Integrin α8 Is Abundant in Human, Rat, and Mouse Trophoblasts - Herdl, Sebastian; Hübner, Hanna; Volkert, Gudrun; Marek, Ines; Menendez-Castro, Carlos; Nögel, Stephanie; Rübner, Matthias; Rascher, Wolfgang; Hartner, Andrea; Fahlbusch, Fabian B. (Reproductive Sciences, 2017)
OBJECTIVE: Integrins exert regulatory functions in placentogenesis. Null mutation of certain integrin α subunits leads to placental defects with subsequent fetal growth restriction or embryonic lethality in mice. So far, the placental role of α8 integrin remains to be determined. METHODS: Localization of α8 integrin and its ligands, fibronectin (FN) and osteopontin (OPN), was studied by immunohistochemistry in human, rat, and mouse placenta. The vascularization of the placental labyrinth layer of α8 integrin-deficient mice was determined by CD31 staining. In humans, α8 integrin expression was assessed via real-time polymerase chain reaction in healthy placentas, in the placental pathologies such as intrauterine growth restriction (IUGR), preeclampsia, and HELLP-syndrome (hemolysis, elevated liver enzymes, low platelet count), as well as in primary extravillous trophoblasts (EVT) and villous trophoblasts. RESULTS: In humans, α8 integrin was detected in first and third trimester syncytiotrophoblast and EVT. Although OPN showed the same localization, FN was observed in EVT only. No expressional changes in α8 integrin were detected in the placental pathologies studied. Rodent placenta showed α8 integrin expression in giant cells and in the labyrinth layer. The localization of OPN and FN, however, showed species-specific differences. Knockout of α8 integrin in mice did not cause IUGR, despite some reduction in labyrinth layer vascularization. CONCLUSION: α8 Integrin is expressed in functional placental compartments among its ligands, OPN and/or FN, across species. Although this may point to a regulatory role in trophoblast function, our data from α8 integrin-deficient mice indicated only mild placental pathology. Thus, the lack of placental α8 integrin seems to be largely compensated for.
EVALuna2:34006

Interaction of the mechano-electrical feedback with passive mechanical models on a 3D rat left ventricle: a computational study - Duong, Minh Tuan; Holz, David; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (Frontiers in Physiology, 2019)
In this paper, we are investigating the interaction between different passive material models and the mechano-electrical feedback (MEF) in cardiac modelling. Various types of passive mechanical laws (nearly incompressible/compressible, polynomial/exponential-type, transversally isotropic/orthotropic material models) are integrated in a fully coupled electromechanical model in order to study their specific influence on the overall MEF behaviour. Our computational model is based on a three-dimensional (3D) geometry of a healthy rat left ventricle reconstructed from magnetic resonance imaging (MRI). The electromechanically coupled problem is solved using a fully implicit finite element-based approach. The effects of different passive material models on the MEF are studied with the help of numerical examples. It turns out that there is a significant difference between the behaviour of the MEF for compressible and incompressible material models. Numerical results for the incompressible models exhibit that a change in the electrophysiology can be observed such that the transmembrane potential (TP) is unable to reach the resting state in the repolarisation phase and this leads to non-zero relaxation deformations. The most significant and strongest effects of the MEF on the rat cardiac muscle response are observed for the exponential passive material law.<br
Keywords: Electromechanics; Excitation-contraction; Mechano-electrical feedback; passive mechanics; rat left ventricle; FEM; Compressible; Incompressible; Exponential; Polynomial; Orthotropic; Transversely isotropic

Interactive virtual stent planning for the treatment of coarctation of the aorta - Neugebauer, Mathias; Glöckler, Martin; Goubergrits, Leonid; Kelm, Marcus; Kuehne, Titus; Hennemuth, Anja (International Journal of Computer Assisted Radiology and Surgery, 2016)
The coarctation of the aorta (CoA), a local narrowing of the aortic arch, accounts for 7 % of all congenital heart defects. Stenting is a recommended therapy to reduce the pressure gradient. This procedure is associated with complications such as the development of adverse flow conditions. A computer-aided treatment planning based on flow simulations can help to predict possible complications. The virtual stent planning is an important, intermediate step in the treatment planning pipeline. We present a novel approach that automatically suggests a stent setup and provides a set of intuitive parameters that allow for an interactive adaption of the suggested stent placement and induced deformation.A high-quality mesh and a centerline are automatically generated. The stent-induced deformation is realized through a deformation of the centerline and a vertex displacement with respect to the deformed centerline and additional stent parameters. The parameterization is automatically derived from the underlying data and can be optionally altered through a condensed set of clinically sound parameters.The automatic deformation can be generated in about 25 s on a consumer system. The interactive adaption can be performed in real time. Compared with manual expert reconstructions of the stented vessel section, the mean difference of vessel path and diameter is below 1 mm.Our approach enables a medical user to easily generate a plausibly deformed vessel mesh which is necessary as input for a simulation-based treatment planning of CoA.
EVALuna2:25115

Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice - Haep, Lisa; Britzen-Laurent, Nathalie; Weber, Thomas G.; Naschberger, Elisabeth; Schäfer, Amrei; Kremmer, Elisabeth; Försch, Sebastian; Scheuer, Werner; Wirtz, Stefan; Waldner, Maximilian; Stürzl, Michael; Vieth, Michael (Inflammatory Bowel Diseases, 2015)
Interferon (IFN)-? is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN-? in IBD have been predominantly investigated. Based on previous studies showing that IFN-? acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN-? on the vascular system in IBD.Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy.We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN-? were more strongly upregulated in colitis tissues. IFN-? exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN-?-induced guanylate binding protein 1 (GBP-1). Neutralization of IFN-? in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability.The dissection of the pleiotropic activities of IFN-? in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.
EVALuna2:1969

Interventions for reducing medication errors in children in hospital - Maaskant, Jolanda M.; Vermeulen, Hester; Apampa, Bugewa; Fernando, Bernard; Ghaleb, Maisoon A.; Neubert, Antje; Thayyil, Sudhin; Soe, Aung (Cochrane Database of Systematic Reviews, 2015)
Many hospitalised patients are affected by medication errors (MEs) that may cause discomfort, harm and even death. Children are at especially high risk of harm as the result of MEs because such errors are potentially more hazardous to them than to adults. Until now, interventions to reduce MEs have led to only limited improvements.To determine the effectiveness of interventions aimed at reducing MEs and related harm in hospitalised children.The Effective Practice and Organisation of Care Group (EPOC) Trials Search Co-ordinator searched the following sources for primary studies: The Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL), the Economic Evaluation Database (EED) and the Health Technology Assessments (HTA) database; MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Proquest Dissertations & Theses, Web of Science (citation indexes and conference proceedings) and the EPOC Register of Studies. Related reviews were identified by searching the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects (DARE). Review authors searched grey literature sources and trial registries. They handsearched selected journals, contacted researchers in the field and scanned reference lists of relevant reviews. They conducted searches in November 2013 and November 2014. They applied neither language nor date limits.Randomised controlled trials, controlled before-after studies and interrupted time series investigating interventions to improve medication safety in hospitalised children (<= 18 years). Participants were healthcare professionals authorised to prescribe, dispense or administer medications. Outcome measures included MEs, (potential) patient harm, resource utilisation and unintended consequences of the interventions.Two review authors independently selected studies, extracted data and assessed study quality using the EPOC data collection checklist. We evaluated the risk of bias of included studies and used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to assess the quality of the body of evidence. We described results narratively and presented them using GRADE tables.We included seven studies describing five different interventions: participation of a clinical pharmacist in a clinical team (n = 2), introduction of a computerised physician order entry system (n = 2), implementation of a barcode medication administration system (n = 1), use of a structured prescribing form (n = 1) and implementation of a check and control checklist in combination with feedback (n = 1).Clinical and methodological heterogeneity between studies precluded meta-analyses. Although some interventions described in this review show a decrease in MEs, the results are not consistent, and none of the studies resulted in a significant reduction in patient harm. Based on the GRADE approach, the overall quality and strengfh of the evidence are low.Current evidence on effective interventions to prevent MEs in a paediatric population in hospital is limited. Comparative studies with robust study designs are needed to investigate interventions including components that focus on specific paediatric safety issues.
EVALuna2:18941

Intracerebral gene therapy of aromatic L-amino acid decarboxylase deficiency with eladocagene exuparvovec. Statement of the Society for Neuropediatrics (GNP), the Working Group on Pediatric Metabolic Disorders (APS), the German Society of Neurosurgery (DGNC) and the German Society of Pediatrics and Adolescent Medicine (DGKJ) - Opladen, Thomas; Brennenstuhl, Heiko; Kuseyri Huebschmann, Oya; Call, Debora; Green, Kim; Schara, Ulrike; Rascher, Wolfgang; Hoevel, Annegret; Assmann, Birgit; Koelker, Stefan; Westhoff, Jens H.; Walter, Magdalena; et al. (Monatsschrift Kinderheilkunde, 2021)
Background: The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) causes a severe combined deficiency of dopamine, serotonin and catecholamines. The clinical picture is characterized by truncal hypotonia, delayed or absent achievement of motor milestones, and oculogyric crises from infancy onwards. The response to conventional drug treatment is very limited, especially in severe cases. The intracerebral application of eladocagene exuparvovec, an AAV2-based gene therapy, which is expected to be approved in mid-2021, is the first available causal therapeutic approach.
CRIS-Team WoS Importer:2021-07-16

Intrafamilial neurological phenotypic variability due to either biallelic or monoallelic pathogenic variants in CACNA1A - Mammadova, Dilbar; Kraus, Cornelia; Leis, Thomas; Popp, Bernt; Zweier, Christiane; Reis, André; Trollmann, Regina (Frontiers in Neurology, 2024)
Pathogenic heterozygous variants in CACNA1A are associated with familial hemiplegic migraine, episodic ataxia type 2 and spinocerebellar ataxia type 6, and more recently, neurodevelopmental disorders. We describe a severe, early-onset phenotype including severe muscular hypotonia, early-onset epileptic seizures, apnoea, optic atrophy and dysphagia in three siblings carrying compound heterozygous frameshift variants in CACNA1A. Two male patients died at the age of 5 or 14 months of suspected SIDS or severe developmental epileptic encephalopathy (DEE) with refractory seizures and apnoea. A male child (index patient) developed severe early-onset DEE including seizures and ictal apnoea at the age of 4 weeks. Another male child developed generalized epilepsy and mild intellectual impairment in late infancy, and his mother and his maternal uncle were identified as carriers of a known CACNA1A pathogenic variant [c.2602delG heterozygous, p. (Ala868Profs*24)] with a diagnosis of episodic ataxia type 2. This maternal pathogenic variant c.2602delG was detected in the index patient and child 2. Trio-Exome sequencing identified an additional heterozygous pathogenic variant in the CACNA1A gene, c.5476delC, p.(His1826Thrfs*30) in the index patient and child 2, which was inherited from the asymptomatic father. In conclusion, the novel compound heterozygosity for two frameshift pathogenic variants, maternally [c.2602delG, p.(Ala868Profs*24)] and paternally [c.5476delC, p.(His1826Thrfs*3)] is associated with a severe phenotype of early-onset DEE. This observation highlights the necessity of additional analyses to clarify unusual phenotypes even if a pathogenic variant has already been identified, and expands the clinical spectrum of CACNA1A-related disorders.
CRIS-Team Scopus Importer:2024-10-25
Keywords: apneic spells; burst suppression; developmental epileptic encephalopathy; early-onset epileptic encephalopathy; generalized epilepsy; optic nerve atrophy

Intranasale Schmerzmittel in der Notfallmedizin - was ist die Evidenz? Teil 1 Fentanyl - Ahne, Gabriele; Dormann, Harald; Neubert, Antje (Notarzt, 2024)
CRIS-Team Scopus Importer:2024-02-23

Intrauterine Growth Restriction (IUGR) Induces Signs of Subclinical Atherosclerosis in 6-Year-Old Infants Despite Absence Of Excessive Growth - Tzschoppe, Anja; Von Kries, Ruediger; Struwe, Ellen; Rascher, Wolfgang; Dörr, Helmuth-Günther; Juengert, Joerg; Rauh, Manfred; Beckmann, Matthias; Schild, Ralf; Goecke, Tamme W.; Doetsch, Joerg (Klinische Pädiatrie, 2017)
Background Postnatal catch-up growth and rapid weight gain after intrauterine growth restriction (IUGR) seem to increase the risk for later disease. This study aimed to compare features of the metabolic syndrome early in life between IUGR and appropriate for gestational age (AGA) infants. Patients Data for 9 infants with IUGR defined by a birth weight<10th percentile and ultrasound-proven placental insufficiency and 11 AGA children were available. Method Postnatal growth, auxological, cardiovascular, and metabolic parameters up to a chronological age of 6 years were assessed: Fasting serum concentrations of LDL-cholesterol, insulin, leptin, IGF-I, DHEAS, skinfold thicknesses, blood pressure, and mean carotid intima-media thickness (cIMT). Results All IUGR infants showed catch-up growth, although mean BMI SDS and total subcutaneous fat mass at the age of 6 years were still slightly lower compared to the AGA cohort. Reduced serum leptin concentrations were observed in IUGR infants (p=0.02), whereas no significant difference was found for IGF-I, insulin, LDL-cholesterol and DHEAS concentrations. Mean cIMT was significantly higher in IUGR infants (p<0.05). Mean arterial pressure did no differ. Discussion and Conclusion In 6-year-old IUGR infants with catch-up growth, who still had a slightly reduced BMI SDS compared to the AGA group, signs of subclinical atherosclerosis were detectable suggesting that cardiovascular risk in IUGR may be present even in the absence of excessive growth.
EVALuna2:34095

Investigating significant health trends in growth hormone treatments registry: rationale, aims and design of a nationwide prospective registry (study protocol) - Schnabel, Dirk; Kreitschmann-Andermahr, Ilonka J.; Strasburger, Christian; Pittrow, David; Pausch, Christine; Wölfle, Joachim; Nsights-Ght Study Grp, (Orphanet Journal of Rare Diseases, 2023)
Background: Somatropin treatment is indicated in a variety of disorders including growth hormone (GH) deficiency, Prader–Willi and Turner syndrome, chronic renal insufficiency and others. To date, almost all studies have been limited to single GH products, and no independent registry across indications and somatropin products was ever established. Aim: The present investigator-initiated registry named INSIGHTS-GHT aims to provide comprehensive information on various aspects of somatropin treatment in Germany in approved indications within routine clinical practice: drug utilization, effectiveness (including real final height, body composition), tolerability, quality of life, other patient related outcomes (PRO), and health economic variables. Methods: Registry (prospective observational study) in specialised pediatric and adult endocrinology centres in Germany. Patients of any age are eligible for documentation, if they are on ongoing or newly initiated treatment with any approved somatropin or somatropin-related product within the labelling, available for long term follow-up documentation, and if they provided informed consent. Subjects may switch, discontinue/interrupt or initiate somatropin products at any time. They are followed up for at least 3 years (minimal study duration). Documentation is planned once or twice per year to record somatropin utilisation (product, dosing), other medications, laboratory status (glucose, lipids, GH function including stimulation tests, IGF-I, IGFBP3), if applicable, pubertal development, auxological parameters, body composition and bone age. Patient reported outcome (PRO) measures include, but are not limited to, Short Form 12 in adults and adolescents aged 14 years and over. Safety reporting includes adverse events. Conclusions: The registry documents children and adults in one joint registry, includes, at present, patients in Germany and allows documentation of patients on all approved somatropin and other growth hormone preparations. It will allow to describe the transition of subjects from adolescence to adulthood (treatment and height), to describe switches between somatotropin preparations, to perform responder analyses, and to analyse differences and similarities of somatropin utilization (by age group, sex, setting, and PRO instrument). INSIGHTS-GHT offers a broad, comprehensive research platform to assess multiple relevant aspects of somatropin treatment and outcomes (including the transition of subjects from adolescence to adulthood), allows the documentation of all GH products including long-acting GH preparations after their introduction, and will evaluate the data independently of funders. Trial registration BfArM Nr. NIS7492, DRKS registry DRKS00027394.
CRIS-Team Scopus Importer:2023-05-26
Keywords: Adults; Children; Growth hormone deficiency; Human growth hormone; Observational; Somatropin

