13/w mit Adipositas und Konzentrationserhöhung des thyreoidstimulierenden Hormons (TSH), Vorbereitung auf die Facharztprüfung: Fall 88 - Wölfle, Joachim; Gohlke, Bettina (Monatsschrift Kinderheilkunde, 2022)
CRIS-Team Scopus Importer:2022-09-30

2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents - Lurbe, Empar; Agabiti-Rosei, Enrico; Cruickshank, J. Kennedy; Dominiczak, Anna; Erdine, Serap; Hirth, Asle; Invitti, Cecilia; Litwin, Mieczyslaw; Mancia, Giuseppe; Pall, Denes; Rascher, Wolfgang; Redon, Josep; et al. (Journal of Hypertension, 2016)
Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.
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23Na MRI Depicts Early Changes in Ion Homeostasis in Skeletal Muscle Tissue of Patients With Duchenne Muscular Dystrophy - Gerhalter, Teresa; Gast, Lena; Marty, Benjamin; Martin, Jan; Trollmann, Regina; Schüssler, Stephanie; Roemer, Frank; Uder, Michael; Schröder, Rolf; Carlier, Pierre G.; Nagel, Armin Michael; Laun, Frederik Bernd (Journal of Magnetic Resonance Imaging, 2019)
BACKGROUND: Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disease leading to progressive muscle wasting. Since there is a need for MRI variables that serve as early sensitive indicators of response to treatment, several quantitative MRI methods have been suggested for disease monitoring. PURPOSE: To evaluate the potential of sodium (23 Na) and proton (1 H) MRI methods to assess early pathological changes in skeletal muscle of DMD. STUDY TYPE: Prospective clinical study. POPULATION: 23 Na and 1 H MRI of the right leg were performed in 13 patients with DMD (age 7.8 ± 2.4) and 14 healthy boys (age 9.5 ± 2.2). FIELD STRENGTH/SEQUENCE: 3 T including a multiecho-spin-echo sequence, diffusion-weighted sequences, 1 H spectroscopy, 3-pt Dixon, and 23 Na ultrashort echo time sequences. ASSESSMENT: We obtained water T2 maps, fat fraction (FF), pH, and diffusion properties of the skeletal muscle tissue. Moreover, total tissue sodium concentration (TSC) was calculated from the 23 Na sequence. Intracellular-weighted 23 Na signal (ICwS) was derived from 23 Na inversion-recovery imaging. STATISTICAL TESTS: Results from DMD patients and controls were compared using Wilcoxon rank-sum tests and repeated analysis of variance (ANOVA). Spearman-rank correlations and area under the curve (AUC) were calculated to assess the performance of the different MRI methods to distinguish dystrophic from healthy muscle tissue. RESULTS: FF, water T2 , and pH were higher in DMD patients (0.07 ± 0.03, 39.4 ± 0.8 msec, 7.06 ± 0.03, all P < 0.05) than in controls (0.02 ± 0.01, 36.0 ± 0.4 msec, 7.03 ± 0.02). No difference was observed in diffusion properties. TSC (26.0 ± 1.3 mM, P < 0.05) and ICwS (0.69 ± 0.05 a.u., P < 0.05) were elevated in DMD (controls: 16.5 ± 1.3 mM and 0.47 ± 0.04 a.u.). The ICwS was frequently abnormal in DMD even when water T2 , FF, and pH were in the normal range. 23 Na MRI showed higher AUC values in comparison to the 1 H methods. DATA CONCLUSION: Sodium anomalies were regularly observed in patients with DMD compared with controls, and were present even in absence of fatty degenerative changes and water T2 increases. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1103-1113.
CRIS-Team Scopus Importer:2019-09-20
Keywords: Duchenne muscular dystrophy; proton MRI; skeletal muscle; sodium MRI

2-Deoxyglucose induced unfolded protein response enhances efficacy of immunotoxin Moxetumomab pasudotox against lymphoma and leukemia xenografts - Wagner, Franziska; Meier, C.; Krumbholz, Manuela; Metzler, Markus; Mackensen, Andreas; Müller, Fabian (ONCOLOGY RESEARCH AND TREATMENT, 2019)
CRIS-Team WoS Importer:2020-10-02

3-years Safety and Efficacy Outcomes of Canakinumab Treatment in Cryopyrin-associated Periodic Syndromes (CAPS) - Data from the RELIANCE Registry - Kuemmerle-Deschner, Jasmin B.; Kortus-Goetze, Birgit; Oommen, Prasad T.; Janda, Ales; Rech, Jürgen; Schuetz, Catharina; Kallinich, Tilmann; Weller-Heinemann, Frank; Horneff, Gerd; Foeldvari, Ivan; Meier, Florian; Borte, Michael; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011 - Brecht, Ines B.; Garbe, Claus; Gefeller, Olaf; Pfahlberg, Annette; Bauer, Jürgen; Eigentler, Thomas K.; Offenmüller, Sonja; Schneider, Dominik T.; Leiter, Ulrike (European Journal of Cancer, 2015)
Malignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents.443 patients ? 18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan-Meier method.Age of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182).Patient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used.
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4D cardiac magnetic resonance imaging, 4D and 2D transthoracic echocardiography: a comparison of in-vivo assessment of ventricular function in rats - Stegmann, Hedwig; Bäuerle, Tobias; Kienle, Katharina; Dittrich, Sven; Alkassar, Muhannad (Laboratory Animals, 2019)
Preclinical cardiovascular research is the foundation of our understanding and broad knowledge of heart function and cardiovascular disease. Reliable cardiac imaging modalities are the basis for applicable results. Four-dimensional cardiac magnetic resonance (4D CMR) has been set as the gold standard for in-vivo assessment of ventricular function in rodents. However, technical improvements in echocardiography now allow us to image the whole heart, which makes four-dimensional echocardiography (4DE) a possible alternative to 4D CMR. To date, no study has systematically assessed 4DE in comparison with 4D CMR in rats. In total we studied 26 juvenile Sprague-Dawley rats (Crl: CD (SD) IGS). Twenty rats underwent echocardiographic imaging (2D and 4D) and 4D CMR. Five of those rats underwent a ligation of the superior and inferior vena cava to reduce the cardiac inflow as a disease model. Six additional rats were used to assess reproducibility of echocardiography and underwent three echocardiographic examinations. 4D CMR was performed on a 7T scanner; 2D and 4D echocardiography was conducted using a 40 MHz transducer. Correlation between 4D CMR, 4DE and 2DE for left-ventricular ejection fraction (LVEF) was assessed. An excellent correlation was observed between 4DE and 4D CMR (r = 0.95, p < 0.001). Correlation of 2DE and 4D CMR was weak (r = 0.57, p < 0.01). 4DE provides results that are equally precise as 4D CMR and highly reproducible with less technical effort than 4D CMR.
CRIS-Team Scopus Importer:2019-05-09
Keywords: cardiac magnetic resonance; echocardiography; four-dimensional cardiac imaging; left ventricular function; rat

ABCA3-related interstitial lung disease beyond infancy - Li, Yang; Seidl, Elias; Knoflach, Katrin; Gothe, Florian; Forstner, Maria Elisabeth; Michel, Katarzyna; Pawlita, Ingo; Gesenhues, Florian; Sattler, Franziska; Yang, Xiaohua; Kroener, Carolin; Reu-Hofer, Simone; et al. (Thorax, 2023)
BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year. MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly. ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function. ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.
CRIS-Team WoS Importer:2023-03-17

Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa - Mittwollen, R.; Wohlfart, S.; Park, J.; Grosch, Ella; Has, C.; Hohenester, E.; Schneider, Holm; Hammersen, Johanna (Journal of the European Academy of Dermatology and Venereology, 2020)
Background: A lack or dysfunction of the anchoring protein laminin-332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin β3-chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. Objective: This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. Methods: LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin-332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real-time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin-332 helped to assess the impact of certain mutations on laminin-332 folding. Results: Both siblings showed diminished LAMB3 expression. Laminin-332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full-length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin-332 folding and secretion. Conclusions: Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin-332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice-site mutations in other hereditary diseases.
CRIS-Team Scopus Importer:2020-06-02

A case of autosomal recessive spinocerebellar ataxia type 18 with a novel mutation in GRID2 - Hetzelt, Katalin; Kraus, Cornelia; Kusnik, Stefan; Thiel, C.; Ekici, Arif Bülent; Reis, André; Zweier, Christiane (EUROPEAN JOURNAL OF HUMAN GENETICS, 2020)
CRIS-Team WoS Importer:2021-01-22

A case of severe autosomal recessive spinocerebellar ataxia type 18 with a novel nonsense variant in GRID2 - Hetzelt, Katalin; Kraus, Cornelia; Kusnik, Stefan; Thiel, Christian; Uebe, Steffen; Ekici, Arif Bülent; Trollmann, Regina; Reis, André; Zweier, Christiane (European Journal of Medical Genetics, 2020)
Autosomal-recessive spinocerebellar ataxia type 18 (SCAR18) is a rare neurologic disorder. It is caused by bi-allelic aberrations in the GRID2 gene, encoding an ionotropic glutamate receptor. In total, 20 affected individuals with mainly homozygous/compound heterozygous intragenic deletions/duplications, two different missense variants and one nonsense variant in GRID2 have been reported, so far. SCAR18 is characterized by delayed psychomotor development, intellectual disability, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and cerebellar atrophy in brain imaging. By trio exome sequencing, we now identified a novel homozygous nonsense variant (c.568C > T; p.Gln190*) in GRID2 in a four year old female from a consanguineous family who presented with a particularly severe manifestation of SCAR18. The girl was born after an uneventful pregnancy and showed early-onset, profoundly delayed psychomotor development with no achieved psychomotor milestones at age 4 years. Additionally, she presented with severe muscular hypotonia, progressive truncal and appendicular ataxia, binocular vertical nystagmus, central hearing loss and incomplete loss of sight. She was dystrophic, interacted only very little and had behavioral anomalies such as eating hair and bruxism. Brain imaging showed cerebellar hypoplasia, extended cerebrospinal fluid spaces and beginning reduction of cerebral volume. Our findings further delineate the mutational and clinical spectrum of GRID2-associated spinocerebellar ataxia type 18 and indicate that homozygous nonsense variants are possibly associated with the severe end of the SCAR18 phenotypic spectrum.
CRIS-Team Scopus Importer:2020-07-31
Keywords: Ataxia; Autosomal-recessive; Cerebellar hypoplasia; GRID2; Psychomotor development; SCAR18

A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement - Schneider, Holm; Schweikl, Christine; Faschingbauer, Florian; Hadj-Rabia, Smail; Schneider, Pascal (International Journal of Molecular Sciences, 2023)
X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by a genetic deficiency of ectodysplasin A1 (EDA1), is a rare developmental disorder of ectodermal derivatives such as hair, sweat glands, and teeth. The absence of sweat glands and perspiration can evoke life-threatening hyperthermia. As molecular genetic findings are not always conclusive, the concentrations of circulating EDA1 may help to distinguish between total and partial EDA1 deficiencies. We previously treated nine male patients with obvious signs of XLHED with a recombinant EDA1 replacement protein, Fc-EDA, either shortly after birth (n = 3) or by prenatal administration in gestational week 26 and beyond (n = 6). Here, we present the long-term follow-up for up to six years. In patients who had received Fc-EDA after birth, neither sweat glands nor sweating ability were detected at the age of 12–60 months. In contrast, prenatal EDA1 replacement resulted in ample sweat gland development and pilocarpine-inducible sweating in all treated subjects, who also attained more permanent teeth than their untreated affected relatives. Normal perspiration has persisted for six years in the two oldest boys treated repeatedly with Fc-EDA in utero. When they had a sauna, adequate thermoregulation was evidenced. Lower sweat production after single prenatal dosing may indicate a dose–response relationship. The absence of circulating EDA1 in five prenatally treated subjects proved that these children would have been unable to perspire if they had been left untreated. The sixth infant was shown to produce an EDA1 molecule that, albeit interacting with its cognate receptor, cannot activate EDA1 signaling. In conclusion, a causal treatment of XLHED before birth is feasible.
CRIS-Team Scopus Importer:2023-05-12
Keywords: AlphaLisa; ectodermal dysplasia; ectodysplasin A; prenatal therapy; protein replacement; sweat glands; tooth development

Accuracy and Specific Value of Cardiovascular 3D-Models in Pediatric CT-Angiography - Hammon, Matthias; Rompel, Oliver; Seuss, Hannes; Dittrich, Sven; Uder, Michael; Rüffer, Andrè; Cesnjevar, Robert; Ehret, Nicole; Glöckler, Martin (Pediatric Cardiology, 2017)
Computed tomography (CT)-angiography is routinely performed prior to catheter-based and surgical treatment in congenital heart disease. To date, little is known about the accuracy and advantage of different 3D-reconstructions in CT-data. Exact anatomical information is crucial. We analyzed 35 consecutive CT-angiographies of infants with congenital heart disease. All datasets are reconstructed three-dimensionally using volume rendering technique (VRT) and threshold-based segmentation (stereolithographic model, STL). Additionally, the two-dimensional maximum intensity projection (MIP) reconstructs two-dimensional data. In each dataset and resulting image, measurements of vascular diameters for four different vessels were estimated and compared to the reference standard, measured via multiplanar reformation (MPR). The resulting measurements obtained via the STL-images, MIP-images, and the VRT-images were compared with the reference standard. There was a significant difference (p < 0.05) between measurements. The mean difference was 0.0 for STL-images, -0.1 for MIP-images, and -0.3 for VRT-images. The range of the differences was -0.7 to 1.0 mm for STL-images, -0.6 to 0.5 mm for MIP-images and -1.1 to 0.7 mm for VRT-images. There was an excellent correlation between the STL-, MIP-, VRT-measurements, and the reference standard. Inter-reader reliability was excellent (p < 0.01). STL-models of cardiovascular structures are more accurate than the traditional VRT-models. Additionally, they can be standardized and are reproducible.
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A classification of abdominal lymphatic perfusion patterns after Fontan surgery - Schroeder, Christian; Moosmann, Julia; Cesnjevar, Robert; Purbojo, Ariawan; Rompel, Oliver; Dittrich, Sven (European Journal of Cardio-Thoracic Surgery, 2022)
OBJECTIVES: Complications after Fontan surgery have been associated with arise and classification of abnormal thoracic lymphatic perfusion pattern. This study compiles abnormal abdominal lymphatic perfusion patterns and investigates their impact on serum protein readings.
CRIS-Team WoS Importer:2022-03-11

