystrophinopathies are predominantly caused by deletions, duplications and point mutations in the coding regions of the dystrophin gene with less than 1% of all pathogenic mutations identified within intronic sequences. We describe a 17-year-old male with a Becker muscular dystrophy diagnosis and mental disability due to an intron mutation that led to aberrant splicing and formation of an additional exon. Histopathological analysis of muscle tissue revealed signs of muscular dystrophy and reduced signal for dystrophin, alpha-sarcoglycan, and alpha-dystroglycan. Multiplex ligation-dependent probe amplification screening and total sequencing of the dystrophin gene did not identify a mutation in the coding regions. However, next generation sequencing revealed an intron mutation between exons 62 and 63 of the dystrophin gene known for pseudoexon formation and disruption of the reading frame. We report a functional consequence of this mutation as an increased intracellular-weighted sodium signal (assessed by 23Na-magnetic resonance imaging) in leg muscles.
CRIS-Team Scopus Importer:2020-08-28
Keywords: 23Na-MRI; Aberrant splicing; Becker muscular dystrophy; Dystrophin; Intracellular-weighted sodium signal; Next generation sequencing

Rare malignant pediatric tumors registered in the German Childhood Cancer Registry 2001-2010 - Brecht, Ines B.; Bremensdorfer, Claudia; Schneider, Dominik T.; Fruehwald, Michael C.; Offenmüller, Sonja; Mertens, Rolf; Vorwerk, Peter; Koscielniak, Ewa; Bielack, Stefan S.; Benesch, Martin; Hero, Barbara; Graf, Norbert; et al. (Pediatric Blood & Cancer, 2014)
The German Childhood Cancer Registry (GCCR) annually registers approximately 2,000 children diagnosed with a malignant disease (completeness of registration >95%). While most pediatric cancer patients are diagnosed and treated according to standardized cooperative protocols of the German Society for Pediatric Oncology and Hematology (GPOH), patients with rare tumors are at risk of not being integrated in the network including trials and reference centers.A retrospective analysis of all rare extracranial solid tumors reported to the GCCR 2001-2010 (age <18 years) was undertaken using a combination of the International Classification of Childhood Cancer (ICCC-3) and the International Classification of Diseases-Oncology (ICD-O-3). Tumors accounting for <0.3% of all malignancies were defined as rare (approx. 6 cases/year and registered malignancy).According to this definition 1,189 rare extracranial solid tumors (18.2% of all malignant extracranial solid tumors) were registered, among these 232 patients (19.5% of rare tumor cases), were not included in preexisting GPOH studies/registries. Within 10 years, the number of registered non-GPOH-trial patients with a rare tumor increased.Though most of the GCCR-registered patients with rare malignant tumors are treated within GPOH trials, there is a considerable number of patients that have been diagnosed and treated outside the structures of the GPOH. These patients should be reported to the recently founded German Pediatric Rare Tumor Registry (STEP). Active data accrual and the development of appropriate structures will allow for better registration and improvement of medical care in these patients.
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Rare pediatric tumors in Germany – not as rare as expected: a study based on data from the Bavarian Cancer Registry and the German Childhood Cancer Registry - Achajew, Aisana; Brecht, Ines B.; Radespiel-Troeger, Martin; Meyer, Martin; Metzler, Markus; Bremensdorfer, Claudia; Spix, Claudia; Erdmann, Friederike; Schneider, Dominik T.; Abele, Michael (European Journal of Pediatrics, 2022)
Very rare pediatric tumors (VRTs) pose a challenge for treating physicians as little is known about the best diagnostic assessment and therapeutic decision-making in these malignancies. A large proportion of these cancers occur in adolescence. Therefore, the established structures of pediatric oncology including cancer registration may partly be circumvented. This may lead to an underregistration in clinical cancer registries of yet unclear extent. The aim of this study is to increase the knowledge on the occurrence of VRTs in pediatric patients in Germany. Pseudonymized data of cases recorded in the Bavarian Cancer Registry (BCR) between 2002 and 2014 were retrieved. VRTs according to the definition of the European Cooperative Study Group for Pediatric Rare Tumors were identified using the ICD and ICD-O classification. The numbers of registered patients were compared to those reported to the German Childhood Cancer Registry (GCCR). 6.3% (n = 290) of all malignancies (n = 4615) in the age below 18 years were classified as VRTs. Median age at diagnosis was 15 years (range 0–17 years). The most common tumor types included malignant melanoma, skin carcinoma, and gonadal tumors. During the same period, 49 pediatric patients from Bavaria with matchable VRTs were reported to the GCCR, accounting for 17% of cases reported to the BCR. Conclusions: The frequency of VRTs in Germany is underestimated in the national GCCR. With this study, we present population-based data on the incidence of VRTs in Germany for the first time. In order to gain additional knowledge about these malignancies, registration of VRTs must be improved through enhanced data exchange between the GCCR, the public cancer registries, and the clinical Registry for Rare Pediatric Tumors (STEP).What is Known:• Rare pediatric tumors pose a challenge for treating physicians as limited knowledge is available on these malignancies for diagnostic and therapeutic decision-making.• Little is known about the frequency of these rare tumors in pediatric patients.What is New:• The frequency of rare pediatric tumors in Germany is distinctly underestimated in the German Childhood Cancer Registry.• We present population-based data on the incidence of these rare pediatric cancers for the first time.
CRIS-Team Scopus Importer:2022-06-17
Keywords: Bavaria; Cancer registry; Germany; Incidence; Pediatric cancers; Rare tumors