In Vivo Assessment of Deep Vascular Patterns in Murine Colitis Using Optoacoustic Mesoscopic Imaging - Bühler, Adrian; Brown, Emma L.; Nedoschill, Emmanuel; Eckstein, Markus; Ludwig, Petra; Wachter, Felix; Mandelbaum, Henriette; Raming, Roman; Oraiopoulou, Mariam Eleni; Paulus, Lars-Philip; Rother, Ulrich; Friedrich, Oliver; et al. (Advanced Science, 2024)
The analysis of vascular morphology and functionality enables the assessment of disease activity and therapeutic effects in various pathologies. Raster-scanning optoacoustic mesoscopy (RSOM) is an imaging modality that enables the visualization of superficial vascular networks in vivo. In murine models of colitis, deep vascular networks in the colon wall can be visualized by transrectal absorber guide raster-scanning optoacoustic mesoscopy (TAG-RSOM). In order to accelerate the implementation of this technology in translational studies of inflammatory bowel disease, an image-processing pipeline for TAG-RSOM data has been developed. Using optoacoustic data from a murine model of chemically-induced colitis, different image segmentation methods are compared for visualization and quantification of deep vascular patterns in terms of vascular network length and complexity, blood volume, and vessel diameter. The presented image-processing pipeline for TAG-RSOM enables label-free in vivo assessment of changes in the vascular network in murine colitis with broad applications for inflammatory bowel disease research.
CRIS-Team Scopus Importer:2024-11-01
Keywords: dextran sodium sulfate induced colitis; inflammatory bowel disease; murine acute colitis; optoacoustic imaging; photoacoustic imaging; raster-scanning optoacoustic mesoscopy; vessel morphology analysis

In vivo evaluation of gene transfer into mesenchymal cells (in view of cartilage repair). - Gelse, Kolja; Schneider, Holm (Methods in Molecular Biology, 2011)
Gene transfer of specific growth factors is suitable for inducing chondrogenic differentiation of -mesenchymal cells to be used for cartilage regeneration. However, extent and quality of repair tissue formation also depend on biomechanical and metabolic influences that can only be studied in vivo. We describe three methods to evaluate viral gene transfer into mesenchymal cells in animal models of articular cartilage defects, e.g., mouse, rat and miniature pig models, focussing on the repair of hyaline cartilage tissue.
CRIS-Team Scopus Importer:2020-07-01

Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study - Düzova, Ali; Karabay Bayazit, Aysun; Canpolat, Nur; Niemirska, Anna; Kaplan Bulut, Ipek; Azukaitis, Karolis; Karagoz, Tevfik; Oguz, Berna; Erdem, Sevcan; Anarat, Ali; Ranchin, Bruno; Shroff, Rukshana; et al. (Journal of Hypertension, 2019)
INTRODUCTION: Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD. METHODS: Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ± 3.2 years, estimated glomerular filtration rate 29 ± 12 ml/min per 1.73 m). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension. RESULTS: Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT. CONCLUSION: INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function.
CRIS-Team Scopus Importer:2019-10-08

Joint recommendations on cost calculation and estimation in paediatric clinical trials - Ahne, Gabriele; Nagel, Julia; Franz, Axel R.; Neubert, Antje; Schachtrup, Kristina; Helms, Simone; Klammt, Sebastian; Schwab, Matthias (GMS German Medical Science, 2024)
The conduct of clinical trials in paediatrics is essential to improve drug therapy in children. In Europe, paediatric clinical trials have been sup-ported by the European Paediatric Regulation since 2007, but there is still a great need for high-quality clinical trials. The personnel and time required to conduct clinical trials in accordance with EU Regulations 536/2014 and 745/2017 is considerably higher compared to other studies, such as observational studies. It is important that this additional workload for the trial centre is fully compensated, also taking into account EU state aid rules. In paediatric trials, it is necessary to take into account the special requirements of paediatric and adolescent medicine when calculating the additional costs. Within the framework of the pan-European paediatric study network c4c/GermanNetPaeT, a working group dealt with specific aspects of cost calculation in order to support paediatric study centres in internal cost calculation as well as in the subsequent preparation of financing requirements for industrial sponsors or public funders. In several workshops the working group developed a cost calculation template with the content derived from the “Joint recommendations for a total services account as a factor in simplifying contracts” of the Deutsche Hochschulmedizin (DHM, German University Medicine), the Netzwerk der Koordinierungszentren für Klinische Studien (KKS Network, Network of Coordinating Centres for Clinical Trials) and the Verband Forschender Arzneimittelhersteller (vfa, German Association of ResearchBased Pharmaceutical Companies). By estimating the specific time required for measures and investigations as part of a sample study, the background to the increased time required was discussed and a list with aspects to be considered for cost calculation was compiled together with the study centres. The paediatrics-specific aspects mentioned in detail are intended to increase understanding of the particular problem of higher costs for clinical trials involving children and adolescents and the need for correspondingly appropriate remuneration. This transparent and comprehensible presentation of the higher financial requirements for both the study centres and the financial supporters is intended to promote the high-quality conduct of clinical trials in paediatric study centres in the long term.
CRIS-Team Scopus Importer:2024-05-31
Keywords: clinical trial; cost calculation; paediatrics

Jumping into a Healthier Future: Trampolining for Increasing Physical Activity in Children - Schöffl, Volker Rainer; Schöffl, Isabelle; Ehrlich, Benedikt; Rottermann, Kathrin; Weigelt, Annika; Dittrich, Sven; Schoeffl, Volker (Sports Medicine - Open, 2021)
Objectives: Physical activity in children and adolescents has positive effects on cardiopulmonary function in this age group as well as later in life. As poor cardiopulmonary function is associated with higher mortality and morbidity, increasing physical activity especially in children needs to become a priority. Trampoline jumping is widely appreciated in children. The objective was to investigate its use as a possible training modality. Methods: Fifteen healthy children (10 boys and 5 girls) with a mean age of 8.8 years undertook one outdoor incremental running test using a mobile cardiopulmonary exercise testing unit. After a rest period of at least 2 weeks, a trampoline test using the mobile unit was realized by all participants consisting of a 5-min interval of moderate-intensity jumping and two high-intensity intervals with vigorous jumping for 2 min, interspersed with 1-min rests. Results: During the interval of moderate intensity, the children achieved V̇ O2-values slightly higher than the first ventilatory threshold (VT1) and during the high-intensity interval comparable to the second ventilatory threshold (VT2) of the outdoor incremental running test. They were able to maintain these values for the duration of the respective intervals. The maximum values recorded during the trampoline test were significantly higher than during the outdoor incremental running test. Conclusion: Trampoline jumping is an adequate tool for implementing high-intensity interval training as well as moderate-intensity continuous training in children. As it is a readily available training device and is greatly enjoyed in this age group, it could be implemented in exercise interventions.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Cardiopulmonary function; Children; Exercise testing; Pediatric cardiology; Pediatrics; Physical activity; Rehabilitation; Training; Training modalities

Juvenile Larynxpapillomatose: Therapieoptionen und Literaturübersicht - Hübner, Matthias; Schützenberger, Anne; Traxdorf, Maximilian; Dittrich, Sven; Iro, Heinrich; Müller, Sarina Katrin (Monatsschrift Kinderheilkunde, 2022)
Background: Despite various therapeutic options, there is currently no cure for juvenile onset recurrent respiratory laryngeal papillomatosis (JORRP). Additionally, for the majority of these therapeutic options mild to severe side effects have been described. Objective: Analysis of the effects and side effects of previous and current therapeutic options. Discussion of active ingredients, dosage and administrative form of the available drugs. Material and methods: Review of literature and analysis of the therapeutic options concerning effects and side effects, active ingredients, dosage and administrative form. Results: Surgery remains the gold standard of all treatment options. There are multiple therapeutic options in the literature; however, no treatment options currently lead to a complete remission. Maintaining the function, increasing the time interval between interventions and diminishing the papilloma load in cases of recurrence remain the utmost priority. Conclusion: There are several promising therapeutic options for the treatment of JORRP; however, the current data situation is not sufficient for a general recommendation or guidelines. In the future, further prospective studies with a larger patient population/juvenile population are necessary.
CRIS-Team Scopus Importer:2022-09-20
Keywords: Bevacizumab; Human papillomavirus; Laryngeal papillomatosis; Programmed cell death 1 receptor; Vaccine

Kann die Ketoacidose bei pädiatrischen Patienten mit Manifestation eines Diabetes mellitus Typ 1 vermieden werden? Lehren aus der COVID-19-Pandemie - Mönkemöller, Kirsten; Kamrath, Clemens; Hammersen, Johanna; Biester, Torben; Warncke, Katharina; Pappa, Angeliki; Fink, Katharina; Raile, Klemens; Rohrer, Tilman R.; Holl, Reinhard W. (Monatsschrift Kinderheilkunde, 2021)
Background: Diabetic ketoacidosis (DKA) is a life-threatening emergency in children and adolescents with manifestation of type 1 diabetes mellitus (DM1) and often associated with delayed diagnosis or previous diagnostic errors. During the coronavirus disease 2019 (COVID-19) lockdown period in Germany, less patients presented at emergency departments and private practices. Objective: The aim of this study was to investigate the DKA risk in children and adolescents with DM1 manifestation during the COVID-19 lockdown and associated risk factors. Material and methods: The frequency of DKA at DM1 onset in patients <18 years between 13 March and 13 May 2020 in pediatric diabetes centers was analyzed. The centers also documented their assessment, if the presentation was delayed or the diagnosis was not made on the first medical consultation. In order to analyze the influence of the risk factors on the frequency of DKA, the data from 2020 were compared with the same periods in 2018 and 2019 using multivariable linear and logistic regression. Results: The data of 532 patients from 216 diabetes centers showed that the risk for DKA increased by 84.7% and the risk for severe DKA increased by 45.3% compared to the years 2018/2019. Children <6 years had the highest risk with an 141.6% increase for DKA and 97.0% for severe DKA compared to the previous years. Migration background was a risk factor independent of COVID-19. Of the patients 31% had either a delayed presentation or a missed diagnosis. Conclusion: During the COVID-19 lockdown the frequency of DKA and severe DKA at DM1 onset was significantly increased for children and adolescents in Germany. Age <6 years, migration background and delayed diagnosis were the main risk factors.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Children < 6 years; COVID-19 lockdown; Delayed presentation; Migration background; Missed diagnosis

Ketoacidosis in Children and Adolescents with Newly Diagnosed Type 1 Diabetes during the COVID-19 Pandemic in Germany - Kamrath, Clemens; Mönkemöller, Kirsten; Biester, Torben; Rohrer, Tilman R.; Warncke, Katharina; Hammersen, Johanna; Holl, Reinhard W. (Journal of the American Medical Association, 2020)
CRIS-Team Scopus Importer:2020-08-07

Kidsafe-improving medication safety for children and adolescents: Implementation and evaluation of a new form of care - Toni, Irmgard; Koenig, Jochem; Makosi, Dorothee Malonga; Urschitz, Michael S.; Rascher, Wolfgang; Neubert, Antje (PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2022)
CRIS-Team WoS Importer:2022-10-28

Klinische Ethikkomitees Chancen, Risiken und Nebenwirkungen - Frewer, Andreas; Fahr, Uwe; Rascher, Wolfgang (2008)

Klinische Ethikkomitees Chancen, Risiken und Nebenwirkungen - Frewer, Andreas; Fahr, Uwe; Rascher, Wolfgang (Königshausen & Neumann, 2008)
UnivIS-Import:2019-03-25:Pub.2008.sonste.verbun.fbzhl.philos

KNOCK-OUT OF THE HUMAN ENDOGENOUS RETROVIRUS ERV3 USING CRISPR/CAS9 TECHNOLOGY - Hübner, Hanna; Fahlbusch, Fabian B.; Ekici, Arif Bülent; Vasileiou, Georgia; Beckmann, Matthias; Strick, Reiner; Rübner, Matthias (2016)
EVALuna2:9327

Label-Free Multiphoton Endomicroscopy for Minimally Invasive In Vivo Imaging - Dilipkumar, Ashwathama; Al-Shemmary, Alaa; Kreiß, Lucas; Cvecek, Kristian; Carlé, Birgitta-Elisabeth; Knieling, Ferdinand; Menezes, Jean Gonzales; Thoma, Oana-Maria; Schmidt, Michael; Neurath, Markus; Waldner, Maximilian; Friedrich, Oliver; et al. (Advanced Science, 2019)
Multiphoton microscopy of cellular autofluorescence and second harmonic generation from collagen facilitates imaging of living cells and tissues without the need for additional fluorescent labels. Here, a compact multiphoton endomicroscope for label-free in vivo imaging in small animals via side-viewing needle objectives is presented. Minimal invasive imaging at cellular resolution is performed in colonoscopy of mice without surgical measures and without fluorescent dyes as a contrast agent. The colon mucosa is imaged repeatedly in the same animal in a mouse model of acute intestinal inflammation to study the process of inflammation at the tissue level within a time period of ten days, demonstrating the capabilities of label-free endomicroscopy for longitudinal studies for the first time.
CRIS-Team Scopus Importer:2019-05-02
Keywords: endoscopy; inflammatory bowel disease; multiphoton microscopy; optical imaging

Lang wirksames Wachstumshormon – eine neue Therapieoption für Kinder mit Wachstumshormonmangel: Status 2024 - Dörr, Helmuth-Günther; Bettendorf, Markus; Wölfle, Joachim; Saenger, Paul; Ranke, Michael B. (Monatsschrift Kinderheilkunde, 2024)
Until recently, daily singular subcutaneous injections of recombinant human growth hormone (rhGH) was the treatment of choice in short-statured children with growth hormone deficiency (GHD). This concept has been effective and safe for almost four decades; however, with this practice of replacement therapy approximately 10–20% of the children did not reach an adult height within the target range of the parents. Among the various factors involved, insufficient adherence, as the consequence of the necessary but inconvenient daily injections has been identified as a particularly important factor. This prompted the development of long-acting growth hormone (LAGH). At the end of 2023 there were three approved LAGH preparations available in Germany for the treatment of children older than 3 years with GHD due to an insufficient secretion of GH. All approved LAGH formulations use different technologies to prolong the half-life of rhGH. The LAGH as well as rhGH bind to the GH receptor and initiate the signal cascade that leads to the activation of growth and metabolism. In phase 3 studies LAGH showed non-inferiority to daily rhGH injections in terms of increasing height as well as comparability in the safety profiles. Thus, the treatment with LAGH offers a new option for children and adolescents with GHD; however, the long-term efficacy and safety need further systematic evaluation. Parents and patients need to be informed about all relevant aspects of the new treatment. This review article discusses the currently approved LAGH preparations in Germany together with the published data from a pediatric perspective.
CRIS-Team Scopus Importer:2024-08-16
Keywords: Adherence; Lonapegsomatropin; Somapacitan; Somatrogon