A common genetic variant within SCN10A modulates cardiac SCN5A expression - Van Den Boogaard, Malou; Smemo, Scott; Burnicka-Turek, Ozanna; Arnolds, David E.; Van De Werken, Harmen J. G.; Klous, Petra; Mckean, David; Muehlschlegel, Jochen D.; Moosmann, Julia; Toka, Okan; Yang, Xinan H.; Koopmann, Tamara T.; et al. (Journal of Clinical Investigation, 2014)
Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
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A Comparison of GFR Estimation Formulae in Pediatric Oncology - Rechenauer, Tobias; Zierk, Jakob; Graefe, Daniel; Rascher, Wolfgang; Rauh, Manfred; Metzler, Markus (Klinische Pädiatrie, 2018)
BACKGROUND: Application of potentially nephrotoxic chemotherapy requires continuous monitoring of renal function for toxicity and dosing. Novel pediatric glomerular filtration rate (GFR) estimating equations including cystatin C have been proposed to enhance the reliability of GFR calculation. MATERIALS AND METHODS: We examined a pediatric oncologic data set with a total of 363 GFR measurements. An analysis of distribution characteristics and comparison of medians was performed to compare creatinine and cystatin C-based GFR estimating formulae. Furthermore, we investigated the clinical impact of different equations in regard to therapeutic consequences. RESULTS: Significant differences in estimated GFR values were calculated depending on the applied formula (range of median GFR from 94.8 to 180.9 mL/min per 1.73 m2) which may result in different therapeutic consequences for the use of potentially nephrotoxic chemotherapeutic agents. Significant correlation for all examined formulae was identified, however there were large fluctuations among the correlation coefficients ranging from 0.254 to 1.0. CONCLUSION: This study compares proposed pediatric GFR estimating equations in a clinical setting. It underlines the current limitations and difficulties of GFR estimation including potential dosing errors. Cystitis C-based equations can be used as alternatives to creatinine-based estimations when the appropriate laboratory method has been applied. A comparative calculator for pediatric GFR estimating equations along with background information is provided at http://gfr.pedz.de and may support clinical decision-making.
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A comparison of the suitability of cathode ray tube (CRT) and liquid crystal display (LCD) monitors as visual stimulators in mfERG diagnostics - Kaltwasser, Christoph; Horn, Folkert; Kremers, Jan; Jünemann, Anselm (Documenta Ophthalmologica, 2009)
The aim of this study was to determine up to which extent the specific characteristics of cathode ray tube (CRT) and liquid crystal display (LCD) monitors influence the retinal biosignal when used as stimulators in ocular electrophysiology. In a conventional CRT monitor, each pixel lights up only for a duration of a few milliseconds during each frame. In contrast, liquid crystal displays are quasi-static, i.e. each pixel has a constant luminance during the whole length of the frame, but lights up only with a certain delay after the trigger. These different display characteristics may affect the mfERG signal. The temporal and spatial luminance distributions of a CRT and an LCD monitor were measured in white flashes. The total amount of emitted light was calculated by integration of the intensity versus time curves. By means of an mfERG recording system (RETIsystem, Roland Consult, Brandenburg, Germany) first-order kernel (FOK) mfERG signals were computed and then analysed using customized MATLAB (TheMathWorks, Natick, MA, USA) software. With the two stimulator monitors, differences in the mfERG signal were observed. The latencies of mfERG responses recorded with the LCD monitor were significantly increased by 7.1 ms for N1 and 9.5 ms for P1 compared to the CRT. Due to a higher luminance, the N1 amplitude was significantly higher by approx. 2 dB in measurements with the LCD monitor while no significant difference could be detected with regard to the more contrast sensitive P1 amplitude. When using LCD monitors as stimulators the increase in latencies and differences in the luminance versus time profile must be taken into account. Prior to clinical application, the establishment of guidelines for the use of LCD monitors is recommended.
Keywords: CRT; LCD; Multifocal ERG; Stimulus delivery

A Complex Intervention to Prevent Medication-Related Hospital Admissions - Neubert, Antje; Toni, Irmgard; König, Jochem; Urschitz, Michael S.; Rascher, Wolfgang (Deutsches Ärzteblatt international, 2023)
BACKGROUND: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents. METHODS: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice. RESULTS: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance. CONCLUSION: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.
CRIS-Team Scopus Importer:2023-09-15

A Comprehensive Review of the Effects of Hyoscine Butylbromide in Childhood - Vázquez Frias, Rodrigo; Hörning, André; Boggio Marzet, Christian; Michel, Martin C. (Journal of Clinical Medicine, 2025)
Background/Objectives: Hyoscine butylbromide (HBB) is a spasmolytic drug classified as indispensable by the World Health Organization. While mostly used in adults, it is also approved for use in adolescents and children aged 6 years and older. We have comprehensively reviewed the efficacy and safety of HBB in approved and off-label childhood indications. Results: Childhood studies covered an age range starting as early as 2 days. A randomized controlled trial (RCT) found a similar efficacy compared to paracetamol in the approved indication of abdominal cramps and pain. Among off-label uses, several studies demonstrate efficacy in general anesthesia and various diagnostic procedures, but the largest body of evidence relates to use in childbirth/labor, including 17 RCTs. While these largely focused on efficacy outcomes on the mother, fetal safety outcomes were reported in 12 of these studies, mostly as effects on the APGAR score and/or heart rate. The overall evidence supports safety in infants and children including those younger than the approved use age of 6 years and older. Conclusions: While only limited pediatric efficacy data from RCTs are available in the approved indications, data from thousands of patients in RCTs, case series, and non-randomized trials do not raise concerns on the safety and tolerability of HBB in childhood. Additional dedicated childhood studies, particularly RCTs, on efficacy are recommended.
CRIS-Team Scopus Importer:2025-05-23
Keywords: abdominal cramps; abdominal pain; childbirth; children; hyoscine butylbromide; infants; vomiting

Action Recommendation in accordance with the Guideline "Syncopes in Childhood and Adolescence" - Dittrich, Sven (Monatsschrift Kinderheilkunde, 2018)
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Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis - Akhmetshina, Alfiya; Palumbo, Katrin; Dees, Clara; Bergmann, Christina; Venalis, Paulius; Zerr, Pawel; Horn, Angelika; Kireva, Trayana; Beyer, Christian; Zwerina, Jochen; Schneider, Holm; Sadowski, Anika; et al. (Nature Communications, 2012)
The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases. © 2012 Macmillan Publishers Limited. All rights reserved.
CRIS-Team Scopus Importer:2020-07-01

Active visfatin is elevated in serum of maintenance haemodialysis patients and correlates inversely with circulating HDL cholesterol - Nuesken, Kai-Dietrich; Petrasch, Maurice; Rauh, Manfred; Stoehr, Wolfgang; Nuesken, Eva; Schneider, Holm; Dötsch, Jörg (Nephrology Dialysis Transplantation, 2009)
Background. Increased circulating visfatin may be associated both with endothelial damage and with increased mortality in end-stage renal disease (ESRD). HDL cholesterol is an independent, strong inverse predictor of cardiovascular events. However, associations between visfatin and parameters of lipid metabolism are unclear. Moreover, serum concentrations of visfatin measured by an enzyme immuno assay (EIA) are conflicting and do not correlate with ELISA (enzyme-linked immunosorbent assay) data, which predominantly detect enzymatically active visfatin.Methods. A total of 74 haemodialysis (HD) patients and 35 control individuals (C) were studied. All subjects (mean age 62.9 years) provided fasted blood samples (HD patients after 66-69 h without dialysis). Circulating visfatin was measured by the ELISA. Body composition was evaluated using waist circumference, skinfold thickness and body impedance analysis. Results obtained by the ELISA were compared with EIA data.Results. Active serum visfatin was increased in HD (5.58 ± 6.50 ngml) versus C 0.97 ± 1.79 ngml, mean ± SD; P < 0.0001 by multiple regression analysis (MRA) independently of plasma glucose, serum insulin, diabetes, HDL cholesterol and body composition. Within the HD group, only plasma HDL cholesterol (4 lower per additional mgdl HDL; P = 0.001) and insulin-treated diabetes mellitus subgroup of n = 18; 119 higher compared with patients without diabetes (n = 40); P = 0.011 were independently (by MRA) associated with active serum visfatin. Visfatin measured by an EIA showed no correlation with ELISA data.Conclusions. Our study provides reliable data on active visfatin in HD patients using a well-characterized ELISA. Loss of renal function is accompanied by increased circulating active visfatin concentrations in our patients. Furthermore, decreased HDL cholesterol may hint at an increased probability of cardiovascular events in HD patients with elevated serum visfatin.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Body composition; Diabetes; End-stage renal disease; HDL cholesterol; Visfatin

Activin A in perinatal brain injury - Brackmann, Florian; Alzheimer, Christian; Trollmann, Regina (Neuropediatrics, 2015)
Activin A is a multifunctional growth and differentiation factor belonging to the transforming growth factor ? (TGF-?) family. Growing evidence indicates its role as a neurotrophic factor and regulator of synaptic transmission as well as its functional importance in several types of cerebral injury. We recently described age-dependent expression of activin A and its regulation at the mRNA and protein level under different conditions of global hypoxia in the neonatal mouse brain. This review discusses the current knowledge of the function and regulation of activin A from human studies as well as from experimental models of brain injury focusing on acquired lesions of the developing rodent brain during the early stages of brain maturation.
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Acute treatment of functional obstipation—What is safe and effective? Akuttherapie der funktionellen Obstipation – Was ist sicher wirksam? - Gramlich, Ursula; Zahn, Julia; Neubert, Antje; Rascher, Wolfgang (Monatsschrift Kinderheilkunde, 2021)
The aim of the pharmacotherapy of functional obstipation is initially to relieve acute constipation (disimpaction) and then to ensure regular pain-free bowel emptying by means of stool-softening long-term treatment. The scientific state of the art of acute pharmacotherapy of constipation with enemas as well as with oral macrogol is analyzed with respect to efficacy and safety. For acute treatment enemas containing phosphate are often used, which in the past have occasionally led to severe complications, including death. These severe complications are exemplified in a case study of a 16-year-old girl. The regulatory background and current changes with new contraindications are presented as they are important for prescription and reimbursement. An alternative safe and appropriate pharmacotherapy for acute constipation is the oral administration of high-dose macrogol and the indications, dose, and data on efficacy and safety are presented. Oral administration of macrogol is a good alternative to enemas, when treating children for acute obstipation. Enemas containing phosphate are dangerous, particularly in young children under 6 years of age if they are not eliminated in a timely manner.
CRIS-Team Scopus Importer:2021-08-20
Keywords: Disimpaction; Enema; Hyperphosphatemia; Macrogol; Medical device

Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles - Hoelsken, Annett; Sill, Martin; Merkle, Jessica; Schweizer, Leonille; Buchfelder, Michael; Flitsch, Joerg; Fahlbusch, Rudolf; Metzler, Markus; Kool, Marcel; Pfister, Stefan M.; Von Deimling, Andreas; Capper, David; et al. (Acta Neuropathologica Communications, 2016)
Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP.BRAF V600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP.AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention.
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Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure - Kovarik, Johannes; Morisawa, Norihiko; Wild, Johannes; Marton, Adriana; Takase-Minegishi, Kaoru; Minegishi, Shintaro; Daub, Steffen; Sands, Jeff M.; Klein, Janet D.; Bailey, James L.; Kovalik, Jean Paul; Rauh, Manfred; et al. (Acta Physiologica, 2021)
Aim: We have reported earlier that a high salt intake triggered an aestivation-like natriuretic-ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods: In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24-hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+, K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra-arterial blood pressure. Results: 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic-metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion: Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under-studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.
CRIS-Team Scopus Importer:2021-03-19
Keywords: aestivation; body sodium; body water; dehydration; double-barrier concept; glucose-alanine-shuttle; glycine methylation; hepato-renal; hypertension; kidney; liver; muscle mass loss; organic osmolytes; purine metabolism; skin; transamination; transepidermal water loss; urea cycle; urine concentration

Adenosine-generating CD39+ plasmablasts predispose to successful infliximab therapy in pediatric IBD - Schnell, Alexander; Schwarz, Benedikt; Schmidt, Hannah; Allabauer, Ida; Schuh, Wolfgang; Regensburger, Adrian; Rauh, Manfred; Wölfle, Joachim; Hörning, André (Life Science Alliance, 2025)
B cells display several immunoregulatory mechanisms including the production of interleukin-10. Ectonucleotidases like CD39 and CD73 influence immune homeostasis by metabolizing eATP and generating immunosuppressive adenosine. The major objective was to examine the expression of those immunoregulatory molecules on B-cell subsets, and, more specifically, to determine their association with an infliximab (IFX) treatment in a pediatric inflammatory bowel disease (IBD) cohort. 42 IBD patients were assessed for IFX response after 12 mo of therapy and compared against 14 healthy controls (HC). Although IL10-producing plas-mablasts were decreased in IFX nonresponders (NRS), we de-tected an up-regulation of CD39 on plasmablasts and increased fractions of CD39/CD73-co-expressing naïve and memory B cells in responding patients (RS). In addition, B cells of responders proved to have superior ATP degradation capacities and aden-osine production before therapy initiation compared with NRS and HC. Moreover, IFX nonresponders had a marked deficiency of α4β7hi plasmablasts, whereas both cohorts had fewer CCR9-expressing plasmablasts. Consequently, CD39+ plasmablasts were decreased in biopsies of inflamed mucosal tissues, espe-cially in IFX nonresponders. Our results highlight the regulatory potential of CD39/CD73-expressing B cells in pediatric IBD and suggest CD39+ plasmablasts as a potential determinant of a successful immunosuppressive therapy with IFX.
CRIS-Team Scopus Importer:2025-05-02