Rare Subsequent Primary Cancers in Pediatric Cancer Survivors - Mertens, Ann C.; Langer, Thorsten (Rare Tumors in Children and Adolescents, 2022)
Advances in cancer therapy during the past four decades have resulted in remarkable increases in survival for most cancers of childhood and adolescence. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program show that the overall 5-year survival rate for childhood cancer has increased from 45% in 1970 to over 80% in 2005 (Ries et al., Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER Program. NIH Publication No. 99-4649, National Cancer Institute, Bethesda, 1999). It is estimated that 1 in every 640 young adults is now a survivor of childhood cancer and that at least 328,000 persons in the USA alone have survived cancer diagnosed before the age of 20 years (Mariotto and Rowland, Cancer Epidemiol Biomarkers Prev 18:1033–1040, 2009). Because of the relatively young age of these survivors, and their potential longevity, the delayed consequences of therapy may have a significant impact on their lives, and on society at large, over an extended period of time.
CRIS-Team Scopus Importer:2022-06-17
Keywords: Cancer survivor; Childhood cancer; Childhood cancer survivor; Standardize incidence ratio; Thyroid cancer

Rare Tumors in Children and Adolescents - the STEP Working Group & apos;s Evolution to a Prospective Registry - Hippert, Felicitas; Desing, Lena; Diez, Sonja; Witowski, Andrea; Bernbeck, Benedikt; Abele, Michael; Seitz, Christian; Erdmann, Friederike; Brecht, Ines; Schneider, Dominik T. (Klinische Pädiatrie, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-12-03

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency - Brackmann, Florian; Kehrer, Christiane; Kustermann, Wibke; Boehringer, Judith; Kraegeloh-Mann, Ingeborg; Trollmann, Regina (Neuropediatrics, 2017)
GM2 gangliosidosis, AB variant, is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein. We report on two patients with typical clinical features suggestive of GM2 gangliosidosis, but normal results for hexosaminidase A and hexosaminidase B as well as their corresponding genes. Genetic analysis of the gene encoding the activator protein, the GM2A gene, elucidated the cause of the disease, adding a novel mutation to the spectrum of GM2 AB variant. This report points out that in typical clinical constellations with normal enzyme results, genetic diagnostic for activator protein defects should be performed.
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Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot - Škorić-Milosavljević, Doris; Lahrouchi, Najim; Bosada, Fernanda M.; Dombrowsky, Gregor; Williams, Simon G.; Lesurf, Robert; Tjong, Fleur V.Y.; Walsh, Roddy; El Bouchikhi, Ihssane; Breckpot, Jeroen; Audain, Enrique; Ilgun, Aho; et al. (Genetics in Medicine, 2021)
Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). Conclusion: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.
CRIS-Team Scopus Importer:2021-06-25

Raster-Scanning Optoacoustic Mesoscopy for Gastrointestinal Imaging at High Resolution - Knieling, Ferdinand; Menezes, Jean Gonzales; Claussen, Jing; Schwarz, Mathias; Neufert, Clemens; Fahlbusch, Fabian B.; Rath, Timo; Thoma, Oana-Maria; Kramer, Viktoria; Menchicchi, Bianca; Kersten, Christina; Scheibe, Kristina; et al. (Gastroenterology, 2018)
EVALuna2:33792