Large amplicon droplet digital PCR for DNA-based monitoring of pediatric chronic myeloid leukaemia - Krumbholz, Manuela; Görlitz, Katharina; Albert, Christian; Lawlor, Jennifer; Suttorp, Meinolf; Metzler, Markus (Journal of Cellular and Molecular Medicine, 2019)
Quantification of tumour-specific molecular markers at the RNA and DNA level for treatment response monitoring is crucial for risk-adapted stratification and guidance of individualized therapy in leukaemia and other malignancies. Most pediatric leukaemias and solid tumours of mesenchymal origin are characterized by a relatively low mutation burden at the single nucleotide level and the presence of recurrent chromosomal translocations. The genomic fusion sites resulting from translocations are stable molecular tumour markers; however, repeat-rich DNA sequences flanking intronic breakpoints limit the design of high sensitivity PCR assays for minimal residual disease (MRD) monitoring. Here, we quantitatively evaluated the impact of repeat elements on assay selection and the feasibility of using extended amplicons (≤1330 bp) amplified by droplet digital PCR to monitor pediatric chronic myeloid leukaemia (CML). Molecular characterization of 178 genomic BCR-ABL1 fusion sites showed that 64% were located within sequence repeat elements, impeding optimal primer/probe design. Comparative quantification of DNA and RNA BCR-ABL1 copy numbers in 687 specimens from 55 pediatric patients revealed that their levels were highly correlated. The combination of droplet digital PCR, double quenched probes and extended amplicons represents a valuable tool for sensitive MRD assessment in CML and may be adapted to other translocation-positive tumours.
CRIS-Team Scopus Importer:2019-08-06
Keywords: BCR-ABL1 fusion; biomarkers; chronic myeloid leukaemia CML; digital PCR; disease monitoring; genomic fusion sequences; pediatric oncology; translocation

L-arginine metabolism as pivotal interface of mutual host–microbe interactions in the gut - Nüse, Björn; Holland, Tim; Rauh, Manfred; Gerlach, Roman; Mattner, Jochen (Gut Microbes, 2023)
L-arginine (L-arg) is a versatile amino acid and a central intestinal metabolite in mammalian and microbial organisms. Thus, L-arg participates as precursor of multiple metabolic pathways in the regulation of cell division and growth. It also serves as a source of carbon, nitrogen, and energy or as a substrate for protein synthesis. Consequently, L-arg can simultaneously modify mammalian immune functions, intraluminal metabolism, intestinal microbiota, and microbial pathogenesis. While dietary intake, protein turnover or de novo synthesis usually supply L-arg in sufficient amounts, the expression of several key enzymes of L-arg metabolism can change rapidly and dramatically following inflammation, sepsis, or injury. Consequently, the availability of L-arg can be restricted due to increased catabolism, transforming L-arg into an essential amino acid. Here, we review the enzymatic pathways of L-arg metabolism in microbial and mammalian cells and their role in immune function, intraluminal metabolism, colonization resistance, and microbial pathogenesis in the gut.
CRIS-Team Scopus Importer:2023-07-21
Keywords: colonization resistance; dietary L-arg supplementation; host–microbe interaction; intestinal microbiota; L-arginine (L-arg); microbial pathogenesis; mucosal immune function; mutual metabolic pathways; virulence factor

Late complete atrioventricular block after closure of an atrial septal defect with a gore septal occluder (GSO(TM)) - Dittrich, Sven; Sigler, Matthias; Priessmann, Helga (Catheterization and Cardiovascular Interventions, 2016)
Temporary intermittent complete heart block (CHB) occurred the day after interventional closure of an ASD with a 30 mm Gore Septal Occluder (GSO(TM)) in a 2 years and 11-month-old female. CHB disappeared without further treatment and stable sinus rhythm recovered within 3 days. Only short episodes of 2nd degree AV-block (Wenckebach periodicity) at rare intervals were documented in Holter-monitors the following 2 months. Eleven months after device implantation the patient suffered from long lasting episodes of CHB. Surgical removal of the device resulted in incomplete recovery of AV-conduction. Histopathological work-up of the explanted GSO showed complete endothelialization of the device and regular scar formation. One year after surgery, the child had sinus rhythm during daytime but needed VVI-pacing while sleeping. Young age, inferior localization of the defect, and use of a large device have been individual risk factors for CHB in this patient. Clinical course and histologic findings indicate that mechanical compression was the only cause for CHB. The cumulative number of reports of CHB after use of different ASD-devices supports the recommendation to postpone the intervention in asymptomatic patients to preschool-age. Early removal of a pushing device may increase the chance of complete recovery from CHB.
EVALuna2:25119

Latency duration of preterm premature rupture of membranes and neonatal outcome: a retrospective single-center experience - Mueller, Hanna; Staehling, Ann-Christin; Bruns, Nora; Weiss, Christel; Ai, Maria; Koeninger, Angela; Felderhoff-Mueser, Ursula (European journal of pediatrics, 2021)
In preterm premature rupture of membranes (PPROM), a decision between early delivery with prematurity complications and pregnancy prolongation bearing the risk of chorioamnionitis has to be made. To define disadvantages of delayed prolongation, latency duration of PPROM in expectantly managed pregnancies was investigated. We included those PPROMs > 48 h leading to preterm birth prior 37 weeks’ gestation and retrospectively analyzed 84 preterm infants fulfilling these criteria. The association between latency duration/appearance of PPROM and respiratory outcome (primary outcomes) and neurological outcome (secondary outcomes) was investigated. The study showed that latency duration of PPROM is not associated with clinical or histological chorioamnionitis (p = 0.275; p = 0.332). As the numerous clinical parameters show multicollinearity between each other, we performed a multiple regression analysis to consider this fact. Respiratory distress syndrome is significantly associated with gestational age at PPROM (p < 0.001), and surfactant application is significantly associated with PPROM duration (p = 0.014). The other respiratory parameters including steroids and diuretics therapy, bronchopulmonary dysplasia, and the neurological parameters (intraventricular hemorrhage, Bayley II testing at a corrected age of 24 months) were not significantly associated with PPROM duration or gestational age at PPROM diagnosis. Conclusion: Latency duration of PPROM was not associated with adverse neonatal outcome in expectantly and carefully managed pregnancies, but respiratory distress syndrome was pronounced. The observed effect of pronounced respiratory distress syndrome can be treated with surfactant preparations and was not followed by increased rate of bronchopulmonary dysplasia.What is Known:• In case of preterm premature rupture of membranes, a decision between pregnancy prolongation with the risk of chorioamnionitis and early delivery with prematurity complications has to be made.• Chorioamnionitis is a dangerous situation for the pregnant woman and the fetus.• Impaired neurodevelopmental outcome is strongly correlated with pronounced prematurity due to the increased rate of serious complications.What is New:• Respiratory distress syndrome is significantly associated with gestational age at PPROM, and surfactant application is significantly associated with PPROM duration.• Latency duration of PPROM is not associated with adverse respiratory neonatal outcome (therapy with continuous positive airway pressure, therapy with diuretics and/or steroids, bronchopulmonary dysplasia) in expectantly and carefully managed pregnancies.• Intraventricular hemorrhage and Bayley II testing at a corrected age of 24 months are not associated with latency duration of PPROM when pregnancies are carefully observed.
CRIS-Team Scopus Importer:2021-10-15
Keywords: Chorioamnionitis; Neurological development; Preterm infant; Preterm premature rupture of membranes; Respiratory distress syndrome

Latent class distributional regression for the estimation of non-linear reference limits from contaminated data sources - Hepp, Tobias; Zierk, Jakob; Rauh, Manfred; Metzler, Markus; Mayr, Andreas (BMC Bioinformatics, 2020)
Background: Medical decision making based on quantitative test results depends on reliable reference intervals, which represent the range of physiological test results in a healthy population. Current methods for the estimation of reference limits focus either on modelling the age-dependent dynamics of different analytes directly in a prospective setting or the extraction of independent distributions from contaminated data sources, e.g. data with latent heterogeneity due to unlabeled pathologic cases. In this article, we propose a new method to estimate indirect reference limits with non-linear dependencies on covariates from contaminated datasets by combining the framework of mixture models and distributional regression. Results: Simulation results based on mixtures of Gaussian and gamma distributions suggest accurate approximation of the true quantiles that improves with increasing sample size and decreasing overlap between the mixture components. Due to the high flexibility of the framework, initialization of the algorithm requires careful considerations regarding appropriate starting weights. Estimated quantiles from the extracted distribution of healthy hemoglobin concentration in boys and girls provide clinically useful pediatric reference limits similar to solutions obtained using different approaches which require more samples and are computationally more expensive. Conclusions: Latent class distributional regression models represent the first method to estimate indirect non-linear reference limits from a single model fit, but the general scope of applications can be extended to other scenarios with latent heterogeneity.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Distributional regression; Finite mixture models; Latent class regression; Reference limits

Lateral spacing of TiO2 nanotubes modulates osteoblast behavior - Necula, Madalina Georgiana; Mazare, Anca Valentina; Ion, Raluca Nicoleta; Özkan, Selda; Park, Jung; Schmuki, Patrik; Cimpean, Anisoara (Materials, 2019)
Titanium dioxide (TiO2) nanotube coated substrates have revolutionized the concept of implant in a number of ways, being endowed with superior osseointegration properties and local drug delivery capacity. While accumulating reports describe the influence of nanotube diameter on cell behavior, little is known about the effects of nanotube lateral spacing on cells involved in bone regeneration. In this context, in the present study the MC3T3-E1 murine pre-osteoblast cells behavior has been investigated by using TiO2 nanotubes of 78 nm diameter and lateral spacing of 18 nm and 80 nm, respectively. Both nanostructured surfaces supported cell viability and proliferation in approximately equal extent. However, obvious differences in the cell spreading areas, morphologies, the organization of the actin cytoskeleton and the pattern of the focal adhesions were noticed. Furthermore, investigation of the pre-osteoblast differentiation potential indicated a higher capacity of larger spacing nanostructure to enhance the expression of the alkaline phosphatase, osteopontin and osteocalcin osteoblast specific markers inducing osteogenic differentiation. These findings provide the proof that lateral spacing of the TiO2 nanotube coated titanium (Ti) surfaces has to be considered in designing bone implants with improved biological performance.
CRIS-Team Scopus Importer:2019-10-01
Keywords: Cell adhesion and morphology; Cell proliferation; Osteoblast; Osteogenic differentiation; Spaced TiO

Lebenssituation von jungen Frauen mit Ullrich-Turner-Syndrom nach dem Ende der Wachstumshormontherapie: Ergebnisse einer Umfrage in Deutschland - Dörr, Helmuth-Günther; Bettendorf, Markus; Binder, Gerhard; Brämswig, Jürgen; Hauffa, Berthold P.; Holterhus, Paul Martin; Mohnike, Klaus; Schmidt, Heinrich; Stalla, Günter K.; Wabitsch, Martin; Wölfle, Joachim (Deutsche Medizinische Wochenschrift, 2019)
Introduction Psychosocial problems such as anxious personality, low self-esteem, late separation from home and/or late sexual experience have been described in girls and women with Turner syndrome (TS). Methods The study was performed in 2015 based on a questionnaire that was sent out to 779 women with TS aged 25 years (median). The questionnaire was devised by a French team and used with their permission. In all, 130 questionnaires (16.7%) could be evaluated. The questions from the individual topics were not always completely answered. Results (mean ± SD). 116 women (89.9%) were not married; 52 women (40%) lived in their parents' home. 47.6% had a high-school/technical diploma or university degree. 60 women (46%) had a job; 51 women (39%) had not completed vocational training. Puberty was induced at the age of 14.2± 2.1 years in 78% of the women. 80% of the women received hormone replacement therapy at the time of the questionnaire survey. 66 of 93 women (71%) found that the disease had a negative influence on emotional life. Love life and sexual relationship was the topic mentioned most frequently by 44 women (66.6%). 116 women answered questions on sexuality. Here, 77% had the first French kiss at the age of 16.4± 3.6 years and 62.4% had sexual intercourse for the first time at the age of 19.0±3.4 years. 81% of the women stated that they had a partner relationship for more than 6 months (94 women had a male partner and 5 had a female partner). The question as to the wish to have children was answered in the affirmative by 89 of 124 women (71.8%); 38.2% desired spontaneous pregnancy and 44.9% had considered in vitro fertilization or adoption. Discussion The women's answers show that care needs to be improved. There are deficits in the topics of family, emotional life, relationships, sexuality, fertility and pregnancy. Therefore, the medical team should also include psychologists and social workers.
CRIS-Team Scopus Importer:2019-07-26
Keywords: emotional life; fertility; questionnaire; sexuality

Letter: Enhancing Predictive Models for Paediatric Ulcerative Colitis—Addressing Socioeconomic, Environmental and Clinical Factors. Authors' Reply - Claßen, Merle; Schiller, Benjamin; Däbritz, Jan (Alimentary Pharmacology & Therapeutics, 2024)
CRIS-Team Scopus Importer:2024-12-06

Levothyroxine Treatment of Euthyroid Children with Autoimmune Hashimoto Thyroiditis: Results of a Multicenter, Randomized, Controlled Trial - Dörr, Helmuth-Günther; Bettendorf, Markus; Binder, Gerhard; Karges, Beate; Kneppo, Carolin; Schmidt, Heinrich; Voss, Egbert; Wabitsch, Martin; Doetsch, Joerg (Hormone Research in Paediatrics, 2015)
Levothyroxine (L-T4) treatment of euthyroid children with Hashimoto thyroiditis (HT) is a controversial issue.We conducted a prospective, randomized, controlled clinical trial. Out of 79 identified euthyroid patients, 59 started the study; 25 patients (21 female, 4 male; age: 11.8 ± 2.3 years) received L-T4 at a mean dose of 1.6 µg/kg (SD, 0.8) daily, and 34 (27 female, 7 male; age: 12.6 ± 1.2 years) were not treated. Patients developing subclinical hypothyroidism during follow-up (n = 13) were treated with L-T4 and removed from the observation group. As the main outcome measures, thyroid gland volume (determined by ultrasound) as well as serum levels of TSH, free T4, and antibodies against thyroid peroxidase and thyroglobulin were assessed every 6 months for 36 months.At the start, the mean thyroid volume (standard deviation score, SDS) was 2.5 in the treatment group and 1.6 in the observation group. There was a constant decline in mean thyroid volume (SDS) from 2.13 (month 12) to 1.12 (month 30) in the treated group, with a delta thyroid volume of -1.01 SDS. In the observation group, the mean delta thyroid volume increased to +0.27 SDS. The change of the delta thyroid volume was statistically significantly different between both groups during the 12- and 30-month time points (p < 0.05). L-T4 had no effect on thyroid function and serum thyroid antibodies.L-T4 treatment can decrease the thyroid volume in euthyroid children with HT, but the effect is limited to a definite time period.
EVALuna2:18916