Adhesive blood microsampling systems for steroid measurement via LC-MS/MS in the rat - Heussner, Kirsten; Rauh, Manfred; Cordasic, Nada; Menendez-Castro, Carlos; Hübner, Hanna; Rübner, Matthias; Schmidt, Marius; Hartner, Andrea; Rascher, Wolfgang; Fahlbusch, Fabian B. (Steroids, 2017)
INTRODUCTION: Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) allows for the direct analysis of multiple hormones in a single probe with minimal sample volume. Rodent-based animal studies strongly rely on microsampling, such as the dry blood spot (DBS) method. However, DBS suffers the drawback of hematocrit-dependence (non-volumetric). Hence, novel volumetric microsampling techniques were introduced recently, allowing sampling of fixed accurate volumes. We compared these methods for steroid analysis in the rat to improve inter-system comparability. EXPERIMENTAL: We analyzed steroid levels in blood using the absorptive microsampling devices Whatman® 903 Protein Saver Cards, Noviplex™ Plasma Prep Cards and the Mitra™ Microsampling device and compared the obtained results to the respective EDTA plasma levels. Quantitative steroid analysis was performed via LC-MS/MS. For the determination of the plasma volume factor for each steroid, their levels in pooled blood samples from each human adults and rats (18weeks) were compared and the transferability of these factors was evaluated in a new set of juvenile (21days) and adult (18weeks) rats. Hematocrit was determined concomitantly. RESULTS: Using these approaches, we were unable to apply one single volume factor for each steroid. Instead, plasma volume factors had to be adjusted for the recovery rate of each steroid and device individually. The tested microsampling systems did not allow the use of one single volume factor for adult and juvenile rats based on an unexpectedly strong hematocrit-dependency and other steroid specific (pre-analytic) factors. DISCUSSION: Our study provides correction factors for LC-MS/MS steroid analysis of volumetric and non-volumetric microsampling systems in comparison to plasma. It argues for thorough analysis of chromatographic effects before the use of novel volumetric systems for steroid analysis.
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A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS - Maccari, Maria Elena; Fuchs, Sebastian; Kury, Patrick; Andrieux, Geoffroy; Bengsch, Bertram; Lorenz, Myriam Ricarda; Heeg, Maximilian; Rohr, Jan; Jägle, Sabine; Castro, Carla N.; Groß, Miriam; Warthorst, Ursula; et al. (Journal of Experimental Medicine, 2021)
The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.
CRIS-Team Scopus Importer:2020-12-18

Adrenal crisis in a 14-year-old boy 12 years after hematopoietic stem cell transplantation - Penger, Theresa; Albrecht, Andrea; Marx, Martin; Stachel, Daniel; Metzler, Markus; Dörr, Helmuth-Günther (Endocrinology, Diabetes and Metabolism Case Reports, 2018)
We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison's disease along with autoimmune thyroid disease and/or type 1 diabetes. Learning points: Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period.Primary adrenal insufficiency after HSCT is absolutely rare.The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2.
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Adrenarche and pubarche in girls with turner syndrome during growth-promoting therapy with human growth hormone - Dörr, Helmuth-Günther; Penger, Theresa; Marx, Martin; Rauh, Manfred; Oppelt, Patricia; Völkl, Thomas (BMC Endocrine Disorders, 2019)
Background: Data on adrenarche and pubarche in girls with Turner syndrome (TS) are inconsistent in the literature. Methods: The cohort consisted of 94 girls and young women with TS born between 1971 and 2001 (age range: 3.1-23.2 yrs.), who were treated with human growth hormone and regularly presented at our outpatient clinic every 4 to 6 months.The longitudinal data of all patients were ascertained retrospectively from patient charts. The data collection ended in January 2016. Adrenarche was assessed by serum DHEAS levels and pubertal status by Tanner stages. Pubarche was defined as the appearance of pubic hair (PH2), whereas spontaneous puberty was defined as Tanner stage B2. The patients were retrospectively subdivided in two groups with regard to pubertal development: group 1 (n = 21) with spontaneous puberty and group 2 (n = 70) with induced puberty. Since blood samples were not taken at every visit, we generated seven groups according to the age of the children at which the blood samples were taken: 3-5, 5-7, 7-9, 9-11, 11-13, 13-15, and 15-17 yrs. Serum DHEAS and follicle-stimulating hormone (FSH) levels were measured by chemiluminescence immunoassay and compared with those of a control group of healthy girls. Results: Adrenarche started in TS girls between 5 and 7 years. TS girls had higher DHEAS levels than the control group, with statistically significant differences in the age groups 7 to 17 years. No differences were determined between the TS girls with spontaneous puberty and those with POI. TS girls in group 2 reached the Tanner stages PH2 (p < 0.04), PH3 (p < 0.01), PH4 and PH5 (p < 0.001) markedly later than TS girls in group 1. Conclusions: The onset of adrenarche in girls with TS undergoing GH therapy does not differ from that in healthy girls. However, adrenarche is more pronounced in girls with TS. There is no difference in DHEAS levels between the TS girls with spontaneous puberty and the TS girls with primary ovarian insufficiency (POI), while the tempo of pubarche is markedly slower in the girls with POI.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Adrenarche; DHEAS; Primary ovarian insufficiency; Turner syndrome

Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males - 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. (Cerebral Cortex, 2022)
Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
CRIS-Team WoS Importer:2022-04-15
Keywords: neutral sphingomyelinase; osteocalcin; depression; alcohol; anxiety

Advanced therapy medicinal products – special features of approval, application and monitoring Arzneimittel für neuartige Therapien – Besonderheiten der Zulassung, Anwendung und Überwachung - Rascher, Wolfgang (Pädiatrische Praxis, 2022)
Advanced therapy medicinal products, such as somatic gene therapy and cell therapy, have a high therapeutic potential for diseases that start very early in life and were previously untreatable. They are often approved at a very early stage of development, when efficacy has been impressively demonstrated in a small number of affected individuals and unprecedented therapeutic success is emerging. Early conditional approval raises new logistical, drug regulatory, and ethical issues for paediatrics. Diseases with very early manifestations in infancy must be diagnosed earlier than in the past, or even as part of newborn screening. Advanced therapy medicinal products have often not been used in sufficient numbers at the time of their approval, so that the necessary evidence for efficacy and safety is not yet available (benefit-risk ratio). For this reason, they are used under strict conditions in specialized treatment centers according to quality criteria defined by the Federal Joint Committee after consultation with the medical societies. Using therapy with advanced therapy medicinal products, as well as the documentation of its course, is considerable. Due to early, conditional approval, the value of an advanced therapy medicinal product becomes clear only with its broader use after approval, similar to the fact that the safety of a drug is not fully known with approval. Nonetheless, these advanced therapies offer great potential for diseases, particularly of children, that are currently untreatable or inadequately treatable.
CRIS-Team Scopus Importer:2024-12-16
Keywords: cell therapy; drug approval; drug safety; gene therapy; newborn screening

Adverse Drug Reactions at Nonelective Hospital Admission in Children and Adolescents: Comparison of 4 Causality Assessment Methods - Neininger, Martina Patrizia; Wehr, Raphaela; Kiesel, Lisa Marie; Neubert, Antje; Kiess, Wieland; Bertsche, Astrid; Bertsche, Thilo (Journal of Patient Safety, 2022)
Objectives This study aimed to compare assessment methods to determine adverse drug reactions (ADRs) at nonelective hospital admission in pediatric patients, to investigate the interrater reliability of assessment methods in pediatric care, and to analyze symptoms related to ADRs and (suicidal) drug intoxications. Methods For 1 year, the medical records of nonelective patients admitted to a university pediatric department were evaluated for potential ADRs using 4 assessments methods by 1 experienced rater. Krippendorff alpha was calculated from a sample of 14 patients evaluated by 4 experienced raters to determine interrater reliability. Results In 1831 nonelective hospital admissions, 63.4% (1161 of 1831) of patients had received at least one drug before admission. We found a potential causal relationship between drugs and symptoms documented at admission and thus potential ADRs according to Naranjo in 23.3% (271 of 1161) of those patients, World Health Organization - Uppsala Monitoring Centre (WHO-UMC) in 22.5% (261 of 1161), Koh in 21.7% (252 of 1161), and Begaud in 16.5% (192 of 1161). The probability rating of the potential causal relationships varied considerably between the methods (Naranjo-Begaud, P < 0.01; Naranjo-Koh, P < 0.001; Koh-Begaud, P < 0.01; Begaud-WHO-UMC, P < 0.01). Acceptable interrater reliability (alpha >= 0.667) was only obtained for WHO-UMC (alpha = 0.7092). The most frequently identified definite ADR was sedation in 1.5% of all nonelective patients with medication before hospital admission. In 1.2% (22 of 1831) of all nonelective admissions, we found drug intoxications with suicidal intent. Conclusions The assessment methods showed a high variability in the determination of a potential causal relationship between drug and documented symptom, in the classification of the probability of ADRs, and suboptimal interrater reliability. Thus, their feasibility in pediatric patients is limited.
CRIS-Team WoS Importer:2022-06-10

Adverse Drug Reactions in Children: Comparison of Reports Collected in a Pharmacovigilance Project Versus Spontaneously Collected ADR Reports - Leitzen, Sarah; Dubrall, Diana; Toni, Irmgard; Stingl, Julia; Christ, Patrick; Koberle, Ursula; Schmid, Matthias; Neubert, Antje; Sachs, Bernhardt (Paediatric Drugs, 2022)
Background: Adverse drug reactions (ADRs) and medication errors in children may result from a lack of appropriate drugs, dosages, and pharmaceutical forms. In addition, children may respond differently to drugs than adults. Reporting of ADRs in the pediatric population is therefore of importance in order to increase the amount of safety data. However, different methodological approaches are used to collect ADRs. Objective: The aim of the present study was to analyze whether there were differences in the ADRs collected in the KiDSafe project (845 ADR reports) compared with the spontaneous ADR reports sent to EudraVigilance (697 reports) in the same time period. The strengths and limitations of these two different approaches should be discussed. Methods: The same inclusion criteria were applied for the systematically collected ADRs in the KiDSafe project and the spontaneous reports from EudraVigilance, and only reports of ADRs coded with hospitalization were considered. In both datasets, the number of reports (related to number of hospitals), their documentation quality (VigiGrade), causal relationship (World Health Organization-Uppsala Monitoring Centre [WHO-UMC] criteria), most frequently reported drugs and ADRs, demographical parameters of the patients, reported medical histories, and the seriousness of ADR reports were analyzed descriptively. The results of the two analyses were compared. Results: There was considerable underreporting of ADRs via the spontaneous reports (0.4 reports per hospital; 697/1902) compared with 70.4 reports per hospital (845/12) in the systematically collected KiDSafe reports. Documentation quality assessment yielded similar results in both datasets. Among the 10 most frequently reported drugs, anticonvulsants such as levetiracetam (6.6%), valproic acid (5.6%), oxcarbazepine (3.6%), and lamotrigine (3.4%) were mainly reported in the KiDSafe reports, while in the EudraVigilance reports, mite allergen extract (4.4%) and allergens (3.6%) were preferentially reported. Seizures were the most frequently reported clinically specific ADRs in the KiDSafe reports, whereas anaphylactic reactions and urticaria were prominent in the spontaneous reports from EudraVigilance. Notably, the proportion of reports referring to medication errors and other medication safety related issues were more prominent in KiDSafe than in the spontaneous reports (27.8% vs. 12.6% and 46.0% vs. 29.0%, respectively). Conclusion: In general, reports from both data sources contributed to the identification of ADRs and dedicated issues related to drug therapy. However, these differed by nature and strength of the signal, likely due to the characteristics of the individual method. A combined approach could likely compensate for limitations inherent to the single approaches, but will most likely only be applied to dedicated pharmacovigilance topics or research objectives.
CRIS-Team Scopus Importer:2022-11-25

aEEG Use in Pediatric Critical Care—An Online Survey - Bruns, Nora; Felderhoff-Müser, Ursula; Dohna-Schwake, Christian; Wölfle, Joachim; Müller, Hanna (Frontiers in Pediatrics, 2020)
Background: Evidence supporting continuous EEG monitoring in pediatric intensive care is increasing, but continuous full-channel EEG is a scarce resource. Amplitude-integrated EEG (aEEG) monitors are broadly available in children's hospitals due to their use in neonatology and can easily be applied to older patients. Objective: The aim of this survey was to evaluate the use of amplitude-integrated EEG in German and Swiss pediatric intensive care units (PICUs). Design: An online survey was sent to German and Swiss PICUs that were identified via databases provided by the German Pediatric Association (DGKJ) and the Swiss Society of Intensive Care (SGI). The questionnaire contained 18 multiple choice questions including the PICU size and specialization, indications for aEEG use, perceived benefits from aEEG, and data storage. Main results: Forty-three (26%) PICUs filled out the questionnaire. Two thirds of all interviewed PICUs use aEEG in non-neonates. Main indications were neurological complications or disease and altered mental state. Features assessed were mostly seizures and side differences, less frequently height of amplitude and background pattern. Interpretation of raw EEG also played an important role. All interviewees would appreciate the establishment of reference values for toddlers and children. Conclusions: aEEG is used in a large proportion of the interviewed PICUs. The wide-spread use without validation of data generates the need for further evaluation of this technique and the establishment of reference values for non-neonates.
CRIS-Team Scopus Importer:2020-02-18
Keywords: aEEG; amplitude-integrated EEG; continuous EEG; neuromonitoring; pediatric critical care; survey

Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect - Wild, Johannes; Jung, Rebecca; Knopp, Tanja; Efentakis, Panagiotis; Benaki, Dimitra; Grill, Alexandra; Wegner, Joanna; Molitor, Michael; Garlapati, Venkata; Rakova, Natalia; Markó, Lajos; Marton, Adriana; et al. (Acta Physiologica, 2021)
Aim: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. Methods: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. Results: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. Conclusion: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting.
CRIS-Team Scopus Importer:2021-03-05
Keywords: aestivation; catabolism; dehydration; double barrier concept; hypertension; transepidermal water loss

AFFERENT RENAL NERVE PATHWAYS IN RATS - RESPONSIVENESS TO HIGH SALT INTAKE - Rodionova, Kristina; Ditting, Tilmann; Fahrmeier, Franziska; Ott, Chirstian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