Ratio of Urinary Proteins to Albumin Excretion Shifts Substantially during Progression of the Podocytopathy Alport Syndrome, and Spot Urine Is a Reliable Method to Detect These Pathologic Changes - Boeckhaus, Jan; Mohr, Lea; Dihazi, Hassan; Tönshoff, Burkhard; Weber, Lutz T.; Pape, Lars; Latta, Kay; Fehrenbach, Henry; Lange-Sperandio, Baerbel; Kettwig, Matthias; Staude, Hagen; König, Sabine; et al. (Cells, 2023)
The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30–300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75–187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7; p < 0.05); it was “only” about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5; p < 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6; p = 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104).
CRIS-Team Scopus Importer:2023-05-26
Keywords: albuminuria; Alport syndrome; diagnostic marker; glomerulus; hereditary kidney diseases; mechanical stretch; podocytes; podocytopathies; proteinuria; renal fibrosis; type IV collagen

Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients - Cherneha, Maxim; Korth, Johannes; Kaulfuss, Meike; Trilling, Mirko; Widera, Marek; Rohn, Hana; Dolff, Sebastian; Babel, Nina; Hörning, André; Kribben, Andreas; Witzke, Oliver (Viruses, 2021)
Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4+ T lymphocytes (p = 0.0002) and CD19+ B lymphocytes (p = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R-) was associated with increased p70S6k phosphorylation in CD19+ B lymphocytes (p = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.
CRIS-Team Scopus Importer:2021-04-16
Keywords: BK polyoma virus; human cytomegalovirus; p70 ribosomal S6 kinase; PyVAN; renal transplantation

Real-world data in children with achondroplasia after licensing of Vosoritide - Palm, Katja; Bechthold-Dalla Pozza, Susanne; Gausche, Ruth; Hoegler, Wolfgang; Hoyer-Kuhn, Heike; Huebner, Angela; Keller, Alexandra; Mirante, Alice; Mohnike, Klaus; Muschol, Nicole; Nader, Sean; Pfaeffle, Roland; et al. (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors - Anderson, Nathaniel D.; De Borja, Richard; Young, Matthew D.; Fuligni, Fabio; Rosic, Andrej; Roberts, Nicola D.; Hajjar, Simon; Layeghifard, Mehdi; Novokmet, Ana; Kowalski, Paul E.; Anaka, Matthew; Davidson, Scott; et al. (Science, 2018)
Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
EVALuna2:35824

Recessive Mutations in CFAP74 Cause Primary Ciliary Dyskinesia with Normal Ciliary Ultrastructure - Biebach, Luisa; Cindrić, Sandra; Koenig, Julia; Aprea, Isabella; Dougherty, Gerard W.; Raidt, Johanna; Bracht, Diana; Ruppel, Renate; Schreiber, Jens; Hjeij, Rim; Olbrich, Heike; Omran, Heymut (American journal of respiratory cell and molecular biology, 2022)
CRIS-Team Scopus Importer:2022-09-16

Recombinant Human Growth Hormone Activates Neuroprotective Growth Factors in Hypoxic Brain Injury in Neonatal Mice - Jung, Susan; Terörde, Klara; Dörr, Helmuth-Günther; Trollmann, Regina (Endocrinology, 2021)
Perinatal hypoxia severely disrupts cerebral metabolic and maturational programs beyond apoptotic cell death. Antiapoptotic treatments such as erythropoietin are suggested to improve outcomes in hypoxic brain injury; however, the results are controversial. We analyzed the neuroprotective effects of recombinant human growth hormone (rhGH) on regenerative mechanisms in the hypoxic developing mouse brain in comparison to controls. Using an established model of neonatal acute hypoxia (8% O2, 6 hours), P7 mice were treated intraperitoneally with rhGH (4000 µg/kg) 0, 12, and 24 hours after hypoxic exposure. After a regeneration period of 48 hours, expression of hypoxia-inducible neurotrophic factors (erythropoietin [EPO], vascular endothelial growth factor A [VEGF-A], insulin-like growth factors 1 and 2 [IGF-1/-2], IGF binding proteins) and proinflammatory markers was analyzed. In vitro experiments were performed using primary mouse cortical neurons (E14, DIV6). rhGH increased neuronal gene expression of EPO, IGF-1, and VEGF (P < .05) in vitro and diminished apoptosis of hypoxic neurons in a dose-dependent manner. In the developing brain, rhGH treatment led to a notable reduction of apoptosis in the subventricular zone and hippocampus (P < .05), abolished hypoxia-induced downregulation of IGF-1/IGF-2 expression (P < .05), and led to a significant accumulation of endogenous EPO protein and anti-inflammatory effects through modulation of interleukin-1β and tumor necrosis factor α signaling as well as upregulation of cerebral phosphorylated extracellularly regulated kinase 1/2 levels (ERK1/2). Indicating stabilizing effects on the blood-brain barrier (BBB), rhGH significantly modified cerebrovascular occludin expression. Thus, we conclude that rhGH mediates neuroprotective effects by the activation of endogenous neurotrophic growth factors and BBB stabilization. In addition, the modification of ERK1/2 pathways is involved in neuroprotective actions of rhGH. The present study adds further evidence that pharmacologic activation of neurotrophic growth factors may be a promising target for neonatal neuroprotection.
CRIS-Team Scopus Importer:2021-03-05
Keywords: apoptosis; BBB; IGF binding proteins; IGF-1; IGF-2; interleukin-1β; neuroprotection; occludin; pERK 1/2; TNF-α; VEGF