Life Situation of Young women with Turner Syndrome: Results of a Questionnaire-based Study in Germany - Dörr, Helmuth-Günther; Bettendorf, Markus; Binder, Gerhard; Braemswig, Juergen; Hauffa, Berthold P.; Holterhus, Paul-Martin; Mohnike, Klaus; Schmidt, Heinrich; Stalla, Gunter K.; Wabitsch, Martin; Woelfle, Joachim (Deutsche Medizinische Wochenschrift, 2019)
INTRODUCTION: Psychosocial problems such as anxious personality, low self-esteem, late separation from home and/or late sexual experience have been described in girls and women with Turner syndrome (TS). METHODS: The study was performed in 2015 based on a questionnaire that was sent out to 779 women with TS aged 25 years (median). The questionnaire was devised by a French team and used with their permission. In all, 130 questionnaires (16.7 %) could be evaluated. The questions from the individual topics were not always completely answered. RESULTS: (mean ± SD).: 116 women (89.9 %) were not married; 52 women (40 %) lived in their parents' home. 47.6 % had a high-school/technical diploma or university degree. 60 women (46 %) had a job; 51 women (39 %) had not completed vocational training. Puberty was induced at the age of 14.2 ± 2.1 years in 78 % of the women. 80 % of the women received hormone replacement therapy at the time of the questionnaire survey. 66 of 93 women (71 %) found that the disease had a negative influence on emotional life. "Love life and sexual relationship" was the topic mentioned most frequently by 44 women (66.6 %). 116 women answered questions on sexuality. Here, 77 % had the first French kiss at the age of 16.4 ± 3.6 years and 62.4 % had sexual intercourse for the first time at the age of 19.0 ± 3.4 years. 81 % of the women stated that they had a partner relationship for more than 6 months (94 women had a male partner and 5 had a female partner). The question as to the wish to have children was answered in the affirmative by 89 of 124 women (71.8 %); 38.2 % desired spontaneous pregnancy and 44.9 % had considered in vitro fertilization or adoption. DISCUSSION: The women's answers show that care needs to be improved. There are deficits in the topics of family, emotional life, relationships, sexuality, fertility and pregnancy. Therefore, the medical team should also include psychologists and social workers.
EVALuna2:202757

Liquid Biopsies in Ewing Sarcoma - Krumbholz, Manuela; Metzler, Markus (Ewing Sarcoma, 2021)
Liquid biopsies enable noninvasive therapy monitoring in patients with solid tumors. Specific serum markers such as proteins, hormones, or enzymes released from tumor cells or in response to tumor growth can be used for quantification of the tumor burden. However, only a fraction of pediatric tumors has none of these serum markers, but tumor-specific genetic alterations represent reliable alternatives. Here we describe a method for using genomic fusion sequences as liquid biopsy markers in Ewing sarcoma patients.
CRIS-Team Scopus Importer:2021-01-01
Keywords: Cell-free circulating DNA; Double-quenched probes; Droplet digital PCR; Ewing sarcoma; Genomic fusion sequences; Liquid biopsy; Serum marker

Local recurrence of breast cancer: conventionally fractionated partial external beam re-irradiation with curative intention - Janssen, S.; Rades, D.; Meyer, A.; Fahlbusch, F. B.; Wildfang, I.; Meier, A.; Schild, S.; Christiansen, H.; Henkenberens, C. (Strahlentherapie und Onkologie, 2018)
PURPOSE: To assess the outcome of breast cancer patients with local recurrence who underwent partial external beam re-irradiation (re-RT) either as part of a second breast-conserving therapy or following mastectomy. METHODS: Between 03/2004 and 10/2016, 83 breast cancer patients with local recurrence were treated with surgery followed by re-RT. The re-RT schedules were 45 Gy (1.8 Gy per fraction) administered either to the partial breast (n = 42) or mastectomy scar (n = 41). The patients and tumor characteristics predictive of local control, distant control, and survival (overall and breast-cancer specific) were evaluated by univariate and multivariate analyses. RESULTS: The median follow-up was 35 months (range 3-143 months). The median time interval between the first irradiation and re-RT was 117 months (range 16-357 months). The prognostic factors for favorable overall survival rates were younger age (p = 0.045), lower T‑category (p = 0.019), and N0 category (p = 0.005). N0 was also superior to N+ with respect to outfield recurrences (p = <0.001) and breast cancer-specific survival (p = 0.025). Acute and late skin toxicity was generally low (
EVALuna2:35729

Long-Acting Growth Hormone Therapy in Pediatric Growth Hormone Deficiency: A Consensus Statement. - Maniatis, Aristides; Cutfield, Wayne; Dattani, Mehul; Deal, Cheri; Collett-Solberg, Paulo Ferrez; Horikawa, Reiko; Maghnie, Mohamad; Miller, Bradley S.; Polak, Michel; Sävendahl, Lars; Wölfle, Joachim (Journal of Clinical Endocrinology and Metabolism, 2025)
CONTEXT: Several long-acting growth hormone (LAGH) therapies have recently become available, but guidance on their usage in children with growth hormone (GH) deficiency is limited. METHODS: International experts in pediatric endocrinology were invited to join a consensus group based on their expertise in treating children with daily GH and LAGH. The group comprised 11 experts from 10 countries across the world. Online group meetings were held in February to March 2024 followed by a 1-day in-person meeting in May 2024 to finalize the consensus recommendations. A targeted literature search approach was used to identify and share evidence ahead of the meetings. Formulations considered were limited to those with international populations in phase III pivotal trials and regulatory approvals in multiple countries. EVIDENCE SYNTHESIS: Topics covered include patient selection and preference, dose adjustment, initiating and switching therapies, administration, adherence and missed doses, practical considerations, and knowledge gaps. LAGH formulations offer a potential advantage over daily GH injections for children with GH deficiency in terms of reduced injection frequency and treatment burden; this may also be associated with improved adherence and treatment outcomes over time. However, data on LAGH in pediatric GH deficiency are mostly limited to clinical trials, and long-term, real-world data are currently lacking. CONCLUSION: This article provides an international consensus on the use of LAGH therapy in children with GH deficiency to guide practitioners when considering these new treatment options for their patients. Long-term data are needed to fill current data gaps and allow the creation of comprehensive evidence-based recommendations.
EVALuna2:586369

LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF) - INTERIM ANALYSIS OF THE RELIANCE REGISTRY - Henes, J.; Kuemmerle-Deschner, J. B.; Krickau, Tobias; Kallinich, T.; Dressler, F.; Horneff, G.; Meier, F.; Foeldvari, I.; Weller-Heinemann, F.; Kortus-Goetze, B.; Hufnagel, M.; Rech, J.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-Term Experience of Arterio-Venous Fistula Surgery in Children on Hemodialysis - Almási-Sperling, Veronika; Gall, Christine; Haney, Briain; Latzel, Nina; Knieling, Ferdinand; Hilger, Alina; Regensburger, Adrian; Meyer, Alexander; Lang, Werner; Rother, Ulrich (Journal of Clinical Medicine, 2024)
Background: Arterio-venous fistulas (AVF) are used as first-line access for hemodialysis (HD) in the pediatric population. The aim of this investigation was to describe a single-center experience in the creation of AVF, together with its patency in children. Methods: This single-center retrospective study included all patients aged ≤18 years with AVFs created between 1993 and 2023. The collected data included patients’ demographics, hemodialysis history, intraoperative data, and required reinterventions in order to determine the impact of these variables on primary, primary-assisted, and secondary patency. Results: Fifty-seven patients were analyzed with a median age of 15 years (range, 7–18 years). Fifty-four forearm and four upper arm fistulas were performed. The median follow-up was 6.9 years (range, 0–23 years). The primary failure rate was 10.5%. The primary patency rate was 67.6%, 53.6%, 51.4%, and 38.1% after 1, 3, 5, and 10 years; primary-assisted patency was 72.9%, 62.8%, 60.6%, and 41.5%; and secondary patency was 87.3%, 81.3%, 76.8%, and 66.6% after 1, 3, 5, and 10 years in the studied population. Conclusions: AVFs showed an acceptable rate of primary failure and excellent long-term patency. In this context, AVFs are an appropriate option for HD access, especially in pediatric patients.
CRIS-Team Scopus Importer:2024-07-12
Keywords: arterio-venous fistula; children; long term; primary patency; secondary patency

Long-term outcomes of very-low-birth-weight and low-birth-weight preterm newborns with neonatal seizures: A single-center perspective - Schüssler, Stephanie; Schmidt, Martina; Deiters, Ludger; Candova, A.; Fahlbusch, Fabian; Trollmann, Regina (European Journal of Paediatric Neurology, 2022)
Objective: Newborn seizures are frequent in preterm newborns and indicate brain lesions in many cases. The objective of this observational study was to investigate the long-term outcome of very-low-birth-weight (VLBW) and low-birth-weight (LBW) preterm infants with neonatal seizures. Methods: We examined 54 preterm infants (40 VLBW and 14 LBW cases) born between 2008 and 2011 with clinical seizures during the neonatal period confirmed by interictal or ictal electroencephalography recordings in a retrospective single-center study. Neurodevelopmental follow-up included an expert neurological examination and cognitive testing (Kaufman Assessment Battery for Children) at a mean age of six years. Results: The (mean ± standard deviation) gestational ages of the VLBW and LBW infants were 27.2 ± 1.9 weeks and 33.4 ± 1.7 weeks, respectively, and the postnatal age at seizure onset was 13 ± 11 days in VLBW infants and 9 ± 8 days in LBW infants, with a wide range of one to 62 days. LBW infants more frequently developed non-motor seizures (50.0%) than VLBW infants did (25.0%), and higher-grade intracranial hemorrhage was the predominant etiology in the VLBW group (18.0%), while the etiology in the LBW group was more heterogeneous and included central nervous system malformations and genetic syndromes. At the mean age of 6.2 ± 2.0, years, 25/54 patients were assessed and 44.4% of the VLBW group and 71.4% of the LBW group showed intellectual impairment. Infantile cerebral palsy was present in 22% of VLBW and 42.9% of LBW infants, respectively. Significance: The present analysis of long-term neurodevelopmental outcomes of preterm neonates who experienced seizures shows that the risk for intellectual impairment is not limited only to VLBW infants but may significantly affect LBW infants as well. The etiological spectrum differs in relation to gestational age.
CRIS-Team Scopus Importer:2022-01-14
Keywords: Cognitive development; Neonatal EEG; Neurodevelopmental outcome; Preterm; Prognosis

Long-term positive and negative psychosocial outcomes in young childhood cancer survivors, type 1 diabetics and their healthy peers - Kremer, Anna-Lena; Schieber, Katharina; Metzler, Markus; Schuster, Sonja; Erim, Yesim (International Journal of Adolescent Medicine and Health, 2016)
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Long-Term Results after Fallot Repair - Kleinöder, Jonas; Purbojo, Ariawan; Blumauer, Robert; Cuomo, Michela; Alkassar, Muhannad; Dittrich, Sven; Cesnjevar, Robert (Thoracic and Cardiovascular Surgeon, 2022)
Background The aim of this study was to evaluate the long-term outcome and freedom from pulmonary valve replacement (PVR) after initial repair of tetralogy of Fallot (TOF). Patients and Methods The cohort of 306 patients treated between 1980 and 2017 was divided into anatomical subgroups according to the diagnosis of TOF-pulmonary stenosis, TOF-pulmonary atresia and TOF-double outlet right ventricle. Patients were treated with transannular patch (TAP), valve sparing repair (VSR), or conduits from the right ventricle to the pulmonary arteries (RVPA conduits). Results There were 21 deaths (6.9%), 14 being hospital deaths (4.6%) after primary correction and four deaths (1.3%) occurred after PVR. One patient died after a non-cardiac operation (0.3%). There were two late deaths (0.7%). During the past 12 years no early mortality has been observed. Ninety-one patients (30.4%) received PVR after a median of 12.1 +/- 7.0 years with an early mortality of 4.4% ( n = 4) and no late mortality. A significant difference in freedom from reoperation after TAP, VSR, and RVPA-conduits could be identified. Multivariate analysis displayed transannular repair ( p = 0.016), primary palliation ( p <0.001), the presence of major aortopulmonary collateral arteries (MAPCA; p = 0.023), and pulmonary valve Z -scores < - 4.0 ( p = 0.040) as significant risk factors for PVR. Conclusion TOF repair has a beneficial long-term prognosis with low morbidity and mortality. Pulmonary valve Z -scores < - 4.0, transannular repair, and presence of MAPCAs are associated with earlier PVR. Non-VSRs and TOF-pulmonary atresia lead to earlier reoperation but have no negative impact on survival.
CRIS-Team WoS Importer:2022-07-29

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry - Kuemmerle-Deschner, Jasmin B.; Kallinich, Tilmann; Henes, Joerg; Kortus-Götze, Birgit; Oommen, Prasad T.; Rech, Jürgen; Krickau, Tobias; Weller-Heinemann, Frank; Horneff, Gerd; Janda, Aleš; Foeldvari, Ivan; Schuetz, Catharina; et al. (RMD Open, 2024)
Objective Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). Methods From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. Results At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (∼70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. Conclusion Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.
CRIS-Team Scopus Importer:2024-03-01
Keywords: Cryopyrin-Associated Periodic Syndromes; Familial Mediterranean Fever; Inflammation

LONG-TERM SAFETY OF CANAKINUMAB IN PATIENTS WITH AUTOINFLAMMATORY DISEASES - INTERIM ANALYSIS OF THE RELIANCE REGISTRY - Kuemmerle-Deschner, J. B.; Henes, J.; Kortus-Goetze, B.; Kallinich, T.; Oommen, P.; Rech, Jürgen; Krickau, Tobias; Weller-Heinemann, F.; Horneff, G.; Janda, A.; Foeldvari, I.; Schuetz, C.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-term safety of deferiprone treatment in children from the Mediterranean region with beta-thalassemia major: the DEEP-3 multi-center observational safety study - Botzenhardt, Sebastian; Felisi, Mariagrazia; Bonifazi, Donato; Del Vecchio, Giovanni C.; Putti, Maria C.; Kattamis, Antonis; Ceci, Adriana; Wong, Ian C. K.; Neubert, Antje (Haematologica, 2018)
EVALuna2:35838

Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study - Man, Kenneth K.C.; Häge, Alexander; Banaschewski, Tobias; Inglis, Sarah K.; Buitelaar, Jan; Carucci, Sara; Danckaerts, Marina; Dittmann, Ralf W.; Falissard, Bruno; Garas, Peter; Hollis, Chris; Konrad, Kerstin; et al. (The Lancet Psychiatry, 2023)
Background: Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. Methods: We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6–17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). Findings: Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7–11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference –0·07 (95% CI –0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. Interpretation: Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring. Funding: EU Seventh Framework Programme.
CRIS-Team Scopus Importer:2023-04-21

Long-term Surveillance of Children with Congenital Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "Hypo Dok") - Ellerbroek, V. L.; Bonfig, W.; Dörr, Helmuth-Günther; Bettendorf, M.; Hauffa, B.; Fricke-Otto, S.; Rohrer, T.; Reschke, F.; Schoenau, E.; Schwab, K. O.; Kapelari, K.; Roehl, F. -W.; et al. (Klinische Pädiatrie, 2015)
The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines.Anonymised data of 1,080 patients from 46 centres were statistically analysed.Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 µg/kg/day or 186.0 µg/m²/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ-testing. Their average IQ was 98.8 ± 13.2 points.In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care.Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement.
EVALuna2:18917

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma - Lin, Shu Hong; Sampson, Joshua N.; Grünewald, Thomas G.P.; Surdez, Didier; Reynaud, Stephanie; Mirabeau, Olivier; Karlins, Eric; Rubio, Rebeca Alba; Zaidi, Sakina; Grossetête-Lalami, Sandrine; Ballet, Stelly; Lapouble, Eve; et al. (PLoS ONE, 2020)
Background Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10−8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10−8). Conclusions These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
CRIS-Team Scopus Importer:2020-09-18

Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial - Kuhlen, Michaela; Bader, Peter; Sauer, Martin; Albert, Michael H.; Gruhn, Bernd; Gungor, Tayfun; Kropshofer, Gabriele; Lang, Peter; Lawitschka, Anita; Metzler, Markus; Pentek, Falk; Rossig, Claudia; et al. (British Journal of Haematology, 2018)
Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3·73, P = 0·009; >15 years vs. <10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.
EVALuna2:35823

Luminal application of a GATA3-specific DNAzyme ameliorates mucosal inflammation in a randomised trial with active ulcerative colitis patients - Atreya, Raja; Kuehbacher, T.; Schmitt, H.; Hirschmann, S.; Waldner, Maximilian; Drvarov, O.; Fischer, Sven Moritz; Vetter, Marcel; Weigmann, Benno; Turowska, A.; Muhl, T.; Homburg, U.; et al. (2018)
EVALuna2:34074

Lung ultrasound in children, WFUMB review paper (part 2) - Dietrich, Christoph F.; Buda, Natalia; Ciuca, Ioana Mihaiela; Dong, Yi; Fang, Cheng; Feldkamp, Axel; Jüngert, Jörg M.; Kosiak, Wojciech; Mentzel, Hans Joachim; Pienar, Corina; Rabat, Jorge S.; Rafailidis, Vasileios; et al. (Medical Ultrasonography, 2021)
Ultrasound (US) is an ideal diagnostic tool for paediatric patients owning to its high spatial and temporal resolution, realtime imaging, and lack of ionizing radiation and bedside availability. In the current World Federation of Societies for Ultrasound in Medicine and Biology (WFUMB) paper series so far (part I) the topic has been introduced and the technical requirements explained. In the present paper the use of US in the lung in paediatric patients is analysed. Lung diseases including the interstitial syndrome, bacterial pneumonia and viral infections, CoViD findings, atelectasis, lung consolidation, bronchiolitis and congenital diseases of the respiratory system including congenital pulmonary airway malformation (CPAM) and sequester but also pneumothorax are discussed.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Atelectasis; CoViD; Guidelines; Pneumonia; Pneumothorax

Lymphocyte Immune Response and T Cell Differentiation in Fontan Patients with protein-losing enteropathy - Moosmann, Julia; Toka, Okan; Lukassen, Sören; Ekici, Arif Bülent; Mackensen, Andreas; Dittrich, Sven; Völkl, Simon (Thoracic and Cardiovascular Surgeon, Supplement, 2021)
Background Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation. There is increasing discussion about whether lymphatic dysregulation is involved as pathomechanism of PLE. This investigation focuses on the interplay between alteration of lymphatic cells and immunologic pathway alterations. Methods Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients (n = 10 Fontan patients with PLE, n = 30 Fontan patients without PLE, and n = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway analysis was performed to identify significantly enriched pathways. To determine lymphocyte populations and subtypes multiparameter flow cytometry was used. Results miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed networks of which four of the ten largest were associated with immunologic processes. This finding is supported by significant T cell deficiency with decreased CD4+ count (p = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ (p < 0.0001) and CD8+ (p = 0.0002) T cell differentiation toward effector and terminal differentiated T cells in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly increased frequencies of CD4+ CD25+ CD127- regulatory T cells (Treg) in Fontan patients with PLE (p = 0.0011). Conclusion PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency, significant alterations of T cell differentiation, and increased Treg frequency reflecting an immune status of chronic inflammation and shortened protection against pathogens and autoimmunity. These cellular alterations seemed to be dysregulated by several miRNA controlled immunological pathways.
CRIS-Team Scopus Importer:2021-03-05
Keywords: congenital heart disease (CHD); genetics; genomics; inflammation; systemic

Machine Learning-Supported Diagnosis of Small Blue Round Cell Sarcomas Using Targeted RNA Sequencing. - Schlieben, Lea D.; Carta, Maria Giulia; Moskalev, Evgeny; Stöhr, Robert; Metzler, Markus; Besendörfer, Manuel; Meidenbauer, Norbert; Semrau, Sabine; Janka, Rolf Matthias; Grützmann, Robert; Wiemann, Stefan; Hartmann, Arndt; et al. (Journal of Molecular Diagnostics, 2024)
Small blue round cell sarcomas (SBRCSs) are a heterogeneous group of tumors with overlapping morphologic features but markedly varying prognosis. They are characterized by distinct chromosomal alterations, particularly rearrangements leading to gene fusions, whose detection currently represents the most reliable diagnostic marker. Ewing sarcomas are the most common SBRCSs, defined by gene fusions involving EWSR1 and transcription factors of the ETS family, and the most frequent non-EWSR1-rearranged SBRCSs harbor a CIC rearrangement. Unfortunately, currently the identification of CIC::DUX4 translocation events, the most common CIC rearrangement, is challenging. Here, we present a machine-learning approach to support SBRCS diagnosis that relies on gene expression profiles measured via targeted sequencing. The analyses on a curated cohort of 69 soft-tissue tumors showed markedly distinct expression patterns for SBRCS subgroups. A random forest classifier trained on Ewing sarcoma and CIC-rearranged cases predicted probabilities of being CIC-rearranged >0.9 for CIC-rearranged-like sarcomas and <0.6 for other SBRCSs. Testing on a retrospective cohort of 1335 routine diagnostic cases identified 15 candidate CIC-rearranged tumors with a probability >0.75, all of which were supported by expert histopathologic reassessment. Furthermore, the multigene random forest classifier appeared advantageous over using high ETV4 expression alone, previously proposed as a surrogate to identify CIC rearrangement. Taken together, the expression-based classifier can offer valuable support for SBRCS pathologic diagnosis.
EVALuna2:565265

Macrophage‐like Cells Are Responsive to Titania Nanotube Intertube Spacing—An In Vitro Study - Necula, Madalina Georgiana; Mazare, Anca Valentina; Negrescu, Andreea Mariana; Mitran, Valentina; Özkan, Selda; Trusca, Roxana; Park, Jung; Schmuki, Patrik; Cimpean, Anisoara (International Journal of Molecular Sciences, 2022)
With the introduction of a new interdisciplinary field, osteoimmunology, today, it is well acknowledged that biomaterial‐induced inflammation is modulated by immune cells, primarily macrophages, and can be controlled by nanotopographical cues. Recent studies have investigated the effect of surface properties in modulating the immune reaction, and literature data indicate that various surface cues can dictate both the immune response and bone tissue repair. In this context, the purpose of the present study was to investigate the effects of titanium dioxide nanotube (TNT) interspacing on the response of the macrophage‐like cell line RAW 264.7. The cells were maintained in contact with the surfaces of flat titanium (Ti) and anodic TNTs with an intertube spacing of 20 nm (TNT20) and 80 nm (TNT80), under standard or pro‐inflammatory conditions. The results revealed that nanotube interspacing can influence macrophage response in terms of cell survival and proliferation, cellular morphology and polarization, cytokine/chemokine expression, and foreign body reaction. While the nanostructured topography did not tune the macrophages’ differentiation into osteoclasts, this behavior was significantly reduced as compared to flat Ti surface. Overall, this study provides a new insight into how nanotubes’ morphological features, particularly intertube spacing, could affect macrophage behavior.
CRIS-Team Scopus Importer:2022-04-22
Keywords: Cytokines; Inflammation; Intertube spacing; Macrophage; Osteoclastogenesis; TiO2 nanotubes

Malignant epithelioid peripheral nerve sheath tumor with prominent reticular/microcystic pattern in a child: a low-grade neoplasm with 18-years follow-up - Agaimy, Abbas; Stachel, Daniel; Jüngert, Jörg; Radkow, Tanja; Carbon, Roman; Metzler, Markus; Holter, Wolfgang (Applied Immunohistochemistry & Molecular Morphology, 2014)
Malignant peripheral nerve sheath tumors (MPNSTs) constitute <2% of soft tissue neoplasms in children and display a wide histologic spectrum including low-grade and epithelioid variants, although most are high-grade spindle cell sarcomas. Here, we describe an unusual case of a large retroperitoneal epithelioid MPNST diagnosed in a 7-year-old girl without family history or clinical features of neurofibromatosis type 1. The patient was treated by repeated surgical interventions, polychemotherapy, autologous stem cell transplantation, and irradiation therapy. Over the years, she developed multiple disseminated abdominal recurrences but is currently alive with very slowly progressing disseminated intra-abdominal disease 18 years from initial diagnosis. Histologically, the tumor was composed of medium-sized polygonal and ovoid-to-spindled cells set within a copious myxoid matrix with a prominent reticular and microcystic pattern reminiscent of the recently described reticular/microcystic schwannoma. Immunohistochemistry revealed strong and diffuse expression of S100, CD56, CD57, collagen IV, and neuron-specific enolase, with negativity for perineurial cell markers (claudin-1, epithelial membrane antigen, and glucose transporter-1) and other lineage-specific mesenchymal and epithelial antigens. This unusual variant of low-grade MPNST must be differentiated from a variety of other entities, in particular benign perineurioma, myxoid neurofibroma, and benign reticular/microcystic schwannoma. Confinement of the recurrent disease to the abdominal cavity emphasizes the necessity of primary curative wide excision of this highly recurring but nonmetastasizing low-grade neoplasm.
EVALuna2:6527

Malignant teratoid tumor of the thyroid gland: an aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations—is the term “thyroblastoma” more appropriate? - Agaimy, Abbas; Witkowski, Leora; Stöhr, Robert; Cuenca, Joseph Christopher Castillo; González-Muller, Carlos Alberto; Brütting, Alfred; Bährle, Markus; Mantsopoulos, Konstantinos; Amin, Randa M.S.; Hartmann, Arndt; Metzler, Markus; Amr, Samir S.; et al. (Virchows Archiv, 2020)
Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known “hotspot” pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that “blastoma” is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term “thyroblastoma” might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.
CRIS-Team Scopus Importer:2020-06-16
Keywords: DICER1; Germ cell tumor; Head and neck; Malignant teratoma; Rhabdomyosarcoma; Teratocarcinosarcoma; Thyroblastoma; Thyroid

Management of children and adolescents with chronic myeloid leukemia in blast phase: International pediatric CML expert panel recommendations - Sembill, Stephanie; Ampatzidou, Maria; Chaudhury, Sonali; Dworzak, Michael; Kalwak, Krzysztof; Karow, Axel; Kiani, Alexander; Krumbholz, Manuela; Luesink, Maaike; Naumann-Bartsch, Nora; De Moerloose, Barbara; Osborn, Michael; et al. (Leukemia, 2023)
Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.
CRIS-Team WoS Importer:2023-02-24

Management of children and adolescents with chronic myeloid leukemia in chronic phase: International pediatric chronic myeloid leukemia expert panel recommendations: CHRONIC MYELOGENOUS LEUKEMIA - Millot, Frédéric; Ampatzidou, Mirella; Moulik, Nirmalya Roy; Tewari, Sanjay; Elhaddad, Alaa; Hammad, Mahmoud; Pichler, Herbert; Lion, Thomas; Tragiannidis, Athanasios; Shima, Haruko; An, Wenbin; Yang, Wenyu; et al. (Leukemia, 2025)
The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis. The treatment recommendations are based on the initiation of therapy with a first- or second-generation TKI according to the allocated European Treatment and Outcome Study (EUTOS) long-term survival score risk group of the patient. The subsequent steps are based on the results of recommended monitoring which can justify a switch to another TKI or a drug in development if there is resistance or toxicity. The panel also provides recommendations regarding the discontinuation criteria for TKIs in children and adolescents in sustained deep molecular response. Allogeneic HSCT is not recommended as the first-line of treatment for children with CML-CP but is to be considered in case of progression to the advanced phase or failure of several lines of treatment. The present treatment and management recommendations are intended to provide advice to clinicians in view of optimizing the care and the outcome of children and adolescents with CML-CP.
CRIS-Team Scopus Importer:2025-03-21

Management von Patienten mit Tracheostoma während der COVID-19-Pandemie: Literaturüberblick und Demonstration - Kempfle, J. S.; Löwenheim, H.; Hübner, Matthias; Iro, Heinrich; Müller, Sarina Katrin (HNO, 2020)
Background: Since emergence of the new coronavirus in China in December 2019, many countries have been struggling to control skyrocketing numbers of infections, including among healthcare personnel. It has now been clearly demonstrated that SARS-CoV‑2 resides in the upper airways and transmits easily via aerosols and droplets, which significantly increases the risk of infection when performing upper airway procedures. Ventilated COVID-19 patients in a critical condition in the intensive care unit may require tracheotomy for long-term ventilation and to improve weaning. However, the risk of secondary infection of medical personnel performing subsequent tracheostomy care remains unclear. Objective: This study aimed to evaluate the risk of droplet dispersion during tracheostomy tube change and overview tracheostomy tube change in COVID-19 patients. Materials and methods: The current literature was reviewed, quantitative and qualitative analyses of droplet formation during tracheostomy tube change in n = 8 patients were performed, and an overview of and checklist for tracheostomy tube change were compiled. Results: This study demonstrates that tracheostomy tube change, in particular insertion of the new tube, may cause significant droplet formation. The aerosolization of particles smaller than 5 µm was not analyzed. Conclusion: Our data, together with the current literature, clearly emphasize that tracheostomy care is associated with a high infection risk and should only be performed by a small group of well-trained, maximally protected healthcare personnel.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Aerosols; COVID-19; Droplets; PPE; Tracheostomy tube change

Manipulation of medicinal products for oral administration to paediatric patients at a german university hospital: An observational study - Zahn, Julia; Hörning, André; Trollmann, Regina; Rascher, Wolfgang; Neubert, Antje (Pharmaceutics, 2020)
Pharmacotherapy in children requires medicinal products in age-appropriate dosage forms and flexible dose strengths. Healthcare professionals often encounter a lack of licensed and commercially available formulations, which results in the need for manipulation. This study aimed to investigate the nature, frequency and preventability of the manipulation of medicinal products before oral drug administration to paediatric inpatients in Germany. A prospective, direct observational approach was used. Two thousand and three medication preparation processes (MPP) in 193 patients were included in the analysis. Medicines were manipulated in 37% of oral administrations, affecting 57% of the patients. The percentage of manipulations was highest in infants/toddlers (42%) and lowest in adolescents (31%). Antiepileptics were most frequently manipulated (27%), followed by vitamins (20%) and drugs for acid-related disorders (13%). Fifty-six per cent of all manipulations were off-label. In 71% of these, no alternative appropriate medicinal product was commercially available. These results demonstrate that the manipulation of medicinal products before oral administration is common in paediatric wards in Germany. About half of the manipulations were off-label, indicating that no suitable formulation was available. Evidence-based guidelines for manipulations are required, with the overall aim of improving the safety of paediatric drug therapy.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Age-appropriate formulation; Drug manipulation; Hospital; Off-label use/manipulation; Oral drug administration; Paediatrics