A framework for criteria-based selection and processing of fast healthcare interoperability resources (FHIR) data for statistical analysis: Design and implementation study - Gründner, Julian; Gulden, Christian; Kampf, Marvin; Mate, Sebastian; Prokosch, Hans-Ulrich; Zierk, Jakob (JMIR Medical Informatics, 2021)
Background: The harmonization and standardization of digital medical information for research purposes is a challenging and ongoing collaborative effort. Current research data repositories typically require extensive efforts in harmonizing and transforming original clinical data. The Fast Healthcare Interoperability Resources (FHIR) format was designed primarily to represent clinical processes; therefore, it closely resembles the clinical data model and is more widely available across modern electronic health records. However, no common standardized data format is directly suitable for statistical analyses, and data need to be preprocessed before statistical analysis. Objective: This study aimed to elucidate how FHIR data can be queried directly with a preprocessing service and be used for statistical analyses. Methods: We propose that the binary JavaScript Object Notation format of the PostgreSQL (PSQL) open source database is suitable for not only storing FHIR data, but also extending it with preprocessing and filtering services, which directly transform data stored in FHIR format into prepared data subsets for statistical analysis. We specified an interface for this preprocessor, implemented and deployed it at University Hospital Erlangen-Nürnberg, generated 3 sample data sets, and analyzed the available data. Results: We imported real-world patient data from 2016 to 2018 into a standard PSQL database, generating a dataset of approximately 35.5 million FHIR resources, including “Patient,” “Encounter,” “Condition” (diagnoses specified using International Classification of Diseases codes), “Procedure,” and “Observation” (laboratory test results). We then integrated the developed preprocessing service with the PSQL database and the locally installed web-based KETOS analysis platform. Advanced statistical analyses were feasible using the developed framework using 3 clinically relevant scenarios (data-driven establishment of hemoglobin reference intervals, assessment of anemia prevalence in patients with cancer, and investigation of the adverse effects of drugs). Conclusions: This study shows how the standard open source database PSQL can be used to store FHIR data and be integrated with a specifically developed preprocessing and analysis framework. This enables dataset generation with advanced medical criteria and the integration of subsequent statistical analysis. The web-based preprocessing service can be deployed locally at the hospital level, protecting patients’ privacy while being integrated with existing open source data analysis tools currently being developed across Germany.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Data analysis; Data harmonization; Data repositories; Data science; Data standardization; Digital medical information; EHealth; Fast healthcare interoperability resources; HL7 FHIR; Medical information; Patient privacy

Age- and sex-specific dynamics in 22 hematologic and biochemical analytes from birth to adolescence - Zierk, Jakob; Arzideh, Farhad; Rechenauer, Tobias; Haeckel, Rainer; Rascher, Wolfgang; Metzler, Markus; Rauh, Manfred (Clinical Chemistry, 2015)
Pediatric laboratory test results must be interpreted in the context of interindividual variation and age- and sex-dependent dynamics. Reference intervals as presently defined for separate age groups can only approximate the age-related dynamics encountered in pediatrics. Continuous reference intervals from birth to adulthood are not available for most laboratory analytes because of the ethical and practical constraints of defining reference intervals using a population of healthy community children. We applied an indirect method to generate continuous reference intervals for 22 hematologic and biochemical analytes by analyzing clinical laboratory data from blood samples taken during clinical care of patients.We included samples from 32 000 different inpatients and outpatients (167 000 samples per analyte) from a German pediatric tertiary care center. Measurements were performed on a Sysmex-XE 2100 and a Cobas Integra 800 during clinical care over a 6-year period. The distribution of samples considered normal was estimated with an established indirect statistical approach and used for the calculation of reference intervals.We provide continuous reference intervals from birth to adulthood for 9 hematology analytes (hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count, and platelet count) and 13 biochemical analytes (sodium, chloride, potassium, calcium, magnesium, phosphate, creatinine, aspartate transaminase, alanine transaminase, ?-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, and total protein).Continuous reference intervals capture the population changes in laboratory analytes during pediatric development more accurately than age groups. After local validation, the reference intervals provided should allow a more precise consideration of these dynamics in clinical decision making.
EVALuna2:18920

Age- and sex-specific pediatric reference intervals for neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio - Moosmann, Julia; Krusemark, Anja; Dittrich, Sven; Ammer, Tatjana; Rauh, Manfred; Wölfle, Joachim; Metzler, Markus; Zierk, Jakob (International Journal of Laboratory Hematology, 2021)
Introduction: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are emerging biomarkers for systemic inflammation and have been shown to predict morbidity and mortality for several diseases. However, lack of pediatric reference intervals (RIs) prevents their comprehensive use in patient care and medical research. Material and Methods: We calculated reference intervals and corresponding confidence intervals for NLR, PLR, and LMR from birth to 18 years using a data-mining approach: We analyzed 232 746 blood counts from 60 685 patients performed during patient care and excluded patients with elevated C-reactive protein and procalcitonin. Test results were separated according to age and sex, and the distribution of physiological ratios was estimated using an indirect approach (refineR). Additionally, we investigated the ratios’ diagnostic benefit for different inflammatory diseases (acute appendicitis, asthma, Bell's palsy, Henoch-Schonlein purpura, and cystic fibrosis) using the newly obtained reference intervals. Results: We estimated age- and sex-specific reference intervals from birth to adulthood for NLR, PLR, and LMR. Analyses in pediatric inflammatory diseases showed that PLR and LMR were poor markers to detect the examined inflammatory diseases, while NLR was significantly increased in patients with appendicitis and asthma. Conclusion: We provide pediatric reference intervals for NLR, PLR, and LMR to improve the interpretation of these biomarkers in children.
CRIS-Team Scopus Importer:2021-12-03
Keywords: blood components; inflammation; leukocytes; monocytes; neutrophils; platelets

Age of epilepsy onset as modulating factor for naming deficit after epilepsy surgery: a voxel-based lesion-symptom mapping study - Reindl, Caroline; Walther, Katrin; Allgäuer, Anna-Lena; Lang, Johannes; Welte, Tamara; Stritzelberger, Jenny; Gollwitzer, Stephanie; Schwarz, Michael; Trollmann, Regina; Madzar, Dominik; Knott, Michael; Dörfler, Arnd; et al. (Scientific Reports, 2023)
Age at onset of epilepsy is an important predictor of deterioration in naming ability following epilepsy surgery. In 141 patients with left hemispheric epilepsy and language dominance who received epilepsy surgery at the Epilepsy Centre Erlangen, naming of objects (Boston naming test, BNT) was assessed preoperatively and 6 months postoperatively. Surgical lesions were plotted on postoperative MRI and normalized for statistical analysis using voxel-based lesion-symptom mapping (VBLSM). The correlation between lesion and presence of postoperative naming deterioration was examined varying the considered age range of epilepsy onsets. The VBLSM analysis showed that volumes of cortex areas in the left temporal lobe, which were associated with postoperative decline of naming, increased with each year of later epilepsy onset. In patients with later onset, an increasing left posterior temporobasal area was significantly associated with a postoperative deficit when included in the resection. For late epilepsy onset, the temporomesial expansion also included the left hippocampus. The results underline that early onset of epilepsy is a good prognostic factor for unchanged postoperative naming ability following epilepsy surgery. For later age of epilepsy onset, the extent of the area at risk of postoperative naming deficit at 6 months after surgery included an increasing left temporobasal area which finally also comprised the hippocampus.
CRIS-Team Scopus Importer:2023-09-08

Age-related Differences in Immune Reactions to SARS-CoV-2 Spike and Nucleocapsid Antigens - Morhart, Patrick; Kehl, Sven; Schuh, Wolfgang; Hermes, Katharina; Meltendorf, Stefan; Neubert, Antje; Schneider, Michael; Brunner-Weinzierl, Monika; Schneider, Holm; Lingel, Holger (In Vivo, 2023)
Background/Aim: The manifestation and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections show a clear correlation to the age of a patient. The younger a person, the less likely the infection results in significant illness. To explore the immunological characteristics behind this phenomenon, we studied the course of SARS-CoV-2 infections in 11 households, including 8 children and 6 infants/neonates of women who got infected with SARS-CoV-2 during pregnancy. Materials and Methods: We investigated the immune responses of peripheral blood mononuclear cells (PBMCs), umbilical cord blood mononuclear cells (UCBCs), and T cells against spike and nucleocapsid antigens of SARS-COV-2 by flow cytometry and cytokine secretion assays. Results: Upon peptide stimulation, UCBC from neonates showed a strongly reduced IFN-γ production, as well as lower levels of IL-5, IL-13, and TNF-α alongside with decreased frequencies of surface CD137/PD-1 co-expressing CD4+ and CD+8 T cells compared with adult PBMCs. The PBMC response of older children instead was characterized by elevated frequencies of IFN-γ+ CD4+ T cells, but significantly lower levels of multiple cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, and TNF-α) and a marked shift of the CD4+/CD8+ T-cell ratio towards CD8+ T cells in comparison to adults. Conclusion: The increased severity of SARS-CoV-2 infections in adults could result from the strong cytokine production and lower potential to immunomodulate the excessive inflammation, while the limited IFN-γ production of responding T cells in infants/neonates and the additional higher frequencies of CD8+ T cells in older children may provide advantages during the course of a SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2023-01-13
Keywords: children; COVID-19; immune response; inflammation; neonates; pediatric immunology; SARS-CoV-2; spike protein

Agreement Between 24-Hour Salt Ingestion and Sodium Excretion in a Controlled Environment - Lerchl, Kathrin; Rakova, Natalia; Dahlmann, Anke; Rauh, Manfred; Goller, Ulrike; Basner, Mathias; Dinges, David F.; Beck, Luis; Agureev, Alexander; Larina, Irina; Baranov, Victor; Morukov, Boris; et al. (Hypertension, 2015)
Accurately collected 24-hour urine collections are presumed to be valid for estimating salt intake in individuals. We performed 2 independent ultralong-term salt balance studies lasting 105 (4 men) and 205 (6 men) days in 10 men simulating a flight to Mars. We controlled dietary intake of all constituents for months at salt intakes of 12, 9, and 6 g/d and collected all urine. The subjects' daily menus consisted of 27 279 individual servings, of which 83.0% were completely consumed, 16.5% completely rejected, and 0.5% incompletely consumed. Urinary recovery of dietary salt was 92% of recorded intake, indicating long-term steady-state sodium balance in both studies. Even at fixed salt intake, 24-hour urine collection for sodium excretion (UNaV) showed infradian rhythmicity. We defined a ±25 mmol deviation from the average difference between recorded sodium intake and UNaV as the prediction interval to accurately classify a 3-g difference in salt intake. Because of the biological variability in UNaV, only every other daily urine sample correctly classified a 3-g difference in salt intake (49%). By increasing the observations to 3 consecutive 24-hour collections and sodium intakes, classification accuracy improved to 75%. Collecting seven 24-hour urines and sodium intake samples improved classification accuracy to 92%. We conclude that single 24-hour urine collections at intakes ranging from 6 to 12 g salt per day were not suitable to detect a 3-g difference in individual salt intake. Repeated measurements of 24-hour UNaV improve precision. This knowledge could be relevant to patient care and the conduct of intervention trials.
EVALuna2:3790

A Half-Century of Heterotopic Heart Transplantation in Mice: The Spearhead of Immunology Research - Yin, Decheng; Dewald, Oliver; Peng, Xiangyu; Nie, Wenlong; Rong, Song; Dudziak, Diana; Lehmann, Christian; Hörning, André; Fu, Jian (Transplantology, 2024)
Since the success of solid organ transplants, such as human kidneys, livers and hearts, from the 50s to the 60s in the last century, the field of organ transplantation has progressed rapidly. Mainly due to modifications in surgical operation techniques and improvements in immunosuppressive therapy regimes, organ survival time can now be greatly prolonged. This progress has also been dependent upon the availability of appropriate animal models for organ transplantation. Therefore, the mouse heart transplantation model has developed into an irreplaceable research model for solid organ transplantation, providing indelible contributions to the field. In this review, we will provide an overview of the technical developments in murine heart transplantation, as well as its historical and current role for alloimmune research. Further, we will describe its current fields of application and its scientific achievements before we discuss potential future applications.
CRIS-Team Scopus Importer:2025-02-04
Keywords: heterotopic heart transplantation; immunology; murine transplantation

A high proportion of germline variants in pediatric chronic myeloid leukemia - Krumbholz, Manuela; Dolnik, Anna; Sträng, Eric; Ghete, Tabita; Skambraks, Sabrina; Hutter, Stephan; Simonis, Alfred; Stegelmann, Frank; Suttorp, Meinolf; Horn, Anselm; Sticht, Heinrich; Haferlach, Torsten; et al. (Molecular Cancer, 2024)
Chronic myeloid leukemia (CML) typically occurs in late adulthood. Pediatric CML is a rare form of leukemia. In all age groups, the characteristic genetic driver of the disease is the BCR::ABL1 fusion gene. However, additional genomic events contribute to leukemic transformation, which is not yet well-characterized in pediatric CML. We investigated the mutational landscape of pediatric CML to determine whether predisposing germline variants may play a role in early-age disease development. Whole exome sequencing and targeted sequencing were performed in pediatric and adult CML samples to identify age-related germline and somatic variants in addition to the BCR::ABL1 translocation. Germline variants were detected in about 60% of pediatric patients with CML, with predominantly hematopoietic genes affected, most frequently ASXL1, NOTCH1, KDM6B, and TET2. The number of germline variants was significantly lower in adult patients with CML. If only confirmed pathogenic variants were regarded as cancer-predisposing variants, the occurrence was 10% of pediatric CML, which is comparable to other hematological malignancies and most childhood cancer entities in general. We hypothesize that the interaction with the strong oncogene BCR::ABL1 may also favor the development of leukemia by weaker variants in the same genes. In pediatric patients, the germline variants of genes associated with clonal hematopoiesis may increase the likelihood that an incidental BCR::ABL1 translocation triggers the early manifestation of CML.
CRIS-Team Scopus Importer:2024-10-04
Keywords: Cancer predisposition; Chronic myeloid leukemia; Germline variants; Pediatric CML