Recommendations of the AGG (Working Group for Obstetrics, Department of Maternal Diseases) on How to Treat Thyroid Function Disorders in Pregnancy. - Hamza, Amr; Schlembach, Dietmar; Schild, Ralf Lothar; Groten, Tanja; Wölfle, Joachim; Battefeld, Wilgard; Kehl, Sven; Schneider, Michael (Geburtshilfe und Frauenheilkunde, 2023)
Objective These recommendations from the AGG (Committee for Obstetrics, Department of Maternal Diseases) on how to treat thyroid function disorder during pregnancy aim to improve the diagnosis and management of thyroid anomalies during pregnancy. Methods Based on the current literature, the task force members have developed the following recommendations and statements. These recommendations were adopted after a consensus by the members of the working group. Recommendations The following manuscript gives an insight into physiological and pathophysiological thyroid changes during pregnancy, recommendations for clinical and subclinical hypo- and hyperthyroidism, as well as fetal and neonatal diagnostic and management strategies.
EVALuna2:548561

Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas - Agaimy, Abbas; Bieg, Matthias; Michal, Michael; Geddert, Helene; Maerkl, Bruno; Seitz, Jan; Moskalev, Evgeny; Schlesner, Matthias; Metzler, Markus; Hartmann, Arndt; Wiemann, Stefan; Michal, Michal; et al. (American Journal of Surgical Pathology, 2017)
Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions.
EVALuna2:6839

Red blood cell omega-3 fatty acids and the risk of ventricular arrhythmias in patients with heart failure - Wilhelm, Matthias; Tobias, Rueth; Asskali, Fatima; Kraehner, Robert; Kuly, Simone; Klinghammer, Lutz; Böhles, Hans Josef; Daniel, Werner (American Heart Journal, 2008)

Redirecting T cells to ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection - Lehner, Manfred; Goetz, Gabriel; Proff, Julia; Schaft, Niels; Dörrie, Jan; Full, Florian; Enßer, Armin; Muller, Yves; Cerwenka, Adelheid; Abken, Hinrich; Parolini, Ornella; Ambros, Peter F.; et al. (PLoS ONE, 2012)
We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8 pos and also CD4 pos cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection. © 2012 Lehner et al.
CRIS-Team Scopus Importer:2021-10-01

Reduced Perinatal Leptin Availability May Contribute to Adverse Metabolic Programming in a Rat Model of Uteroplacental Insufficiency - Nuesken, Eva; Wohlfarth, Maria; Lippach, Gregor; Rauh, Manfred; Schneider, Holm; Doetsch, Joerg; Nuesken, Kai-Dietrich (Endocrinology, 2016)
Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.
EVALuna2:33880

Reduction of Tissue Na+ Accumulation After Renal Transplantation - Dahlmann, Anke; Linz, Peter; Zucker, Isabelle; Haag, Viktor; Jantsch, Jonathan; Dienemann, Thomas; Nagel, Armin Michael; Neubert, Patrick; Rosenhauer, Daniela; Rauh, Manfred; Horn, Stephan; Müller, Dominik N.; et al. (Kidney International Reports, 2021)
Introduction: Chronic kidney disease (CKD) engenders salt-sensitive hypertension. Whether or not tissue Nathorn accumulation is increased in CKD patients remains uncertain. How tissue Nathorn is affected after renal transplantation has not been assessed.
CRIS-Team WoS Importer:2021-10-01

Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic) - Zierk, Jakob; Arzideh, Farhad; Kapsner, Lorenz; Prokosch, Hans-Ulrich; Metzler, Markus; Rauh, Manfred (Scientific Reports, 2020)
Appropriate reference intervals are essential when using laboratory test results to guide medical decisions. Conventional approaches for the establishment of reference intervals rely on large samples from healthy and homogenous reference populations. However, this approach is associated with substantial financial and logistic challenges, subject to ethical restrictions in children, and limited in older individuals due to the high prevalence of chronic morbidities and medication. We implemented an indirect method for reference interval estimation, which uses mixed physiological and abnormal test results from clinical information systems, to overcome these restrictions. The algorithm minimizes the difference between an estimated parametrical distribution and a truncated part of the observed distribution, specifically, the Kolmogorov-Smirnov-distance between a hypothetical Gaussian distribution and the observed distribution of test results after Box-Cox-transformation. Simulations of common laboratory tests with increasing proportions of abnormal test results show reliable reference interval estimations even in challenging simulation scenarios, when <20% test results are abnormal. Additionally, reference intervals generated using samples from a university hospital’s laboratory information system, with a gradually increasing proportion of abnormal test results remained stable, even if samples from units with a substantial prevalence of pathologies were included. A high-performance open-source C++ implementation is available at https://gitlab.miracum.org/kosmic.
CRIS-Team Scopus Importer:2020-02-14

Reference Intervals of Serum TSH from Mixed Distributions Using Truncation Points and the Kolmogorov-Smirnov Distance - Ahmed, Sibtain; Zierk, Jakob; Khan, Aysha H.; Jafri, Lena; Majid, Hafsa; Ghani, Farooq; Siddiqui, Imran (Clinical Laboratory, 2022)
Background: Serum TSH reference intervals (RIs) are methodology, population, and age specific. However, the ethical and practical challenges restrict the establishment of pediatric RIs using conventional approaches and advocates the use of indirect data mining-based algorithms. This study was carried out to estimate the reference interval of neonatal serum TSH in Pakistani population using an indirect approach. Methods: A data mining of serum TSH results of neonates (<= 1 month of age) from 2013 -2018 was done. Two sub-groups on the basis of age from birth to 5 days and 6 -30 days were assessed. The German study group's pre -vali-dated indirect algorithm 'KOSMIC' was utilized for the statistical analysis. Results: A total of non-duplicate 82,299 neonatal serum TSH tests were retrieved over a period of 6 years, includ-ing 88% (n = 70,788) aged 0 -5 days and 12% (n = 11,511) ranging from 6 days to 1 month. The estimated RIs for the first age partition was 0.7 (90% CI 0.6 -0.8) to 15.5 (90% CI 12.9 -16.2) and for the second group 0.7 (90% CI 0.5 -0.9) to 7.8 (90% CI 6.1 -9.9) mu IU/mL. Conclusions: This study revealed age related trends in serum TSH. The study advocates the need for population specific RIs owing to the significant variations noted on comparison with previously published literature. Precise RIs become vital particularly when serum TSH is undertaken as a confirmatory test for presumptive positive re-sults on newborn screening for congenital hypothyroidism. (Clin. Lab. 2022
CRIS-Team WoS Importer:2022-08-12

refineR: A Novel Algorithm for Reference Interval Estimation from Real-World Data - Ammer, Tatjana; Schuetzenmeister, Andre; Prokosch, Hans-Ulrich; Rauh, Manfred; Rank, Christopher M.; Zierk, Jakob (Scientific Reports, 2021)
Reference intervals are essential for the interpretation of laboratory test results in medicine. We propose a novel indirect approach to estimate reference intervals from real-world data as an alternative to direct methods, which require samples from healthy individuals. The presented refineR algorithm separates the non-pathological distribution from the pathological distribution of observed test results using an inverse approach and identifies the model that best explains the non-pathological distribution. To evaluate its performance, we simulated test results from six common laboratory analytes with a varying location and fraction of pathological test results. Estimated reference intervals were compared to the ground truth, an alternative indirect method (kosmic), and the direct method (N = 120 and N = 400 samples). Overall, refineR achieved the lowest mean percentage error of all methods (2.77%). Analyzing the amount of reference intervals within ± 1 total error deviation from the ground truth, refineR (82.5%) was inferior to the direct method with N = 400 samples (90.1%), but outperformed kosmic (70.8%) and the direct method with N = 120 (67.4%). Additionally, reference intervals estimated from pediatric data were comparable to published direct method studies. In conclusion, the refineR algorithm enables precise estimation of reference intervals from real-world data and represents a viable complement to the direct method.
CRIS-Team Scopus Importer:2021-08-27

Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma - Li, Nina; Mirzakhani, Hoomann; Kiefer, Alexander; Kölle, Julia; Vuorinen, Tytti; Rauh, Manfred; Yang, Zuqin; Krammer, Susanne; Xepapadaki, Paraskevi; Lewandowska-Polak, Anna; Lukkarinen, Heikki; Zhang, Nan; et al. (iScience, 2021)
RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.
CRIS-Team WoS Importer:2021-11-19