Manufacturer switch of anti-seizure drugs may not increase the risk of seizure recurrence in Children: A nationwide study of prescription data in Germany - Lang, Johannes; Kostev, Karel; Reindl, Caroline; Müller, Tamara; Stritzelberger, Jenny; Gollwitzer, Stephanie; Westermayer, Vivien; Trollmann, Regina; Hamer, Hajo (Epilepsy & Behavior, 2021)
Objective: Several publications on the exchangeability of antiepileptic drugs in clinical settings revealed an increased risk for seizure recurrence after changing the manufacturer of anti-seizure drugs (ASD) in adults, possibly due to a decline of adherence. It is unclear whether this holds true in children and adolescents. Methods: Patient data of children and adolescents (<18 years) were collected anonymously from 236 German pediatricians and pediatric neurologists between January 2011 and December 2018 using the IMS® Disease Analyzer database (IQVIA, Frankfurt, Germany). Patients with epilepsy were included if at least 2 prescriptions within 360 days and 1 within 180 days prior to the index date were available. The cohort was separated into a seizure group and seizure-free controls. Both groups were matched 1:1 according to age, gender, insurance status, and treating pediatrician. The risk for seizure recurrence after a manufacturer switch of the same ASD at the last prescription before the index date was analyzed using a multivariate regression model. Results: A total of 678 children and adolescents with epilepsy were included (each group: n = 339; age: 9.6 ± 4.4 years). Comparing both groups, the risk for seizures recurrence was not increased after a manufacturer switch had occurred. Albeit changes during the last prescription before the index date had occurred more often in the seizure-free group, neither change of branded and generic products nor substances reached significance. Only change of ASD strength showed a significantly reduced odds ratio for seizures (OR 0.40, 95% CI 0.24–0.65, p < 0.001). Significance: In contrast to the available evidence in adults, changing the manufacturer did not appear to increase the risk for seizure recurrence in previously seizure-free children and adolescents with epilepsy.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Anti-seizure drugs; Manufacturer changes; Relapse seizures

MAP2K1-MUTATED ECD/RDD-OVERLAP NON-LANGERHANS CELL HISTIOCYTOSIS RESPONDING TO COBIMETINIB - Classen, Carl Friedrich; Leyh, Jörg; Rümmele, Petra; Rosenwald, Andreas; Metzler, Markus (PEDIATRIC BLOOD & CANCER, 2021)
CRIS-Team WoS Importer:2020-12-18

MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and golgi architecture as a central mechanism in growth regulation - Zahnleiter, Diana; Hauer, Nadine; Keßler, Kristin; Uebe, Steffen; Sugano, Yuya; Neuhauss, Stephan C. F.; Gießl, Andreas; Ekici, Arif Bülent; Blessing, Holger; Sticht, Heinrich; Dörr, Helmuth-Günther; Reis, André; et al. (Human Mutation, 2015)
Numerous genes are involved in human growth regulation. Recently, autosomal-recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly, or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly, we used homozygosity mapping and next-generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High-expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule-dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary, and Golgi regulation associated with severe short stature.
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Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy - Kriegsmann, Mark; Casadonte, Rita; Maurer, Nadine; Stoehr, Christine; Erlmeier, Franziska; Moch, Holger; Junker, Klaus; Zgorzelski, Christiane; Weichert, Wilko; Schwamborn, Kristina; Deininger, Soeren-Oliver; Gaida, Matthias; et al. (Journal of Cancer, 2020)
Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge.
CRIS-Team WoS Importer:2020-09-11

Maternal SARS-CoV-2 infection during pregnancy: possible impact on the infant - Morhart, Patrick; Mardin, Christian; Rauh, Manfred; Juengert, Joerg; Hammersen, Johanna; Kehl, Sven; Schuh, Wolfgang; Maier-Wohlfart, Sigrun; Hermes, Katharina; Neubert, Antje; Schneider, Michael; Hein, Alexander; et al. (European Journal of Pediatrics, 2021)
The risk and potential consequences of mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy are still a matter of debate. We studied the impact of SARS-CoV-2 infection on 56 complete households, including 27 newborns whose mothers were pregnant when exposed to the virus. Two PCR-confirmed perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded. In addition, we observed a severe eye malformation (unilateral microphthalmia, optic nerve hypoplasia, and congenital retinopathy) associated with maternal SARS-CoV-2 infection in weeks 5 and 6 of embryonic development. This embryopathy could not be explained by other infectious agents, genetic factors, drug use, or maternal disease during pregnancy. Eight other women with a history of SARS-CoV-2 infection prior to gestational week 12, however, delivered healthy infants. Conclusion: The repeated occurrence of mother-to-child transmission in our cohort with risks that remain incompletely understood, such as long-term effects and the possibility of an embryopathy, should sensitize researchers and stimulate further studies as well as support COVID-19 vaccination recommendations for pregnant women. Trial registration number: NCT04741412. Date of registration: November 18, 2020What is Known:•Materno-fetal transmission of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) during pregnancy has rarely been reported so far, but was demonstrated in isolated cases.What is New:•In a study of complete households with documented SARS-CoV-2 infection, including a cohort of pregnant women, we observed perinatal coronavirus transmission at a higher frequency than expected.•We also describe a newborn boy with an eye malformation reminiscent of rubella embryopathy but associated with early gestation SARS-CoV-2 infection of his mother.•A coronavirus-related embryopathy, reported here for the first time, is a finding that requires further investigation.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Case report; Coronavirus; Embryopathy; Malformation; Materno-fetal transmission

Measurement of amniotic fluid steroids of midgestation via LC-MS/MS - Fahlbusch, Fabian B.; Heussner, Kirsten; Schmid, Matthias; Schild, Ralf; Rübner, Matthias; Hübner, Hanna; Rascher, Wolfgang; Dörr, Helmuth-Günther; Rauh, Manfred (Journal of Steroid Biochemistry and Molecular Biology, 2015)
Analysis of steroids by mass spectrometry (MS) has evolved into a reliable tool for the simultaneous detection of multiple steroids. As amniotic fluid (AF) and fetal serum composition of early pregnancy are closely related, the analysis of AF can yield information on the physiological status of the developing fetus. We evaluated the use of liquid-chromatography tandem mass spectrometry (LC-MS/MS) for AF steroid analysis, including the analysis of its sensitivity and accuracy for gender verification in healthy subjects.AF of 78 male and 94 female healthy newborns was analyzed by LC-MS/MS at 16 weeks of gestation. The levels of androstenedione, corticosterone, cortisol, cortisone, deoxycorticosterone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), 17-hydroxyprogesterone, progesterone (17-OHP) and testosterone were measured. Steroid levels were compared to RIA and GC-MS levels of midgestation from the literature. Cross-validated logistic regression was used to obtain statistical predictions of gender at birth from testosterone and the above steroids.LC-MS/MS analysis of AF steroids yielded comparable results with published GC-MS data. Gender specific differences were found for androstenedione and testosterone concentrations with higher levels in the male fetus. In contrast to published RIA data no gender specific differences were observed for 17-hydroxyprogesterone and dehydroepiandrosterone AF concentrations. Testosterone concentrations yielded highly accurate predictions for male gender at birth. Additional analysis of further steroids did neither increase the accuracy, sensitivity nor specificity of this prediction. The estimated optimal cut-off value for amniotic testosterone level was 0.074 ?g/L for healthy male newborns.LC-MS/MS is a reliable method for the determination of steroids in amniotic fluid. The determination of testosterone in amniotic fluid by LC-MS/MS in early pregnancy of healthy subjects can be used to offer a reliable prediction of fetal gender at birth.
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MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia - Germeshausen, Manuela; Ancliff, Phil; Estrada, Jaime; Metzler, Markus; Ponstingl, Eva; Ruetschle, Horst; Schwabe, Dirk; Scott, Richard H.; Unal, Sule; Wawer, Angela; Zeller, Bernward; Ballmaier, Matthias (Blood Advances, 2018)
Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.
EVALuna2:35827

Medical care of adults with congenital heart diseases : Present and future - Neidenbach, R.; Achenbach, Stephan; Andonian, C.; Beckmann, J.; Biber, S.; Dittrich, Sven; Ewert, P.; Freilinger, S.; Huntgeburth, M.; Nagdyman, N.; Oberhoffer, R.; Pieper, L.; et al. (Herz, 2019)
Congenital heart diseases (CHD) are the most common types of congenital organ defects. Thanks to medical progress in congenital cardiology and heart surgery, most children with CHD reach adulthood. Despite primarily successful treatment residual and subsequent conditions as well as (non)cardiac comorbidities can influence the chronic course of the disease and lead to a higher morbidity and mortality. Adults with congenital heart disease (ACHD) in Germany are not tied to the healthcare structure despite the great need for aftercare. According to the results of the medical care of ACHD (MC-ACHD) study, ACHD centers and specialists in Germany are insufficiently perceived despite increased complication rates and the great need for specialist guidance. General practitioners and patients are not adequately informed about existing ACHD facilities. A better awareness of the ACHD problem should be created at the level of primary medical supply in order to optimize care and to reduce morbidity and mortality. Improved future-oriented patient care includes lifelong regular follow-up and the possibility of interdisciplinary, integrated medical care of CHD.
EVALuna2:212989

Medication safety in children : What role do dosing and formulations play? - Neubert, Antje; Rascher, Wolfgang (Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz, 2018)
Medication errors are more common in children compared to adults due to often missing efficacy evidence and limited or missing regulatory approvals for paediatric drugs.Roots of errors are located at different levels. They result, for example, from missing clinical studies that particularly investigate efficacy and correct dosing in younger age groups, the lack of age-appropriate dosage forms, the use of harmful ingredients, as well as the complicated and high-risk prescribing process.Electronic systems may improve the quality of drug prescriptions and reduce medication errors. The basic assumption is valid, evidence-based data behind such a system. In contrast to other countries, such a database is not yet available in Germany. The Plan of Action for the improvement of medication safety in Germany 2016-2019 (Aktionsplan) contains an action point "Creation of a database for dosing of paediatric medicines". Initial funding for 2 years has been granted for its implementation.Through systematic literature searches and the availability and provision of up-to-date knowledge on paediatric medicines, medication safety for children and adolescents can be improved. A database with relevant information to support more correct prescriptions within the paediatric population appears productive. The Aktionsplan has paved the way for the dissemination of evidence-based drug information for the country's paediatric population.
EVALuna2:35727

Medication safety with oral antitumour therapeutics in paediatrics (youngAMBORA): A mixed-methods approach towards a tailored care program. - Lensker, Phyllis; Cuba, Lisa; Geßner, Katja; Fromm, Martin; Dörje, Frank; Metzler, Markus (PLoS ONE, 2024)
OBJECTIVE: Oral antitumour therapeutics (OAT) are increasingly used due to improvements in outcomes and their convenient application. However, complex intake regimens pose several challenges. The randomised AMBORA trial (Medication Safety With Oral Antitumour Drugs) demonstrated highly positive outcomes of a clinical pharmacological/pharmaceutical care program for adults treated with numerous OAT, but comparable concepts in paediatrics are lacking so far. METHODS: We used a parallel mixed-methods approach to develop a tailored pharmacological/pharmaceutical care program for OAT in paediatrics (youngAMBORA). We combined a quantitative analysis of tumour entities and used OAT in a paediatric cancer centre with a qualitative survey for patients, caregivers, and healthcare professionals to identify particular demands and educational needs (e.g., application problems, side effects). RESULTS: Leukaemia (77/315) and antimetabolites (95/151) were the most frequently observed entity and OAT, respectively. Of 22 surveyed patients, 81.8% wanted to be involved in oral medication education. Compared to caregivers, significantly more healthcare professionals graded the three most common application problems to be challenging ('Smell/taste': 32/36 vs. 23/42, p = 0.001; 'Refusal of intake': 31/36 vs. 16/42, p<0.001; 'Swallowing problems': 28/36 vs. 21/42, p = 0.011). We identified nine relevant side effects, of which two ('Skin dryness', 'Taste changes') were not included in 15 previously published core side effects of the Common Terminology Criteria of Adverse Events (CTCAE) item library. CONCLUSION: Based on the present findings, the tailored youngAMBORA care program will include: 1) counselling sessions for classic and targeted OAT, 2) child-friendly support with drug application, and 3) systematic evaluation of 17 relevant side effects from patients' and caregivers' points of view including age-appropriate information material.
EVALuna2:583325

Medikamentenpriming am Beispiel der Therapie der Aufmerksamkeits-Defizit-Hyperaktivitäts-Störung (ADHS) - Rascher, Wolfgang (Drug Research, 2018)
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Medizinische Versorgung von Erwachsenen mit angeborenen Herzfehlern: Gegenwart und Zukunft - Neidenbach, R.; Achenbach, Stephan; Andonian, C.; Beckmann, J.; Biber, S.; Dittrich, Sven; Ewert, P.; Freilinger, S.; Huntgeburth, M.; Nagdyman, N.; Oberhoffer, R.; Pieper, L.; et al. (Herz, 2019)
Congenital heart diseases (CHD) are the most common types of congenital organ defects. Thanks to medical progress in congenital cardiology and heart surgery, most children with CHD reach adulthood. Despite primarily successful treatment residual and subsequent conditions as well as (non)cardiac comorbidities can influence the chronic course of the disease and lead to a higher morbidity and mortality. Adults with congenital heart disease (ACHD) in Germany are not tied to the healthcare structure despite the great need for aftercare. According to the results of the medical care of ACHD (MC-ACHD) study, ACHD centers and specialists in Germany are insufficiently perceived despite increased complication rates and the great need for specialist guidance. General practitioners and patients are not adequately informed about existing ACHD facilities. A better awareness of the ACHD problem should be created at the level of primary medical supply in order to optimize care and to reduce morbidity and mortality. Improved future-oriented patient care includes lifelong regular follow-up and the possibility of interdisciplinary, integrated medical care of CHD.
CRIS-Team Scopus Importer:2019-08-06
Keywords: ACHD; Cardiology; Comorbidities; Congenital heart defects; Prevention

Medizin, Moral und Gefühl. Emotionen im ethischen Diskurs - Frewer, Andreas; Rascher, Wolfgang; Bruns, Florian (Königshausen & Neumann, 2012)

Mehr Sicherheit bei der Arzneimitteltherapie von Kindern und Jugendlichen: Das Kinderformularium.DE als Referenzwerk fur padiatrische Arzneimittelinformationen - Haering-Zahn, Julia; Gramlich, Ursula; Ahne, Gabriele; Rascher, Wolfgang; Neubert, Antje (Krankenhauspharmazie, 2023)
Children are at a disadvantage compared to adults when it comes to drug therapy. In the paediatric inpatient sector, up to 90 % of all medicines are being used offlabel, i. e. outside of the scope of the license. This results in a special need for scientifically sound information in order to be able to carry out rational pharmacotherapy according to the current scientific knowledge. Kinderformularium.DE is a web-based platform with evidence-based information for drug therapy in children and adolescents. The core of the database are monographs of active substances with dosing recommendations for the on- and off-label therapy. Additional information is provided, i a., on commercial formulations suitable for children, the licensing status and other child-specific information relevant for safe drug therapy. The content addresses medical and pharmaceutical professionals and is free of charge. The information provided on the platform is independent of industry and is maintained by a project team at the Department of Paediatrics and Adolescent Medicine of the University Hospital Erlangen, Germany. The platform is a result of the "Action Plan to Improve Medication Safety in Germany" (Aktionsplan zur Verbesserung der Arzneimitteltherapiesicherheit in Deutschland) of the Federal Ministry of Health (funding period: 2016 to 2022). Through international cooperation with the Netherlands, Austria and Norway, synergies are used to develop paediatric dosing recommendations based on the best available evidence and to harmonise them internationally. Results of a user survey and continually increasing user numbers demonstrate the relevance of the database in healthcare practice. Kinderformularium.DE aims to improve long-term medication safety in children of all ages by providing scientifically sound, practically applicable information.
CRIS-Team Scopus Importer:2023-08-18
Keywords: evidence-based drug therapy; medication safety; Paediatrics