A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation - Jobin, Katarzyna; Stumpf, Natascha E.; Schwab, Sebastian; Eichler, Melanie; Neubert, Patrick; Rauh, Manfred; Adamowski, Marek; Babyak, Olena; Hinze, Daniel; Sivalingam, Sugirthan; Weisheit, Christina; Hochheiser, Katharina; et al. (Science Translational Medicine, 2020)
The Western diet is rich in salt, which poses various health risks. A high-salt diet (HSD) can stimulate immunity through the nuclear factor of activated T cells 5 (Nfat5)-signaling pathway, especially in the skin, where sodium is stored. The kidney medulla also accumulates sodium to build an osmotic gradient for water conservation. Here, we studied the effect of an HSD on the immune defense against uropathogenic E. coli-induced pyelonephritis, the most common kidney infection. Unexpectedly, pyelonephritis was aggravated in mice on an HSD by two mechanisms. First, on an HSD, sodium must be excreted; therefore, the kidney used urea instead to build the osmotic gradient. However, in contrast to sodium, urea suppressed the antibacterial functionality of neutrophils, the principal immune effectors against pyelonephritis. Second, the body excretes sodium by lowering mineralocorticoid production via suppressing aldosterone synthase. This caused an accumulation of aldosterone precursors with glucocorticoid functionality, which abolished the diurnal adrenocorticotropic hormone-driven glucocorticoid rhythm and compromised neutrophil development and antibacterial functionality systemically. Consistently, under an HSD, systemic Listeria monocytogenes infection was also aggravated in a glucocorticoid-dependent manner. Glucocorticoids directly induced Nfat5 expression, but pharmacological normalization of renal Nfat5 expression failed to restore the antibacterial defense. Last, healthy humans consuming an HSD for 1 week showed hyperglucocorticoidism and impaired antibacterial neutrophil function. In summary, an HSD suppresses intrarenal neutrophils Nfat5-independently by altering the local microenvironment and systemically by glucocorticoid-mediated immunosuppression. These findings argue against high-salt consumption during bacterial infections.
CRIS-Team Scopus Importer:2020-04-07

A homozygous splice site mutation in SLC25A42, encoding the mitochondrial transporter of coenzyme a, causes metabolic crises and epileptic encephalopathy - Iuso, Arcangela; Alhaddad, Bader; Weigel, Corina; Kotzaeridou, Urania; Mastantuono, Elisa; Schwarzmayr, Thomas; Graf, Elisabeth; Terrile, Caterina; Prokisch, Holger; Strom, Tim M.; Hoffmann, Georg F.; Meitinger, Thomas; et al. (Springer, 2019)
SLC25A42 is an inner mitochondrial membrane protein which has been shown to transport coenzyme A through a lipid bilayer in vitro. A homozygous missense variant in this gene has been recently reported in 13 subjects of Arab descent presenting with mitochondriopathy with variable clinical manifestations. By exome sequencing, we identified two additional individuals carrying rare variants in this gene. One subject was found to carry the previously reported missense variant in homozygous state, while the second subject carried a homozygous canonical splice site variant resulting in a splice defect. With the identification of two additional cases, we corroborate the association between rare variants in SLC25A42 and a clinical presentation characterized by myopathy, developmental delay, lactic acidosis, and encephalopathy. Furthermore, we highlight the biochemical consequences of the splice defect by measuring a mild decrease of coenzyme A content in SLC25A42-mutant fibroblasts.
CRIS-Team Scopus Importer:2019-05-07

ALOX12B and PNPLA1 Have Distinct Roles in Epidermal Lipid Lamellar Organization - Meyer, Jason M.; Vávrová, Kateřina; Radner, Franz P.W.; Schneider, Holm; Dick, Angela; Mauro, Theodora M.; Elias, Peter M. (Journal of Investigative Dermatology, 2022)
CRIS-Team Scopus Importer:2022-12-16

Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation - Krieg, Peter; Rosenberger, Sabine; De Juanes, Silvia; Latzko, Susanne; Hou, Jin; Dick, Angela; Kloz, Ulrich; Van Der Hoeven, Frank; Hausser, Ingrid; Esposito, Irene; Rauh, Manfred; Schneider, Holm (Journal of Investigative Dermatology, 2013)
Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R-LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway. © 2013 The Society for Investigative Dermatology.
CRIS-Team Scopus Importer:2020-07-01

Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover - Marek, Ines; Lichtneger, Till-Simon; Cordasic, Nada; Hilgers, Karl Friedrich; Volkert, Gudrun; Fahlbusch, Fabian; Rascher, Wolfgang; Menendez-Castro, Carlos; Hartner, Andrea (PLoS ONE, 2016)
The ?8 integrin (Itga8) chain contributes to the regulation of cell proliferation and apoptosis in renal glomerular cells. In unilateral ureteral obstruction Itga8 is de novo expressed in the tubulointerstitium and a deficiency of Itga8 results in more severe renal fibrosis after unilateral ureteral obstruction. We hypothesized that the increased tubulointerstitial damage after unilateral ureteral obstruction observed in mice deficient for Itga8 is associated with altered tubulointerstitial cell turnover and apoptotic mechanisms resulting from the lack of Itga8 in cells of the tubulointerstitium. Induction of unilateral ureteral obstruction was achieved by ligation of the right ureter in mice lacking Itga8. Unilateral ureteral obstruction increased proliferation and apoptosis rates of tubuloepithelial and interstitial cells, however, no differences were observed in the tubulointerstitium of mice lacking Itga8 and wild type controls regarding fibroblast or proliferating cell numbers as well as markers of endoplasmic reticulum stress and apoptosis after unilateral ureteral obstruction. In contrast, unilateral ureteral obstruction in mice lacking Itga8 led to more pronounced tubulointerstitial cell activation i.e. to the appearance of more phospho-SMAD2/3-positive cells and more ?-smooth muscle actin-positive cells in the tubulointerstitium. Furthermore, a more severe macrophage and T-cell infiltration was observed in these animals compared to controls. Thus, Itga8 seems to attenuate tubulointerstitial fibrosis in unilateral ureteral obstruction not via regulation of cell turnover, but via regulation of TGF-? signalling, fibroblast activation and/or immune cell infiltration.
EVALuna2:3858

Altered patterns of heartbeat-evoked potentials in depersonalization/derealization disorder: neurophysiological evidence for impaired cortical representation of bodily signals - Schulz, Andre; Koester, Susann; Beutel, Manfred E.; Schaechinger, Hartmut; Voegele, Claus; Rost, Silke; Rauh, Manfred; Michal, Matthias (Psychosomatic Medicine, 2015)
Core features of depersonalization/derealization disorder (DPD) are emotional numbing and feelings of disembodiment. Although there are several neurophysiological findings supporting subjective emotional numbing, the psychobiology of disembodiment remains unclear.Heartbeat-evoked potentials (HEPs), which are considered psychophysiological indicators for the cortical representation of afferent signals originating from the cardiovascular system, were assessed in 23 patients with DPD and 24 healthy control individuals during rest and while performing a heartbeat perception task.Absolute HEP amplitudes did not differ between groups. Nevertheless, healthy individuals showed higher HEPs during the heartbeat perception task than during rest, whereas no such effect was found in patients with DPD (p = .031). Patients with DPD had higher total levels of salivary ?-amylase than did healthy individuals (9626.6 [8200.0] versus 5344.3 [3745.8] kU min/l; p = .029), but there were no group differences in cardiovascular measures (heart rate = 76.2 [10.1] versus 74.3 [7.5] beats/min, p = .60; normalized low-frequency heart rate variability = 0.63 [0.15] versus 0.56 [0.15] normalized units, p = .099; low frequency/high frequency ratio = 249.3 [242.7] versus 164.8 [108.8], p = .10), salivary cortisol (57.5 [46.7] versus 55.1 [43.6] nmol min/l, p = .86), or cortisone levels (593.2 [260.3] versus 543.8 [257.1] nmol min/l, p = .52).These results suggest altered cortical representation of afferent signals originating from the cardiovascular system in patients with DPD, which may be associated with higher sympathetic tone. These findings may reflect difficulties of patients with DPD to attend to their actual bodily experiences.
EVALuna2:18929

A mathematical model of white blood cell dynamics during maintenance therapy of childhood acute lymphoblastic leukemia - Le, Thuy T.T.; Jost, Felix; Raupach, Thomas; Zierk, Jakob; Rauh, Manfred; Suttorp, Meinolf; Stanulla, Martin; Metzler, Markus; Sager, Sebastian (Mathematical Medicine and Biology, 2019)
Acute lymphoblastic leukemia is the most common malignancy in childhood and requires prolonged oral maintenance chemotherapy to prevent disease relapse after remission induction with intensive intravenous chemotherapy. In maintenance therapy, drug doses of 6-mercaptopurine (6-MP) and methotrexate (MTX) are adjusted to achieve sustained antileukemic activity without excessive myelosuppression. However, uncertainty exists regarding timing and extent of drug dose responses and optimal dose adaptation strategies. We propose a novel comprehensive mathematical model for 6-MP and MTX pharmacokinetics, pharmacodynamics and myelosuppression in acute lymphoblastic maintenance therapy. We personalize and cross-validate the mathematical model using clinical data and propose a real-time algorithm to predict chemotherapy responses with a clinical decision support system as a potential future application.
CRIS-Team Scopus Importer:2019-12-24
Keywords: chemotherapy; childhood acute lymphoblastic leukemia; maintenance therapy; ordinary differential equations; parameter estimation; real-time algorithm

A mini-review of non-parenteral clonidine preparations for paediatric sedation - Hanning, Sara M.; Gul, Mine Orlu; Toni, Irmgard; Neubert, Antje; Tuleu, Catherine (Journal of Pharmacy and Pharmacology, 2017)
OBJECTIVE: To provide an overview of non-parenteral clonidine formulations and assess the feasibility of their use for paediatric sedation. METHODS: A literature search was conducted using electronic databases and a combination of search terms. Forty articles met the inclusion criteria. Publications were grouped into different dosage forms and assessed for their potential application for sedation of children in intensive care. KEY FINDINGS: Several routes of clonidine administration have been investigated for numerous indications in children, including perioperative sedation and analgesia. These include oral liquids, tablets, oral transmucosal systems, nasal sprays and rectal suspensions. Conflicting studies on oral transmucosal clonidine formulations suggest that further research is required to fully establish efficacy. Nasal sprays and rectal suspensions have the advantages of rapid onset of action and potential for dose flexibility, but predictable absorption is difficult to obtain. CONCLUSIONS: Provided age-appropriate strengths are available, intravenous formulations remain the most predictable in terms of bioavailability and flexible in terms of dose adjustment. However, as with all routes, down-titration is difficult given the long half-life of clonidine. Oral transmucosal systems, nasal sprays and rectal suspensions have potential in a less acute setting, but significant clinical work is required to elucidate a full pharmacokinetic and pharmacodynamic profile.
EVALuna2:34282

A Modified Surgical Technique for Kidney Transplantation in Mice - Yin, Decheng; Fu, Jian; Chen, Rongjun; Shushakova, Nelli; Allabauer, Ida; Wei, Xinyi; Schiffer, Mario; Dudziak, Diana; Rong, Song; Hörning, André (Journal of Visualized Experiments, 2022)
Kidney transplantation in mice is a complicated and challenging surgery procedure. There are very few publications demonstrating the key steps of this operation. Therefore, this article introduces the technique and points out the surgical caveats associated with this operation. In addition, important modifications in comparison to the conventional procedure are demonstrated. Firstly, a patch of the abdominal aorta is cut and prepared so that the proximal bifurcations of the renal artery, including the ureteral artery are transected together with the donor kidney en bloc. This reduces the risk of a ureter necrosis and avoids the development of a urinary tract occlusion. Secondly, a new method of the vascular anastomosis is demonstrated that allows the operator to flexibly increase or decrease the size of the anastomosis after renal transplant reperfusion has already been initiated. This avoids the development of vessel strictures and intraabdominal bleeding. Thirdly, a technique that enables the anastomosis of the delicate donor ureter and the recipient bladder that does not cause a trauma is shown. Adopting this protocol can shorten the operation time and reduces the damage to the recipient's bladder, thereby significantly increasing the operation success rate for the recipient mice.
CRIS-Team Scopus Importer:2022-08-19

A mouse organotypic tissue culture model for autosomal recessive congenital ichthyosis - Rosenberger, S.; Dick, Angela; Latzko, S.; Hausser, I.; Stark, H. -J.; Rauh, Manfred; Schneider, Holm; Krieg, P. (British Journal of Dermatology, 2014)
Autosomal recessive congenital ichthyoses (ARCIs) are keratinization disorders caused by impaired skin barrier function. Mutations in the genes encoding the lipoxygenases 12R-LOX and eLOX-3 are the second most common cause of ARCIs. In recent years, human skin equivalents recapitulating the ARCI phenotype have been established.To develop a murine organotypic tissue culture model for ARCI.Epidermal keratinocytes were isolated from newborn 12R-LOX-deficient mice and cocultivated with mouse dermal fibroblasts embedded in a scaffold of native collagen type I.With this experimental set-up the keratinocytes formed a well-organized multilayered stratified epithelium resembling skin architecture in vivo. All epidermal layers were present and the keratinocytes within showed the characteristic morphological features. Markers for differentiation and maturation indicated regular epidermal morphogenesis. The major components of epidermal structures were expressed, and were obviously processed and assembled properly. In contrast to their wild-type counterparts, 12R-LOX-deficient skin equivalents showed abnormal vesicular structures in the upper epidermal layers correlating with altered lipid composition and increased transepidermal water loss, comparable with 12R-LOX-deficient mice.The mouse skin equivalents faithfully recapitulate the 12R-LOX-deficient phenotype observed in vivo, classifying them as appropriate in vitro models to study molecular mechanisms involved in the development of ARCI and to evaluate novel therapeutic agents. In contrast to existing human three-dimensional skin models, the generation of these murine models is not constrained by a limited supply of material and does not depend on in vitro expansion and/or genetic manipulations that could result in inadvertent genotypic and phenotypic alterations.
EVALuna2:18903

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany - Strzelczyk, Adam; Schubert-Bast, Susanne; Bast, Thomas; Bettendorf, Ulrich; Fiedler, Barbara; Hamer, Hajo; Herting, Arne; Kalski, Malin; Kay, Lara; Kieslich, Matthias; Klein, Karl Martin; Kluger, Gerhard; et al. (Epilepsia, 2019)
Objective: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. Methods: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). Results: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001). Significance: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.
CRIS-Team Scopus Importer:2019-07-09
Keywords: costs; depression; encephalopathy; quality of life; Severe myoclonic epilepsy of infants

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome - Gross, Oliver; Tönshoff, Burkhard; Weber, Lutz T.; Pape, Lars; Latta, Kay; Fehrenbach, Henry; Lange-Sperandio, Baerbel; Zappel, Hildegard; Hoyer, Peter; Staude, Hagen; König, Sabine; John, Ulrike; et al. (Kidney International, 2020)
Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.
CRIS-Team Scopus Importer:2020-04-24
Keywords: ACE inhibitors; albuminuria; Alport syndrome; chronic kidney disease; pediatric nephrology; renin-angiotensin system

A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus - Zenner, Hans-Peter; Delb, Wolfgang; Kroener-Herwig, Birgit; Jaeger, Burkhard; Peroz, Ingrid; Hesse, Gerhard; Mazurek, Birgit; Goebel, Gerhard; Gerloff, Christian; Trollmann, Regina; Biesinger, Eberhard; Seidler, Harald; et al. (European Archives of Oto-Rhino-Laryngology, 2017)
The majority of tinnitus patients are affected by chronic idiopathic tinnitus, and almost 60 different treatment modalities have been reported. The present study is a multidisciplinary systematic analysis of the evidence for the different forms of treatment for chronic tinnitus. The results are used to form the basis of an S3 guideline. A systematic search was carried out in PubMed and the Cochrane Library. The basis for presenting the level of evidence was the evidence classification of the Oxford Centre of Evidence-based Medicine. Whenever available, randomised controlled trials were given preference for discussing therapeutic issues. All systematic reviews and meta-analyses were assessed for their methodological quality, and effect size was taken into account. As the need for patient counselling is self-evident, specific tinnitus counselling should be performed. Due to the high level of evidence, validated tinnitus-specific, cognitive behavioural therapy is strongly recommended. In addition, auditory therapeutic measures can be recommended for the treatment of concomitant hearing loss and comorbidities; those should also be treated with drugs whenever appropriate. In particular, depression should be treated, with pharmacological support if necessary. If needed, psychiatric treatment should also be given on a case-by-case basis. With simultaneous deafness or hearing loss bordering on deafness, a CI can also be indicated. For auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation.
EVALuna2:34026

A Multimodal Lifestyle Psychosocial Survivorship Program in Young Cancer Survivors: The CARE for CAYA Program-A Randomized Clinical Trial Embedded in a Longitudinal Cohort Study - von Grundherr, Julia; Elmers, Simon; Koch, Barbara; Hail, Lesley-Ann; Mann, Julia; Escherich, Gabriele; Bergelt, Corinna; Samland, Luisa; Jensen, Wiebke; Vettorazzi, Eik; Stark, Maria; Valentini, Luzia; et al. (JAMA Network Open, 2024)
Importance: There is a lack of trials examining the effect of counseling interventions for child, adolescent, and younger adult (CAYA) cancer survivors. Objective: To assess lifestyle habits and the psychosocial situation of CAYAs to determine the efficacy of needs-based interventions in the CARE for CAYA program (CFC-P). Design, Setting, and Participants: The CFC-P was conducted as a multicenter program in 14 German outpatient clinics, mainly university cancer centers. Recruitment began January 1, 2018; a randomized clinical trial was conducted until July 15, 2019; and intervention was continued as a longitudinal cohort study until March 31, 2021. Data preparation was conducted from April 1, 2021, and analysis was conducted from August 14, 2021, to May 31, 2022. Herein, predefined confirmatory analyses pertain to the RCT and descriptive results relate to the overall longitudinal study. Data analysis was based on the full analysis set, which is as close as possible to the intention-to-treat principle. Intervention: A comprehensive assessment determined needs in physical activity, nutrition and psychooncology. Those with high needs participated in 1 to 3 modules. In the RCT, the IG received 5 counseling sessions plus newsletters, while the control group CG received 1 counseling session. Main Outcomes and Measures: The primary outcome was the change in the rate of CAYAs with high needs at 52 weeks. Secondary outcomes were feasibility, modular-specific end points, satisfaction, quality of life, and fatigue. Results: Of 1502 approached CAYAs aged 15 to 39 years, 692 declined participation. Another 22 CAYAs were excluded, resulting in 788 participants. In the randomized clinical trial, 359 CAYAs were randomized (intervention group [IG], n = 183; control group [CG], n = 176), and 274 were followed up. In the RCT, the median age was 25.0 (IQR, 19.9-32.2) years; 226 were female (63.0%) and 133 male (37.0%). After 52 weeks, 120 CAYAs (87.0%) in the IG and 115 (86.5%) in the CG still had a high need in at least 1 module (odds ratio, 1.04; 95% CI, 0.51-2.11; P = .91). Both groups reported reduced needs, improved quality of life, reduced fatigue, and high satisfaction with the CFC-P. Conclusions and Relevance: In this randomized clinical trial, the implementation of a lifestyle program in this cohort was deemed necessary, despite not meeting the primary outcome. The interventions did not alter the rate of high needs. The results may provide guidance for the development of multimodal interventions in the follow-up care of CAYAs. Trial Registration: German Clinical Trial Register: DRKS00012504.
CRIS-Team Scopus Importer:2024-04-05

A Multi-User Terminology Mapping Toolbox - Mate, Sebastian; Seuchter, Susanne A.; Ehrenberg, Katharina; Deppenwiese, Noemi; Zierk, Jakob; Prokosch, Hans-Ulrich; Kraska, Detlef; Kapsner, Lorenz (German Medical Data Sciences: Bringing Data to Life, 2021)
Semantic interoperability is a major challenge in multi-center data sharing projects, a challenge that the German Initiative for Medical Informatics is taking up. With respect to laboratory data, enriching site-specific tests and measurements with LOINC codes appears to be a crucial step in supporting cross-institutional research. However, this effort is very time-consuming, as it requires expert knowledge of local site specifics. To ease this process, we developed a generic manual collaborative terminology mapping tool, the MIRACUM Mapper. It allows the creation of arbitrary mapping workflows involving different user roles. A mapping workflow with two user roles has been implemented at University Hospital Erlangen to support the local LOINC mapping. Additionally, the MIRACUM LabVisualizeR provides summary statistics and visualizations of analyte data. We developed a toolbox that facilitates the collaborative creation of mappings and streamlines the review as well as the validation process. The two tools are available under an open source license.
CRIS-Team Scopus Importer:2021-06-11
Keywords: Interoperability; Laboratory; LOINC; Secondary Use; Terminology

A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition - Rauh, Robert; Diakov, Alexei; Tzschoppe, Anja; Korbmacher, Judit; Azad, Abul Kalam; Cuppens, Harry; Cassiman, Jean-Jaques; Dötsch, Jörg; Sticht, Heinrich; Korbmacher, Christoph (The Journal of Physiology, 2010)
Increased activity of the epithelial sodium channel (ENaC) in the respiratory airways contributes to the pathophysiology of cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In some patients suffering from atypical CF a mutation can be identified in only one CFTR allele. We recently identified in this group of CF patients a heterozygous mutation (W493R) in the α-subunit of ENaC. Here, we investigate the functional effects of this mutation by expressing wild-type αβγENaC or mutant αW493RβγENaC in Xenopus oocytes. The αW493R mutation stimulated amiloride-sensitive whole-cell currents (ΔIami) by ∼4-fold without altering the single-channel conductance or surface expression of ENaC. As these data suggest that the open probability (Po) of the mutant channel is increased, we investigated the proteolytic activation of ENaC by chymotrypsin. Single-channel recordings revealed that chymotrypsin activated near-silent channels in outside-out membrane patches from oocytes expressing wild-type ENaC, but not in membrane patches from oocytes expressing the mutant channel. In addition, the αW493R mutation abolished Na+ self inhibition of ENaC, which might also contribute to its gain-of-function effects. We conclude that the αW493R mutation promotes constitutive activation of ENaC by reducing the inhibitory effect of extracellular Na+ and decreasing the pool of near-silent channels. The resulting gain-of-function phenotype of the mutant channel might contribute to the pathophysiology of CF in patients carrying this mutation. © 2010 The Authors. Journal compilation © 2010 The Physiological Society.
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Anaesthesia for orphan disease: Haddad syndrome (Ondine-Hirschsprung disease) - Prottengeier, Johannes; Münster, Tino; Wintermeyer, Philip; Schmidt, Joachim (European Journal of Anaesthesiology, 2014)
EVALuna2:16670

Analgesic Drug Prescription Patterns on Five International Paediatric Wards - Botzenhardt, Sebastian; Rashed, Asia N.; Wong, Ian C. K.; Tomlin, Stephen; Neubert, Antje (Paediatric Drugs, 2016)
AIM: Analgesic and anti-inflammatory drugs are frequently prescribed in paediatrics. Prescribing and dosing patterns in hospitalised children are not well known. This study explores analgesic drug utilisation on five paediatric wards and discusses its findings in comparison with World Health Organization (WHO) guidelines. METHOD: A sub-analysis of a prospective, multicentre, observational cohort study was undertaken. Prescription data of children aged up to ≤18 years were collected between October 2008 and December 2009 on paediatric general medical wards in five hospitals in Australia, Germany, the United Kingdom (UK), Hong Kong (HK) and Malaysia. Analgesic drug prescriptions were analysed for prescribing patterns in terms of dosing, frequency and route of administration. Dosing data were compared with local recommendations and WHO guidelines for children. RESULTS: In the study cohort, 56.8 % (726/1278) of paediatric patients received at least one analgesic drug prescription (1227 prescriptions). The median age of patients with analgesics was 2.2 years [interquartile range (IQR) 0.8-7.3], and the median number of prescriptions per patient was one (IQR 1-2). The most commonly prescribed drugs were oral paracetamol (45.9 %, 563/1227) and oral ibuprofen (19.9 %, 244/1227). Daily doses of paracetamol ranged from 30 mg/kg/day in Germany to 67-68 mg/kg/day in the UK and HK (p < 0.05). For ibuprofen, single doses ranged from 5-6 mg/kg in HK and the UK to 10 mg/kg in Germany and Australia (p < 0.001). Opioid use prevalence was statistically different between the centres and ranged from 0 to 17.6 % (p < 0.001). CONCLUSION: This study provides a comprehensive overview of analgesic drug use of hospitalised children. Similar to primary care data, paracetamol is the most commonly used analgesic. As recommended by WHO guidelines, oral medication was favoured and opioids used in addition to paracetamol and ibuprofen. Overall drug utilisation was in line with local recommendations and WHO guidelines. Differences in use of paracetamol and ibuprofen among countries were seen, indicating that safety concerns are perceived differently. More large-scale safety studies are needed.
EVALuna2:34010

Analysis of CFTR mRNA and Protein in Peripheral Blood Mononuclear Cells via Quantitative Real-Time PCR and Western Blot - Schnell, Alexander; Tamm, Stephanie; Hedtfeld, Silke; Rodriguez Gonzalez, Claudio; Hörning, André; Lachmann, Nico; Stanke, Frauke; Dittrich, Anna Maria; Munder, Antje (International Journal of Molecular Sciences, 2024)
The Cystic Fibrosis Conductance Transmembrane Regulator gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result in impaired ion transport, subsequently leading to perturbed secretion in all exocrine glands and, therefore, the multi-organ disease cystic fibrosis (CF). In recent years, several studies have reported on CFTR expression in immune cells as demonstrated by immunofluorescence, flow cytometry, and immunoblotting. However, these data are mainly restricted to single-cell populations and show significant variation depending on the methodology used. Here, we investigated CFTR transcription and protein expression using standardized protocols in a comprehensive panel of immune cells. Methods: We applied a high-resolution Western blot protocol using a combination of highly specific monoclonal CFTR antibodies that have been optimized for the detection of CFTR in epithelial cells and healthy primary immune cell subpopulations sorted by flow cytometry and used immortalized cell lines as controls. The specificity of CFTR protein detection was controlled by peptide competition and enzymatic Peptide-N-Glycosidase-F (PNGase) digest. CFTR transcripts were analyzed using quantitative real-time PCR and normalized to the level of epithelial T84 cells as a reference. Results: CFTR mRNA expression could be shown for primary CD4+ T cells, NK cells, as well as differentiated THP-1 and Jurkat T cells. In contrast, we failed to detect CFTR transcripts for CD14+ monocytes and undifferentiated THP-1 cells, as well as for B cells and CD8+ T cells. Prominent immunoreactive bands were detectable by immunoblotting with the combination of four CFTR antibodies targeting different epitopes of the CFTR protein. However, in biosamples of non-epithelial origin, these CFTR-like protein bands could be unmasked as false positives through peptide competition or PNGase digest, meaning that the observed mRNA transcripts were not necessarily translated into CFTR proteins, which could be detected via immunoblotting. Our results confirm that mRNA expression in immune cells is many times lower than in that cells of epithelial origin. The immunoreactive signals in immune cells turned out to be false positives, and may be provoked by the presence of a high-affinity protein with a similar epitope. Non-specific binding (e.g., Fab-interaction with glycosyl branches) might also contribute to false positive signals. Our findings highlight the necessity of accurate controls, such as CFTR-negative cells, as well as peptide competition and glycolytic digest in order to identify genuine CFTR protein by immunoblotting. Our data suggest, furthermore, that CFTR protein expression data from techniques such as histology, for which the absence of a molecular weight or other independent control prevents the unmasking of false positive immunoreactive signals, must be interpreted carefully as well.
CRIS-Team Scopus Importer:2024-07-12
Keywords: CFTR; cystic fibrosis; expression; immune cell lines; immune cells; leukocytes; protein; qPCR; RNA; Western blot

Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019 - Leitzen, Sarah; Dubrall, Diana; Toni, Irmgard; Stingl, Julia; Schulz, Maike; Schmid, Matthias; Neubert, Antje; Sachs, Bernhardt (PLoS ONE, 2021)
The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0-17 years were identified in the European ADR database Eudra- Vigilance for the time period 01.01.2000-28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0-1 month), 11.0% (2 months-1 year), 7.4% (2-3 years), 9.3% (4-6 years), 25.8% (7-12 years), and 34.8% (13-17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety.
CRIS-Team Scopus Importer:2021-03-26