Membranous septum length as predictor for permanent pacemaker implantation after TAVI - Jung, Susan; Ammon, Fabian; Smolka, Silvia; Moshage, Maximilian; Marwan, Mohamed; Achenbach, Susanne (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

Memorandum on the use of information technology to improve medication safety - Ammenwerth, E.; Aly, A. -F.; Bürkle, Thomas; Christ, P.; Dormann, H.; Friesdorf, W.; Haas, C.; Haefeli, W. E.; Jeske, M.; Kaltschmidt, J.; Menges, K.; Moeller, H.; et al. (Methods of Information in Medicine, 2014)
Information technology in health care has a clear potential to improve the quality and efficiency of health care, especially in the area of medication processes. On the other hand, existing studies show possible adverse effects on patient safety when IT for medication-related processes is developed, introduced or used inappropriately.To summarize definitions and observations on IT usage in pharmacotherapy and to derive recommendations and future research priorities for decision makers and domain experts.This memorandum was developed in a consensus-based iterative process that included workshops and e-mail discussions among 21 experts coordinated by the Drug Information Systems Working Group of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS).The recommendations address, among other things, a stepwise and comprehensive strategy for IT usage in medication processes, the integration of contextual information for alert generation, the involvement of patients, the semantic integration of information resources, usability and adaptability of IT solutions, and the need for their continuous evaluation.Information technology can help to improve medication safety. However, challenges remain regarding access to information, quality of information, and measurable benefits.
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Memorandum on the use of information technology to improve medication safety (Memorandum AMTS-IT) Zum Einsatz von Informationstechnologie zur verbesserung der Arzneimitteltherapiesicherheit (Memorandum amts-it) - Aly, Amin Farid; Bürkle, Thomas; Christ, Petra; Dormann, Harald; Friesdorf, Wolfgang; Haas, Christine; Haefeli, Walter E.; Jeske, Martina; Kaltschmidt, Jens; Menges, Klaus; Möller, Horst; Neubert, Antje; et al. (Deutsche Gesellschaft fur Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS), 2014)
Information technology in health care has a clear potential to improve quality and efficiency of health care, especially in the area of medication processes. On the other side, existing studies show possible adverse effects on patient safety when IT for medication-related processes is developed, introduced or used inappropriately. The objective of this paper is to summarize definitions and observations on IT usage in pharmacotherapy, and to derive recommendations and future research priorities for decision makers and domain experts. The recommendations address, among others, a stepwise and comprehensive strategy for IT usage in medication processes, the integration of contextual information for alert generation, the involvement of patients, the semantic integration of information resources, usability and adaptability of IT solutions and the need for their continuous evaluation.
CRIS-Team Scopus Importer:2025-02-03
Keywords: Decision support systems; Drug therapy safety; Information technology; Medication safety; Medication safety; Patient safety

Metabolic and molecular imaging in inflammatory arthritis - Noversa de Sousa, Rita; Tascilar, Koray; Corte, Giulia; Atzinger, Armin; Minopoulou, Ioanna; Ohrndorf, Sarah; Waldner, Maximilian; Schmidkonz, Christian; Kuwert, Torsten; Knieling, Ferdinand; Kleyer, Arnd; Ramming, Andreas; et al. (RMD Open, 2024)
It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively. Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation. Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.
CRIS-Team Scopus Importer:2024-02-23

Metabolic control during the first two years of the COVID-19 pandemic in pediatric patients with type 1 diabetes: results from the German DPV initiative - Hammersen, Johanna; Tittel, Sascha R.; Khodaverdi, Semik; Reschke, Felix; Flury, Monika; Menzel, Ulrike; Mönkemöller, Kirsten; Meissner, Thomas; Karges, Beate; Holl, Reinhard W. (Acta Diabetologica, 2023)
Aim: To assess effects of the SARS-CoV2 pandemic on metabolic control in youth with type 1 diabetes (T1D) in Germany in a population-based analysis. Methods: Data from 33,372 pediatric T1D patients from the Diabetes Prospective Follow-up (DPV) registry, with face-to-face visits or telemedicine contacts in the years 2019–2021, were available. Datasets from eight time periods between March 15, 2020, and December 31, 2021, according to SARS-CoV2 incidence waves, were compared to those from five control time periods. Parameters of metabolic control were assessed with adjustment for sex, age, diabetes duration, and repeated measurements. Laboratory-measured HbA1c values and those estimated from CGM were aggregated into a combined glucose indicator (CGI). Results: There was no clinically relevant difference in metabolic control between pandemic and control time periods with adjusted CGI values ranging from 7.61% [7.60–7.63] (mean [95% confidence interval (CI)]) in the third quarter of 2019 to 7.83% [7.82–7.85] in the time period from January 1 to March 15 2020, in the other control periods, and during the pandemic, CGI values lay between these values. BMI-SDS rose during the pandemic from 0.29 [0.28–0.30] (mean [95% CI]) in the third quarter of 2019 to 0.40 [0.39–0.41] during the fourth wave. Adjusted insulin dose rose during the pandemic. Event rates for hypoglycemic coma and diabetic ketoacidosis remained unchanged. Conclusions: We found no clinically relevant change of glycemic control or incidence of acute diabetes complications during the pandemic. The observed BMI increase may represent an important health risk for youth with T1D.
CRIS-Team Scopus Importer:2023-03-17
Keywords: Lockdown; Metabolic control; Pediatric diabetes; SARS-CoV2 pandemic

Metabolic control during the SARS-CoV-2 lockdown in a large German cohort of pediatric patients with type 1 diabetes: Results from the DPV initiative - Hammersen, Johanna; Reschke, Felix; Tittel, Sascha R.; Pappa, Angeliki; Dost, Axel; Köstner, Katharina; Rosenbauer, Joachim; Kapellen, Thomas M.; Rohrer, Tilman R.; Holl, Reinhard W. (Pediatric Diabetes, 2022)
Objective: To assess if metabolic control worsened during the SARS-CoV2 lockdown in spring 2020 in youth with type 1 diabetes (T1D) in Germany. Methods: Data from 19,729 pediatric T1D patients from the diabetes prospective follow-up (DPV) registry were available. Data sets from four time-periods between January 1 and June 30, 2020, were compared with data from the whole year 2019 in the same patient; differences were adjusted for seasonality, increasing age, and longer diabetes duration. HbA1c values from laboratory measurements and estimates derived from continuous glucose monitoring (CGM) were aggregated into a combined glucose indicator (CGI), expressed in analogy to HbA1c. Results: Based on regression models adjusted for differences of sex, age, diabetes duration, and migratory background between the four time-periods, CGI values in 2020 were slightly higher than in 2019, for example, by 0.044% (0.042–0.046) (median [95% CI]) in the second lockdown month, time-period 3. Insulin dose and BMI-SDS were also marginally higher. In 2020, there were fewer hospitalizations (e.g., incidence risk ratio in time-period 3 compared with 2019: 0.52 [95% CI: 0.46–0.58]). In a subgroup of patients reporting CGM data in both years, metrics in 2020 improved: time in target increased, and mean sensor glucose fell, for example, by 2.8% (2.7–2.9), and by 4.4 mg/dl (4.3–4.6) in time-period 3. Conclusion: Before, during, and after the lockdown in spring 2020, metabolic control in youth with T1D in Germany did not differ significantly from the preceding year. Further effects of the ongoing pandemic on pediatric T1D patients need to be evaluated.
CRIS-Team Scopus Importer:2022-02-25
Keywords: children; diabetes management; glycemic control; quarantine; SARS-CoV-2 pandemic; school closures

Metamizole Use in Children: Analysis of Drug Utilisation and Adverse Drug Reactions at a German University Hospital between 2015 and 2020 - Zahn, Julia; Eberl, Sonja; Rödle, Wolfgang; Rascher, Wolfgang; Neubert, Antje; Toni, Irmgard (Paediatric Drugs, 2021)
Background: Metamizole use is controversially discussed due to its potentially serious adverse drug reactions (ADRs). In Germany, however, it remains a popular analgesic and antipyretic drug. Objective: The aim of this study was to discuss the safety profile of metamizole in children by analysing the inpatient prescription patterns and presenting the metamizole-related ADRs at a paediatric hospital between 2015 and 2020. Methods: Metamizole utilisation data were retrospectively analysed from electronic medical records. ADRs were prospectively recorded via the hospital’s stimulated reporting system and analysed accordingly. Patients aged < 18 years admitted to one of the general wards of the department of paediatrics and adolescent medicine of a German university hospital between June 2015 and May 2020 who received at least one drug therapy within their inpatient stay were included in the analysis. Causality of ADRs was rated according to the World Health Organisation causality assessment. Results: In 31.7% (3759/11,857) of the inpatient stays of 7809 patients, metamizole was administered. Metamizole exposure was highest in adolescents (37.9%) and lowest in newborns (9.9%). Overall, metamizole was administered parenterally in about 90%. Three cases of agranulocytosis, one allergic shock and one rash with possible or higher causality to metamizole treatment were reported. Three of these occurred prior to hospitalisation. All patients recovered without remaining harm. Discussion: Metamizole is commonly used in paediatric inpatients in Germany. Serious ADRs occur but rarely. Continuous monitoring of drug therapy through, for example, stimulated reporting systems ensures that serious ADRs are detected, and appropriate interventions can be introduced.
CRIS-Team Scopus Importer:2021-12-17

Methods for the Administration of EDAR Pathway Modulators in Mice - Schuepbach-Mallepell, Sonia; Kowalczyk-Quintas, Christine; Dick, Angela; Eslami, Mahya; Vigolo, Michele; Headon, Denis J.; Cheeseman, Michael; Schneider, Holm; Schneider, Pascal (The TNF Superfamily, 2021)
Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia, a congenital condition characterized by the absence or abnormal formation of sweat glands, teeth, and several skin appendages. Stimulation of the EDA receptor (EDAR) with agonists in the form of recombinant EDA or anti-EDAR antibodies can compensate for the absence of Eda in a mouse model of Eda deficiency, provided that agonists are administered in a timely manner during fetal development. Here we provide detailed protocols for the administration of EDAR agonists or antagonists, or other proteins, by the intravenous, intraperitoneal, and intra-amniotic routes as well as protocols to collect blood, to visualize sweat gland function, and to prepare skulls in mice.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Amniotic fluid; Ectodermal dysplasia; EDAR signaling; Protein replacement therapy; Route of administration

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study - Häge, Alexander; Man, Kenneth K.C.; Inglis, Sarah K.; Buitelaar, Jan; Carucci, Sara; Danckaerts, Marina; Dittmann, Ralf W.; Falissard, Bruno; Garas, Peter; Hollis, Chris; Konrad, Kerstin; Kovshoff, Hanna; et al. (Journal of Attention Disorders, 2024)
Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children’s-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don’t suggest significant negative long-term effects of MPH on sleep.
CRIS-Team Scopus Importer:2024-03-15
Keywords: ADHD; long-term safety; methylphenidate; pharmacovigilance; sleep problems

Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system - Man, K. K. C.; Coghill, D.; Chan, E. W.; Lau, W. C. Y.; Hollis, Chris; Liddle, Elizabeth; Banaschewski, T.; Mccarthy, S.; Neubert, Antje; Sayal, Kapil; Ip, P.; Wong, I. C. K. (Translational Psychiatry, 2016)
Previous studies have suggested that risk of psychotic events may be increased in children exposed to methylphenidate (MPH). However, this risk has not been fully examined, and the possibility of confounding factors has not been excluded. Patients aged 6-19 years who received at least one MPH prescription were identified using Hong Kong population-based electronic medical records on the Clinical Data Analysis and Reporting System (2001-2014). Using the self-controlled case series design, relative incidence of psychotic events was calculated comparing periods when patients were exposed to MPH with non-exposed periods. Of 20,586 patients prescribed MPH, 103 had an incident psychotic event; 72 (69.9%) were male and 31 (30.1%) female. The mean age at commencement of observation was 6.95 years and the mean follow-up per participant was 10.16 years. On average, each participant was exposed to MPH for 2.17 years. The overall incidence of psychotic events during the MPH exposure period was 6.14 per 10,000 patient-years. No increased risk was found during MPH-exposed compared with non-exposed periods (incidence rate ratio (IRR) 1.02 (0.53-1.97)). However, an increased risk was found during the pre-exposure period (IRR 4.64 (2.17-9.92)). Results were consistent across all sensitivity analyses. This study does not support the hypothesis that MPH increases risk of incident psychotic events. It does indicate an increased risk of psychotic events before the first prescription of MPH, which may be because of an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment.
EVALuna2:34011

Microbiota-Derived Propionate Modulates Megakaryopoiesis and Platelet Function - Dürholz, Kerstin; Schmid, Eva; Frech, Michael; Azizov, Vugar; Otterbein, Nadine; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (Frontiers in Immunology, 2022)
Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular events driven by abnormal platelet clotting effects. Platelets are produced by megakaryocytes, deriving from megakaryocyte erythrocyte progenitors (MEP) in the bone marrow. Increased megakaryocyte expansion across common autoimmune diseases was shown for RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS). In this context, we evaluated the role of the microbial-derived short chain fatty acid (SCFA) propionate on hematopoietic progenitors in the collagen induced inflammatory arthritis model (CIA) as we recently showed attenuating effects of preventive propionate treatment on CIA severity. In vivo, propionate treatment starting 21 days post immunization (dpi) reduced the frequency of MEPs in the bone marrow of CIA and naïve mice. Megakaryocytes numbers were reduced but increased the expression of the maturation marker CD61. Consistent with this, functional analysis of platelets showed an upregulated reactivity state following propionate-treatment. This was confirmed by elevated histone 3 acetylation and propionylation as well as by RNAseq analysis in Meg-01 cells. Taken together, we identified a novel nutritional axis that skews platelet formation and function.
CRIS-Team Scopus Importer:2022-08-05
Keywords: hematopoietic progenitors; megakaryocytes; microbiota; platelets; rheumatoid arthritis; short-chain fatty acids

Microbiota-derived propionate modulates megakaryopoiesis and platelet function - Schmid, Erik; Dürholz, Kerstin; Frech, Michael; Otterbein, N.; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Microplegia in paediatric hearts - Münch, Frank; Kwapil, Nicola; Teske, Andreas; Rueffer, Andre; Dittrich, Sven; Volk, Tilmann; Purbojo, Ariawan (Perfusion-Uk, 2022)
Introduction A basic prerequisite for a good surgical outcome in heart surgery is optimal myocardial protection. However, cardioplegia strategies used in adult cardiac surgery are not directly transferable to infant hearts. Paediatric microplegia, analogous to Calafiore cardioplegia used in adult cardiac surgery, offers the advantage of safe myocardial protection without haemodilution. The use of concentration-dependent paediatric microplegia is new in clinical implementation. Material and methods Paediatric microplegia has been in clinical use in our institution since late 2014. It is applied via an 1/8 inch tube of a S5-HLM roller pump (LivaNova, Italy). As cardioplegic additive, a mixture of potassium (K) 20 mL (2 mmol/mL potassium chloride 14.9% Braun) and magnesium (Mg) 10 mL (4 mmol/mL Mg-sulphate Verla (R) i. v. 50%) is fixed into a syringe-pump (B. Braun, Germany). This additive is mixed with arterial patient blood from the oxygenator in different flow dependent ratios to form an effective cardioplegia. Technique After microplegia application of initially 25 mmol/L K with 11 mmol/L Mg for 2 min, a safe cardioplegic cardiac arrest is achieved, which after release of the coronary circulation, immediately returns to a spontaneous cardiac-rhythm. In the case of prolonged aortic clamping, microplegia is repeated every 20 min with a reduction of the application dose of K by 20% and Mg by 30% (20 mmol/L K; 8.5 mmol/L Mg) and a further reduction down to a maintenance dose (15 mmol/L K; 6 mmol/L Mg) after additional 20 min. The microplegia adapted to the needs of paediatric myocardium is convincing due to its simple technical implementation for the perfusionist while avoiding haemodilution. However, the required intraoperative interval of microplegia of approx. 20 min demands adapted intraoperative management from the surgeon.
CRIS-Team WoS Importer:2022-09-30