Analysis of Two Protection Strategies for Reducing Aerosol Expulsion from Wind Instruments - Baron, Miriam; Tur, Bogac; Köberlein, Marie; Hermann, Laila Ava; Gantner, Sophia; Echternach, Matthias; Kniesburges, Stefan (Fluids, 2025)
(1) Background: the aim of this study is to assess the effectiveness of two protection systems for aerosol cloud reduction while playing different wind instruments. (2) Methods: The protection systems used were a cotton molton construction combined with a bell filter attached at the bell of the instruments, as well as a household paper towel. For visualization of the emitted aerosol particles, e-cigarettes were used. With three full HD cameras, cloud dispersion was captured in the forward, sideways, and upwards directions. The effectiveness of aerosol spread reduction was statistically evaluated. (3) Results: Without protection, aerosol clouds dispersed, on average, up to 1.23 m in the forward direction, 0.46 m sideways, and 0.86 m upwards. The cotton molton mask reduced forward spread by 42%, while the paper towel achieved a 15% reduction, although both systems increased lateral and vertical dispersion. Specifically, the cotton molton mask yielded a 9% increase to the side and 7% in the upward direction, while the paper towel resulted in a 66% increase to the sides and a 10% increase in the upward direction. The cotton molton mask’s effectiveness was attributed to its additional coverage of the tone holes, which contribute to aerosol emission in woodwind instruments. A statistical analysis via the Friedman test confirmed significant reductions in forward dispersion with the cotton molton system. (4) Conclusions: Protective systems can partially reduce aerosol emissions. However, these alone are not sufficient, and further measures to reduce the spread of particles are necessary.
CRIS-Team Scopus Importer:2025-06-06
Keywords: aerosol dispersion; aerosol particle reduction; playing wind instruments

An artificial intelligence-assisted clinical framework to facilitate diagnostics and translational discovery in hematologic neoplasia - Tang, Ming; Antić, Željko; Fardzadeh, Pedram; Pietzsch, Stefan; Schröder, Charlotte; Eberhardt, Adrian; van Bömmel, Alena; Escherich, Gabriele; Hofmann, Winfried; Horstmann, Martin A.; Illig, Thomas; McCrary, J. Matt; et al. (EBioMedicine, 2024)
Background: The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. Methods: We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. Findings: By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients’ subgroups. Interpretation: An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. Funding: German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.
CRIS-Team Scopus Importer:2024-06-07
Keywords: Clinical framework; Data integration; Leukaemia; Machine learning

Anatomical Left Superior Vena Cava Correction: An Option for Left Ventricular Recruitment? - Bieling, Frederike; Cesnjevar, Robert A.; Cuomo, Michela; Weigelt, Annika; Dittrich, Sven; Purbojo, Ariawan (Thoracic and Cardiovascular Surgeon, 2025)
Left superior vena cava (LSVC)-related obstruction of mitral inflow is a rare condition in patients with complex cardiac anomalies like hypoplastic left heart complex. We report on the impact of establishing LSVC to right superior vena cava (RSVC) continuity on the growth of borderline hypoplastic left ventricular structures as an addendum to our previously published work.Twenty-two patients underwent LSVC to RSVC anastomosis, whereas six had LSVC ligation (n = 4) or clip closure (n = 2), all alongside congenital heart defect correction. The indication was LSVC-related obstruction of left ventricular inflow due to a dilated coronary sinus. Clinical data were systematically reviewed, with regular follow-up. Left ventricular end diastolic diameters (LVEDD), aortic valve diameters, and left ventricular outflow tract (LVOT) diameters were recorded using echocardiography.Follow-up showed 90% survival at 3.3 ± 0.4 years. Mean LVEDD Z-scores improved from -2.19 ± 0.35 to -1.24 ± 0.26 after repair (p < 0.01) and to -1.33 ± 0.56 at 6-month follow-up. In patients without mitral repair, LVEDD Z-scores improved from -2.11 ± 0.62 preoperatively to -1.85 ± 0.88 postoperatively (p < 0.05). LVOT Z-scores increased from -2.49 ± 0.48 to -0.87 ± 0.75 (p < 0.05) and aortic valve Z-scores improved from -1.08 ± 0.57 to 0.5 ± 0.39 over 24 months (p < 0.05).Anatomical LSVC correction may improve left ventricular filling and growth of the left ventricle, aortic valve, and LVOT in patients with borderline left ventricles and could be considered without as a potential recruitment strategy.
CRIS-Team Scopus Importer:2025-04-25

A new approach of three-dimensional guidance in paediatric cath lab: segmented and tessellated heart models for cardiovascular interventions in CHD - Ehret, Nicole; Alkassar, Muhannad; Dittrich, Sven; Cesnjevar, Robert; Ruffer, Andre; Uder, Michael; Rompel, Oliver; Hammon, Matthias; Glöckler, Martin (Cardiology in the Young, 2018)
BACKGROUND: Optimal imaging is essential for catheter-based interventions in CHD. The three-dimensional models in volume-rendering technique currently in use are not standardised. This paper investigates the feasibility and impact of novel three-dimensional guidance with segmented and tessellated three-dimensional heart models in catheterisation of CHD. In addition, a nearly radiation-free two- to three-dimensional registration and a biplane overlay were used.Methods and resultsWe analysed 60 consecutive cases in which segmented tessellated three-dimensional heart models were merged with live fluoroscopy images and aligned using the tracheal bifurcation as a fiducial mark. The models were generated from previous MRI or CT by dedicated medical software. We chose the stereo-lithography format, as this promises advantage over volume-rendering-technique models regarding visualisation. Prospects, potential benefits, and accuracy of the two- to three-dimensional registration were rated separately by two paediatric interventionalists on a five-point Likert scale. Fluoroscopy time, radiation dose, and contrast dye consumption were evaluated. Over a 10-month study period, two- to three-dimensional image fusion was applied to 60 out of 354 cases. Of the 60 catheterisations, 73.3% were performed in the context of interventions. The accuracy of two- to three-dimensional registration was sufficient in all cases. Three-dimensional guidance was rated superior to conventional biplane imaging in all 60 cases. We registered significantly smaller amounts of used contrast dye (p<0.01), lower levels of radiation dose (p<0.02), and less fluoroscopy time (p<0.01) during interventions concerning the aortic arch compared with a control group. CONCLUSIONS: Two- to three-dimensional image fusion can be applied successfully in most catheter-based interventions of CHD. Meshes in stereo-lithography format are accurate and base for standardised and reproducible three-dimensional models.
EVALuna2:34698

A New Mouse Model of Junctional Epidermolysis Bullosa: The LAMB3 628G > A Knockin Mouse - Hammersen, Johanna; Hou, Jin; Wünsche, Stephanie; Brenner, Sven; Winkler, Thomas; Schneider, Holm (Journal of Investigative Dermatology, 2015)

Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension - Hilgers, Karl Friedrich; Hartner, Andrea; Porst, Markus; Veelken, Roland; Mann, Johannes (Circulation, 2001)
Background— Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect. Methods and Results— Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg · kg−1 · d−1 or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects. Conclusions— Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsarta
Keywords: angiotensin; hypertension; kidney; leukocytes; survival

Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure - Bosch, Agnes; Poglitsch, Marko; Kannenkeril, Dennis; Kolwelter, Julie; Striepe, Kristina; Ott, Christian; Rauh, Manfred; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (ESC Heart Failure, 2023)
Aims: Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin–angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme–angiotensin II–angiotensin-1 receptor axis (Ang I–ACE–Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2–angiotensin-(1-7)–Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects. Methods: We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II–III) in a randomized placebo-controlled clinical trial ‘Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)’. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication. Results: Empagliflozin medication induced a significant rise in Ang-II [68.5 pmol/L (21.3–324.2) vs. 131.5 pmol/L (34.9–564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol/L (21.5–236.6) vs. 125.9 pmol/L (52.6–512.9), P < 0.001], Ang-(1-7) [3.0 pmol/L (3.0–15.0) vs. 10.1 pmol/L (3.0–31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0–22.9) vs. 9.9 pmol/L (2.8–36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2–750.6) vs. 568.2 pmol/L (164.7–1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0–14.1) vs. 15.0 pmol/L (3.0–31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8–46.6) vs. 36.4 pmol/L (11.1–90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0–60.8) vs. 26.4 pmol/L (10.7–63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0–20.7) vs. 10.5 pmol/L (3.0–50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0–8.4) vs. 2.8 pmol/L (2.0–6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment). Conclusions: Our data indicate that empagliflozin might lead to an activation of both the Ang I–ACE–Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I–ACE–Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Angiotensin profiles; Cardioprotective effects; Chronic heart failure; Empagliflozin; Renin–angiotensin system

An isotope dilution LC–MS/MS-based candidate reference method for the quantification of androstenedione in human serum and plasma - Gradl, Katrin; Taibon, Judith; Singh, Neeraj; Albrecht, Eva; Geistanger, Andrea; Pongratz, Stephan; Hutzler, Stefan; Mayer, Magdalena; Kleinschmidt, Christine; Geletneky, Christian; Hofmann, Verena; Köppl, Daniel; et al. (Clinical Mass Spectrometry, 2020)
The accurate measurement of androstenedione in human serum and plasma is required for steroid profiling to assure the appropriate diagnosis and differential diagnosis of hyperandrogenism. In this work, we introduce an isotope dilution liquid chromatography–tandem mass spectrometry (LC–MS/MS) candidate reference measurement procedure for the quantification of androstenedione in human serum and plasma. The performance of the procedure enables its use in the evaluation and standardization of routine assays and for the evaluation of patient samples to ensure the traceability of individual patient results. As the primary standard, a certified reference material from NMIA (National Measurement Institute, Australia) was used. Additionally, a quantitative nuclear magnetic resonance (qNMR) method was developed for the value assignment of the primary reference material, which ensures the direct traceability to SI units, as well as the independence from the availability of reference materials. 13C3-labeled androstenedione was used as the internal standard. The introduced method allows the measurement of androstenedione in the range of 0.05–12 ng/mL, and the assay imprecision was found to be <2% between 5 and 12 ng/mL, 3.5% at 1.5 ng/mL, and 5.2% at 0.05 ng/mL, with an accuracy of 95–105% for the serum and 91–103% for the plasma matrix. The transferability to a second laboratory was validated by method comparison based on 112 patient samples. The comparison of the results obtained from the presented method and an LC–MS/MS routine assay, using 150 native patient samples, showed a good correlation with a bias of the routine method of ≤4.0%.
CRIS-Team Scopus Importer:2020-02-14
Keywords: Androstenedione; Human serum; LC–MS/MS; Quantitative NMR; Reference measurement procedure

An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of cortisol in human serum and plasma - Ott, Myriam; Singh, Neeraj; Bauland, Friederike; Köppl, Daniel; Kandler, Kerstin; Gaudl, Alexander; Geistanger, Andrea; Ceglarek, Uta; Rauh, Manfred; Geletneky, Christian; Taibon, Judith (Clinical Chemistry and Laboratory Medicine, 2025)
Accurate measurement of serum cortisol is crucial for the diagnosis and management of adrenal disorders. Thus, we have developed a novel isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) to quantify cortisol in human serum/plasma, offering higher sensitivity and reliability compared to existing RMPs. Quantitative Nuclear Magnetic Resonance spectroscopic (qNMR) methodology has been utilized to assign the absolute content (g/g) and SI-traceability to the reference materials. A novel two-dimensional heart-cut liquid chromatography (LC) approach was implemented for the LC-MS/MS, combined with a supported liquid extraction (SLE) sample preparation protocol. A multi-day validation experiment assessed precision and accuracy. Reproducibility was assessed by comparing procedure results between two independent laboratories, and measurement uncertainty (MU) was evaluated in compliance with current guidelines. The established RMP exhibited high sensitivity, with a quantification range of 0.800-600 » ng/mL (2.21-1,655 » nmol/L), exceeding the ranges of existing JCTLM-listed RMPs. Intermediate precision was ≤2.6 » %, and repeatability ranged from 0.9 to 1.9 » % across all concentration levels. The relative mean bias ranged from -1.3 to 1.4 » % for all matrices and concentration levels. Measurement uncertainties (MU) for cortisol in single measurements were ≤2.8 » % regardless of the concentration level and sample type. Using the certified International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference panel, the equivalence between the candidate RMP and the Joint Committee on Traceability in Laboratory Medicine (JCTLM) listed RMPs (NRMeth 57 and NRMeth 8) was assessed, revealing excellent agreement. This RMP allows for highly sensitive and reproducible determination of cortisol. The performance of the RMP facilitates the standardization of routine assays and ensures traceability in the measurement of individual patient samples.
CRIS-Team Scopus Importer:2025-02-28
Keywords: cortisol; isotope dilution-liquid chromatography-tandem mass spectrometry; qNMR characterization; reference measurement procedure; SI units; traceability

An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of aldosterone in human serum and plasma - Taibon, Judith; Santner, Tobias; Singh, Neeraj; Ibrahim, Sara Cheikh; Babitzki, Galina; Koeppl, Daniel; Gaudl, Alexander; Geistanger, Andrea; Ceglarek, Uta; Rauh, Manfred; Geletneky, Christian (Clinical Chemistry and Laboratory Medicine, 2023)
Objectives: An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) for aldosterone quantification in human serum and plasma is presented.Methods: The material used in this RMP was characterized by quantitative nuclear magnetic resonance (qNMR) to assure traceability to SI Units. For liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis a two-dimensional heart cut LC approach, in combination with an optimal supported liquid extraction protocol, was established for the accurate analysis of aldosterone in human serum and plasma in order to minimize matrix effects and avoid the co-elution of interferences. Assay validation was performed according to current guidelines. Selectivity and specificity were assessed using spiked serum; potential matrix effects were examined by a post column infusion experiment and the comparison of standard line slopes. An extensive protocol over 5 days was applied to determine precision, accuracy and trueness. Measurement uncertainty was evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM), for which three individual sample preparations were performed on at least two different days.Results: The RMP allowed aldosterone quantification within the range of 20-1,200 pg/mL without interference from structurally-related compounds and no evidence of matrix effects. Intermediate precision was =4.7% and repeatability was 2.8-3.7% for all analyte concentrations. The bias ranged between -2.2 and 0.5% for all levels and matrices. Total measurement uncertainties for target value assignment (n=6) were found to be =2.3%; expanded uncertainties were =4.6% (k=2) for all levels.Conclusions: The RMP showed high analytical performance for aldosterone quantification in human serum and plasma. The traceability to SI units was established by qNMR content determination of aldosterone, which was utilized for direct calibration of the RMP. Thus, this candidate RMP is suitable for routine assay standardization and evaluation of clinical samples.
CRIS-Team WoS Importer:2023-04-21