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

Models for the marrow: A comprehensive review of AI-based cell classification methods and malignancy detection in bone marrow aspirate smears. - Ghete, Tabita; Kock, Farina; Pontones, Martina; Pfrang, David; Westphal, Max; Höfener, Henning; Metzler, Markus (HemaSphere, 2024)
Given the high prevalence of artificial intelligence (AI) research in medicine, the development of deep learning (DL) algorithms based on image recognition, such as the analysis of bone marrow aspirate (BMA) smears, is rapidly increasing in the field of hematology and oncology. The models are trained to identify the optimal regions of the BMA smear for differential cell count and subsequently detect and classify a number of cell types, which can ultimately be utilized for diagnostic purposes. Moreover, AI is capable of identifying genetic mutations phenotypically. This pipeline has the potential to offer an accurate and rapid preliminary analysis of the bone marrow in the clinical routine. However, the intrinsic complexity of hematological diseases presents several challenges for the automatic morphological assessment. To ensure general applicability across multiple medical centers and to deliver high accuracy on prospective clinical data, AI models would require highly heterogeneous training datasets. This review presents a systematic analysis of models for cell classification and detection of hematological malignancies published in the last 5 years (2019-2024). It provides insight into the challenges and opportunities of these DL-assisted tasks.
EVALuna2:583328

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

Molecular Therapies - Schneider, Holm; Schneider, Pascal (Springer Nature, 2025)
This chapter describes the development of molecular therapies for X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common ectodermal dysplasia syndrome, and for the cutaneous and ocular manifestations of p63-associated syndromes. Large parts of the text are based on the following previously published journal article by Holm Schneider: “Ectodermal dysplasias: New perspectives on the treatment of so far immedicable genetic disorders”, Front Genet. 13:1000744, doi: 10.3389/fgene.2022.1000744; available under the terms of the Creative Commons Attribution License (CC BY).
CRIS-Team Scopus Importer:2025-05-02
Keywords: Ectodysplasin A; Molecular therapy; Neonatal Fc receptor; P63 PRIMA-1MET

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

Monitoring spinal muscular atrophy with three-dimensional optoacoustic imaging - Nedoschill, Emmanuel; Wagner, Alexandra L.; Danko, Vera; Bühler, Adrian; Raming, Roman; Jüngert, Jörg M.; Neurath, Markus; Waldner, Maximilian; Rother, Ulrich; Wölfle, Joachim; Trollmann, Regina; Knieling, Ferdinand; et al. (Med, 2024)
Background: Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy. Methods: In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475). Findings: We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls. Conclusions: This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time. Funding: The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R.
CRIS-Team Scopus Importer:2024-05-03
Keywords: gene therapy; non-invasive imaging; optoacoustic imaging; pediatric spinal muscular atrophy; photoacoustic imaging; spinal muscular atrophy; Translation to patients

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

Mountains and Waves: Fontan Circulation in Different Environmental Conditions - Peter, S.; Müller, N.; Schöffl, Isabelle; Michaelis, A.; Weickmann, J.; Klehs, S.; Härtel, J.; Kratz, T.; Dähnert, I.; Paech, C. (Pediatric Cardiology, 2024)
As surgical options and medical care for patients with univentricular heart physiology continue to improve, leading to increased life expectancy and quality of life, a new population of Fontan patients is growing up with the desire to participate in leisure activities, including aquatic activities, high-altitude stays, and air travel. Due to significant data gaps and insufficient experience, current guidelines do not provide clear recommendations, leading to uncertainty and sometimes restrictive patient management. This review summarizes new insights and the current state of research on this subject and provides an overview of the long overdue change in policies toward less restrictive counseling for Fontan patients regarding swimming, diving, high-altitude stays, and air travel. The current review summarizes the physiologic impact of aquatic and high-altitude activities on the cardiovascular system and presents currently available data on this topic in Fontan patients. Patients with Fontan circulation in good clinical shape can tolerate activities in the water and in the mountains as well as air traveling without critical events. In order to be able to make general recommendations, further studies with larger numbers of cases must be carried out.
CRIS-Team Scopus Importer:2024-11-22
Keywords: Altitude; Diving; Fontan; Hypobaric medicine; Hypoxia; Swimming

MRI in LARS1 deficiency—Spectrum, patterns, and correlation with acute neurological deterioration - Hammann, Nicole; Lenz, Dominic; Bianzano, Alyssa; Husain, Ralf A.; Forman, Eva; Bernstein, Jonathan A.; Dattner, Tal; Engelen, Marc; Hanson-Kahn, Andrea K.; Isidor, Bertrand; Kotzaeridou, Urania; Tietze, Anna; et al. (Journal of Inherited Metabolic Disease, 2024)
Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.
CRIS-Team Scopus Importer:2024-07-19
Keywords: acute liver failure; aminoacyl-tRNA synthetase deficiencies; cerebellar watershed; encephalopathy; ILFS1; LARS1; metabolic stroke; MRI; thalamus

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 Approach to Ectodermal Dysplasia - Tadini, Gianluca; Wright, John Timothy; Hadj-Rabia, Smail; Schneider, Holm (Springer Nature, 2025)

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.
EVALuna2:34532

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.
EVALuna2:34223

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.
EVALuna2:35725

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

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects - Kalinichenko, Liubov; Mühle, Christiane; Jia, Tianye; Anderheiden, Felix; Datz, Maria; Eberle, Anna-Lisa; Eulenburg, Volker; Granzow, Jonas; Hofer, Martin Jürgen; Hohenschild, Julia; Huber, Sabine; Kämpf, Stefanie; et al. (Molecular Psychiatry, 2021)
Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias.
CRIS-Team Scopus Importer:2021-10-08

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)
EVALuna2:32792

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

NFATc1 in CD4+ T cells and CD11c+ dendritic cells drives TH2-mediated eosinophilic inflammation in allergic asthma - Yang, Zuqin; Krammer, Susanne; Mitländer, Hannah; Grund, Janina; Zirlik, Sabine; Wirtz, Stefan; Rauh, Manfred; Sadeghi Shermeh, Atefeh; Finotto, Susetta (Journal of Allergy and Clinical Immunology: Global, 2025)
Background: Asthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased TH2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells, B cells, and effector cells. Nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood. Objective: We explored NFATc1’s role in T cells and DCs in modulating TH2 immune responses within the pathophysiology of allergic asthma. Methods: We induced asthma in mice lacking Nfatc1 in CD4+ T cells or CD11c+ DCs using house dust mite, thereby enabling investigation into NFATc1’s role in both cell types in experimental allergic asthma. Additionally, we examined NFATc1 expression in these cell types and its correlation with blood eosinophil levels in an adult asthma cohort. Results: In a house dust mite–induced asthma model, we found that Nfatc1 deficiency either in CD4+ T cells or CD11c+ DCs resulted in reduced TH2-driven eosinophilic inflammation, IgE levels, and mast cell presence in the lung of asthmatic mice. Nfatc1’s absence in CD4+ T cells directly hampered TH2 cell polarization and functionality, whereas in CD11c+ DCs, it affected DC differentiation and maturation, thereby weakening T-cell priming, proliferation, and subsequent TH2 differentiation. Correspondingly, translational research indicated significant correlations between CD4+NFATc1+ and CD11c+NFATc1+ cell populations and eosinophil levels in asthmatic patients, but not in healthy controls. Conclusion: NFATc1 in T cells and DCs modulates TH2-mediated eosinophilic inflammation in allergic asthma, thus offering insight into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.
CRIS-Team Scopus Importer:2024-11-15
Keywords: allergic asthma; dendritic cells; eosinophils; NFATc1; T cells; T

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

Noduläre Schilddrüsenbefunde bei zwei Patienten im Alter von 6 und 13 Jahren - Wowra, T.; Deeg, K. H. (Tägliche Praxis, 2021)
CRIS-Team Scopus Importer:2024-12-16

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

Non-invasive optoacoustic imaging of glycogen-storage and muscle degeneration in late-onset Pompe disease. - Tan, Lina; Zschüntzsch, Jana; Meyer, Stefanie; Stobbe, Alica; Bruex, Hannah; Regensburger, Adrian; Claßen, Merle; Alves, Frauke; Jüngert, Jörg; Rother, Ulrich; Li, Yi; Danko, Vera; et al. (Nature Communications, 2024)
Pompe disease (PD) is a rare autosomal recessive glycogen storage disorder that causes proximal muscle weakness and loss of respiratory function. While enzyme replacement therapy (ERT) is the only effective treatment, biomarkers for disease monitoring are scarce. Following ex vivo biomarker validation in phantom studies, we apply multispectral optoacoustic tomography (MSOT), a laser- and ultrasound-based non-invasive imaging approach, in a clinical trial (NCT05083806) to image the biceps muscles of 10 late-onset PD (LOPD) patients and 10 matched healthy controls. MSOT is compared with muscle magnetic resonance imaging (MRI), ultrasound, spirometry, muscle testing and quality of life scores. Next, results are validated in an independent LOPD patient cohort from a second clinical site. Our study demonstrates that MSOT enables imaging of subcellular disease pathology with increases in glycogen/water, collagen and lipid signals, providing higher sensitivity in detecting muscle degeneration than current methods. This translational approach suggests implementation in the complex care of these rare disease patients.
EVALuna2:571098

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
EVALuna2:17430

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)

Non-Syndromic and Syndromic Defects in Children with Extracranial Germ Cell Tumors: Data of 2610 Children Registered with the German MAKEI 96/MAHO 98 Registry Compared to the General Population - Schultewolter, Judit H.; Rissmann, Anke; von Schweinitz, Dietrich; Frühwald, Michael; Blattmann, Claudia; Fischer, Lars; Lange, Björn Sönke; Wessalowski, Rüdiger; Fröhlich, Birgit; Behnisch, Wolfgang; Schmid, Irene; Reinhard, Harald; et al. (Cancers, 2024)
GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum’s holistic concept, malignant and benign teratomas were registered. We used a case–control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7–2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2–88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.
CRIS-Team Scopus Importer:2024-06-21
Keywords: Currarino syndrome; developmental tumor; germ cell tumor; MAKEI 96/MAHO 98; non-syndromic defect; Swyer syndrome; syndrome

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

Notch3 is an asymmetric gene and a modifier of heart looping defects in Nodal mouse mutants - Holm Bønnelykke, Tobias; Chabry, Marie Amandine; Perthame, Emeline; Dombrowsky, Gregor; Berger, Felix; Dittrich, Sven; Hitz, Marc Phillip; Desgrange, Audrey; Meilhac, Sigolène M. (Plos Biology, 2025)
The TGFβ secreted factor NODAL is a major left determinant required for the asymmetric morphogenesis of visceral organs, including the heart. Yet, when this signaling is absent, shape asymmetry, for example of the embryonic heart loop, is not fully abrogated, indicating that there are other factors regulating left–right patterning. Here, we used a tailored transcriptomic approach to screen for genes asymmetrically expressed in the field of heart progenitors. We thus identify Notch3 as a novel left-enriched gene and validate, by quantitative in situ hybridization, its transient asymmetry in the lateral plate mesoderm and node crown, overlapping with Nodal. In mutant embryos, we analyzed the regulatory hierarchy and demonstrate that Nodal in the lateral plate mesoderm amplifies Notch3 asymmetric expression. The function of Notch3 was uncovered in an allelic series of mutants. In single neonate mutants, we observe that Notch3 is required with partial penetrance for ventricle thickness, septation and aortic valve, in addition to its known role in coronary arteries. In compound mutants, we reveal that Notch3 acts as a genetic modifier of heart looping direction and shape defects in Nodal mutants. Whereas Notch3 was previously mainly associated with the CADASIL syndrome, our observations in the mouse and a human cohort support a novel role in congenital heart defects and laterality defects.
CRIS-Team Scopus Importer:2025-04-11

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.
EVALuna2:9256

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).
EVALuna2:21033

„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.
EVALuna2:18923

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
Keywords: MSOT; Optoacoustics; Imaging inflammation; Molecular imaging; RSOM; PAI; Photoacoustics; Chronic inflammation; Acute inflammation

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 Lesley; 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

Osteosarcomas in retinoblastoma-survivors. A report of 28 affected patients from the Cooperative Osteosarcoma Study Group (COSS) - Bielack, Stefan S.; Baumhoer, Daniel; Hecker-Nolting, Stefanie; Hettmer, Simone; Kager, Leo; Ketteler, Petra; Kevric, Matthias; Kratz, Christian P.; Kühne, Thomas; Mettmann, Vanessa; Metzler, Markus; Reinhardt, Dirk; et al. (EJC Pediatric Oncology, 2024)
Purpose: Many publications address the epidemiology of secondary osteosarcomas following retinoblastoma. Treatment- and outcome-related information is, however, scarce. We used a large cooperative group's database to study this issue. Patients and methods: The database Cooperative Osteosarcoma Study Group COSS was searched for patients with osteosarcoma following a previous retinoblastoma. Patients were then analyzed for demographic factors, local/systemic treatments received, and outcomes. Results: 28 eligible patients were identified. Median age at retinoblastoma was.5 years, 89% occurred bilaterally. Retinoblastoma-therapy was by surgery in 26/27, radiotherapy in 26/27, chemotherapy in 10/26 (rest unknown). Osteosarcoma was diagnosed after 13.7 (3.1 – 36.1) years, extremities and head/neck affected in 14/28, each. Four/28 patients had primary metastases. Osteosarcoma treatment included chemotherapy in all cases, local therapy surgery in 27/28. Histological response was good in 9/16 evaluable cases. Surgery of all sites was macroscopically complete in 23/27 operated tumors and microscopically complete in 17/26 (1 unknown). Radiotherapy was administered to 3 craniofacial tumors. Median follow-up was 3.5 (.4 – 30.1) years from osteosarcoma diagnosis, 8/28 patients remaining event-free. Altogether, five patients suffered further secondary malignancies. Actuarial overall and event-free survival at 2 and 5 years from osteosarcoma were 73% (standard error: 8%) / 50% (10%) and 47% (10%) / 22% (9%), respectively. Conclusion: This comparatively large cohort of osteosarcomas after retinoblastoma proves that the latter may be treated curatively. While their prognosis is far worse than that of primary osteosarcomas, partly due to a predilection for craniofacial involvement, selected patients may still become long-term survivors with appropriate therapies.
CRIS-Team Scopus Importer:2024-05-03
Keywords: Chemotherapy; Osteosarcoma; Prognosis; Radiotherapy; Retinoblastoma; Surgery

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