Anorectal malformations - de Blaauw, Ivo; Stenström, Pernilla; Yamataka, Atsuyuki; Miyake, Yuichiro; Reutter, Heiko Martin; Midrio, Paola; Wood, Richard; Grano, Caterina; Pakarinen, Mikko (Nature Reviews Disease Primers, 2024)
Anorectal malformations (ARM) are rare congenital anomalies with an overall prevalence of 3.32 per 10,000 pregnancies. ARM describe a spectrum of anomalies of the anus and rectum ranging from a minimally displaced anal canal to a complete fusion of the anorectum, vagina and urethra with hypoplastic sphincter and pelvic floor muscle. Aberrant septation of the hindgut with anomalous cloacal membrane during weeks 6 to 9 of gestation form the developmental basis for a spectrum of anomalies defined as ARM. Although underlying specific syndromes and occasional familiar occurrence suggest genetic aetiology, most ARM are non-syndromic and their causal genetic mechanisms and non-genetic insults remain unclear. ARM is a clinical diagnosis, generally made early after birth via careful inspection of the perineum. Prenatal detection remains rare, and modern technical developments have added little to prenatal diagnostics. ARM is corrected surgically. Since its introduction in 1982, posterior sagittal anorectoplasty is the most common surgery for ARM reconstruction. Subsequent surgical adaptations focus on minimizing iatrogenic operative injury by limiting surgical invasiveness. They include laparoscopic procedures and shortening of incisions with confined dissection in open surgery. Although outcomes in patients with ARM have evolved throughout the past decades, there is urgent need for further improvements both in functional outcomes and quality of life. The importance of psychosocial experiences of affected patients is increasingly recognized. Continued research is necessary to improve prenatal detection, to elucidate genetic and epigenetic alterations and to refine optimal surgical procedures.
CRIS-Team Scopus Importer:2024-11-29

Anorexia Athletica and Relative Energy Deficiency - Schöffl, Isabelle; Schöffl, Volker (Springer International Publishing, 2022)
Climbing belongs to the sport disciplines in which low body weight represents an advantage. Many athletes therefore use at least one unhealthy way of controlling their weight. The consequence is relative energy deficiency in sport or RED-S with possible long-term complications like dental caries, osteoporosis, renal insufficiency, anemia, and recognized psychiatric disorders. The most common psychiatric disorders resulting from RED-S, formerly titled anorexia athletica, are true anorexia nervosa and depression. Some of the athletes are so convinced of the dependence of their weight on their performance, and this wrong belief is so firmly ingrained that they suffer their whole life from the mental consequences. Early detection of possible warning signs and providing assistance early on is therefore a priority in order to reduce long-term damage.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Anorexia athletica; Athlete female triad; RED-S

A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia - Wohlfart, Sigrun; Söder, Stephan; Smahi, Asma; Schneider, Holm (American Journal of Medical Genetics Part A, 2016)
Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-?B signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-?B signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.
EVALuna2:6777

A novel mutation of the StAR gene with congenital adrenal hyperplasia and its association with heterochromia iridis: a case report - Splittstösser, Vera; Schreiner, Felix; Gohlke, Bettina; Welzel, Maik; Holterhus, Paul Martin; Wölfle, Joachim (BMC Endocrine Disorders, 2019)
BACKGROUND: We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. CASE PRESENTATION: In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1-10,1 pmol/l), elevated renin (836 ng/l; ref. level 5-308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886-3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. CONCLUSION: A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency.
CRIS-Team Scopus Importer:2019-11-12
Keywords: Heterochromia iridis; Lipoid congenital adrenal hyperplasia; StAR

Anterosuperior diverticula of the right ventricle: morphological spectrum and long-term outcome of a distinct cardiac anomaly - Wiegand, Gesa; Rauch, Ralf; Singer, Helmut; Koch, Andreas; Hofbeck, Michael (Pediatric Cardiology, 2014)
Right-ventricular diverticula (RVD), although rare, have particular characteristics. Our study describes the morphology of anterosuperior diverticula of the right ventricle (RV) and patient outcome for this anomaly. Retrospective analysis was performed on all patients with anterosuperior RVD diagnosed in two tertiary referral centres. From January 1982 to December 2012, five patients were diagnosed with anterosuperior RVD (median 4 months). Four patients had perimembranous ventricular septal defects (VSDs) with no clinical symptoms related to RVD. Communication of the RVD with the RV was located either close to the VSD (two patients) or in the anterior free wall of the RV opposite the VSD (two patients). In the remaining patient, the diverticulum was connected with the left ventricle (LV) by a tunnel-like structure originating from the left-ventricular outflow tract; the RVD communicated with the RV by way of a restrictive opening. Four patients underwent surgical repair including patch closure of the VSD (one patient) and patch closure of the VSD through an incision of the RVD followed by plication of the diverticulum or closure of its communication with the RV (three patients). All patients remained asymptomatic during a median follow-up of 14.8 years. Anterosuperior RVD is a specific congenital cardiovascular anomaly frequently associated with additional congenital heart disease. There are significant variations in how the RVD communicates with the RV with each requiring a different surgical repair strategy. According to the experience in our small cohort, the long-term prognosis of patients with anterosuperior RVD appears excellent after surgical correction of associated congenital heart disease.
EVALuna2:25110

Anti-TNF alpha/azathioprine therapy modulates the Natural killer cell compartment in pediatric inflammatory bowel disease - Knieling, Ferdinand; Schnell, Alexander; Allabauer, I.; Schwarz, B.; Rechenauer, Tobias; Kaspar, S.; Siebenlist, G.; Rueckel, A.; Hartmann, Arndt; Wahlbuhl-Becker, Mandy; Hoerning, A. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Antwort auf den Leserbrief zum Beitrag: Evidenzbasierte Arzneimittelinformation für den pädiatrischen Notfall - Neubert, Antje; Gramlich-Günther, Ursula; Rascher, Wolfgang; Ittner, Karl Peter (Notarzt, 2023)
CRIS-Team Scopus Importer:2023-11-03

Aortic arch obstruction neonates with biventricular physiology: left-open compared to closed inter-atrial communication during primary repair - a retrospective study - Rueffer, Andre; Bechtold, Caroline; Purbojo, Ariawan; Toka, Okan; Glöckler, Martin; Dittrich, Sven; Cesnjevar, Robert (Journal of Cardiothoracic Surgery, 2015)
Leaving an inter-atrial communication (IAC) open for left atrial decompression is often recommended in neonates with aortic arch obstruction undergoing primary repair. In this study, outcomes in these patients were compared to those with intact atrial septum after repair.Between 2000 and 2013, 53 consecutive neonates with severe aortic arch obstruction (hypoplasia: n = 45, interruption: n = 8) underwent primary repair from an anterior approach. Median age and weight were 8 days (range: 2-30) and 3.2 kg (range: 2.4-4.4), respectively. Cardiac morphology included a ventricular septal defect (VSD, large: n = 28, small: n = 7), malposition of great arteries (n = 10), and severe left ventricular outflow tract obstruction (LVOTO, n = 10). During corrective surgery IAC was closed (group-I, n = 37) or partially left-open (group-II, n = 16). Primary endpoints were hospital death, and re-intervention (surgery and/or balloon) due to aortic arch re-coarctation or recurrent LVOTO. Statistically significant variables by univariate analysis were incorporated in the corresponding multivariable regression model.Regarding morphological discrepancies more patients in group-II presented with LVOTO (p = 0.05), or the combination of arch hypoplasia, intact ventricular septum and normal ventriculo-arterial connection (p = 0.017). Hospital mortality was 8.1% in group-I and 37.5% in group-II (p = 0.016). Re-intervention was performed in 13 patients (group-I: n = 6 vs. group-II: n = 7) due to aortic arch re-coarctation (n = 12) and/or recurrent LVOTO (n = 3), and resulted in a Kaplan-Meier freedom from re-intervention of 87 ± 6% and 79 ± 8% in group-I, and 64 ± 14% and 64 ± 14% in group-II after 1 and 5 years, respectively (p = 0.016). Multivariate analysis revealed LVOTO as an independent risk factor for hospital death (p = 0.042), whereas both LVOTO and left-open IAC (p = 0.001 and 0.01) were independent risk factors for re-intervention.A left-open IAC increases risk of re-intervention at the left heart aorta complex. Sustained left-to-right shunting on atrial level seems to induce preload reduction of the often restrictive left ventricle leading to decreased aortic blood flow.
EVALuna2:25113

Aortic Arch Reconstruction in Neonates with Biventricular Morphology: Increased Risk for Development of Recoarctation by Use of Autologous Pericardium - Bechtold, Caroline; Purbojo, Ariawan; Schwitulla, Judith; Glöckler, Martin; Toka, Okan; Dittrich, Sven; Cesnjevar, Robert; Rüffer, André (Thoracic and Cardiovascular Surgeon, 2015)
Background The aim of this study was to analyze risk factors promoting development of recoarctation (Re-CoA) in neonates who survived aortic arch repair from an anterior approach. Methods Fifty consecutive neonates with biventricular morphology and ductal-dependent lower body perfusion who were discharged home following aortic arch repair with cardiopulmonary bypass between 2000 and 2012 were retrospectively reviewed. Arch anatomy was either interruption (n = 10) or hypoplasia with coarctation (n = 40). Aortic arch reconstruction was performed by using patch material (bovine pericardium, n = 30, homograft, n = 10, or glutaraldehyde-treated autologous pericardium, n = 7), and three patients underwent direct end-to-side anastomosis. Antegrade cerebral and continuous myocardial perfusion was performed in 39 and 21 patients, respectively. Kaplan-Meier freedom from Re-CoA was calculated. Morphologic and perioperative data indicating increased risk of Re-CoA by univariate analysis were included in multivariate Cox regression analysis. Results Mean follow-up was 5.3 ± 4.1 years. Re-CoA occurred in 13 patients and was treated successfully by balloon dilatation (n = 6) or surgery (n = 7). Freedom from Re-CoA after 1 and 5 years was 83 ± 5 and 79 ± 6%, respectively. Two patients died early after surgical repair of Re-CoA. The use of autologous pericardium for aortic arch augmentation was the only independent risk factor for development of Re-CoA (hazard ratio: 4.3 [95% confidence interval: 1.2-16.1]; p = 0.028). Conclusion Re-CoA following neonatal aortic arch surgery can be treated by balloon dilatation or surgery, if adequate. In this study, the risk for development of Re-CoA was independently increased by the use of autologous pericardium during initial arch repair.
EVALuna2:5488

A pipeline for the fully automated estimation of continuous reference intervals using real-world data - Ammer, Tatjana; Schützenmeister, André; Prokosch, Hans-Ulrich; Rauh, Manfred; Rank, Christopher M.; Zierk, Jakob (Scientific Reports, 2023)
Reference intervals are essential for interpreting laboratory test results. Continuous reference intervals precisely capture physiological age-specific dynamics that occur throughout life, and thus have the potential to improve clinical decision-making. However, established approaches for estimating continuous reference intervals require samples from healthy individuals, and are therefore substantially restricted. Indirect methods operating on routine measurements enable the estimation of one-dimensional reference intervals, however, no automated approach exists that integrates the dependency on a continuous covariate like age. We propose an integrated pipeline for the fully automated estimation of continuous reference intervals expressed as a generalized additive model for location, scale and shape based on discrete model estimates using an indirect method (refineR). The results are free of subjective user-input, enable conversion of test results into z-scores and can be integrated into laboratory information systems. Comparison of our results to established and validated reference intervals from the CALIPER and PEDREF studies and manufacturers’ package inserts shows good agreement of reference limits, indicating that the proposed pipeline generates high-quality results. In conclusion, the developed pipeline enables the generation of high-precision percentile charts and continuous reference intervals. It represents the first parameter-less and fully automated solution for the indirect estimation of continuous reference intervals.
CRIS-Team Scopus Importer:2023-09-01

A point mutation c.473A > G of ITGB3 is responsible for the formation of the Wo(a) human platelet alloantigen - Holzwarth, Sarah T.; Strobel, Julian; Cooper, Nina; Leyh, Jörg; Bayat, Behnaz; Bein, Gregor; Zingsem, Juergen; Sachs, Ulrich J. (Transfusion, 2019)
CRIS-Team WoS Importer:2020-01-03

APPLICATION OF A CENTRAL ILIAC ARTERIOVENOUS COUPLER DEVICE IN SEVERE TREATMENT-RESISTANT ARTERIAL HYPERTENSION: A FOUR-YEAR FOLLOW-UP - Jung, Susan; Ott, Christian; Karg, M.; Bosch, A.; Schmid, M.; Schlundt, Christian; Achenbach, Stephan; Schmieder, Roland (2018)
EVALuna2:35985

Application of Dual-Source-Computed Tomography in Pediatric Cardiology in Children Within the First Year of Life - Hausmann, P.; Stenger, Anna; Dittrich, Sven; Cesnjevar, Robert; Rueffer, A.; Hammon, Matthias; Uder, Michael; Rompel, O.; Glöckler, Martin (Röfo-Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren, 2016)
To assess fields of application and value of dual source computed tomography (DSCT) for diagnostics and therapy in patients with congenital heart disease during their first year of life. Evaluation of image quality, surgical use and radiation exposure of 2nd and 3 rd generation DSCT.DSCT was applied in 118 cases between January 2012 and October 2014 for diagnostics of congenital heart defects. 2nd generation was used in 91 cases until April 2014 and 3 rd generation in 27 cases during the period thereafter. 3 D reconstructions of the image data were created for clinical diagnostics and planning of interventions. Image quality was assessed using a 4-point-scale. The visibility of the mammary arteries was analyzed, and signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR) were calculated. The usefulness of 3D-reconstructions for surgical planning was rated using a 5-point-scale. Radiation exposure and contrast dye consumption were determined. All cases were analyzed retrospectively.DSCT was successfully used in 118 cases. All image data obtained were interpretable. More than 60 percent of cases did not show any artifacts. The mammary arteries were visible down to the diaphragmatic arch in more than 80 percent of cases. Diagnostic value and surgical benefit were evaluated as "useful" or as "essential" in all cases. Median radiation dose was 0.4 mSv and 0.27 mSv for the 2nd and 3 rd generation DSCT, respectively. Consumption of contrast dye was 2 ml/kg in all cases.DSCT is a modern and extremely helpful technique for diagnostics and planning of interventions in patients with complex congenital heart defects. Extracardiac vascular structures in particular can be depicted three-dimensionally at high resolution. The use of iterative reconstruction with 3 rd generation DSCT yielded image quality similar to that of 2nd generation DSCT at considerably reduced radiation exposure level compared to 2nd generation DSCT. 3 rd generation DSCT is a low risk, accurate and extremely fast technique for diagnosing unstable patients with CHD.Expanded scope of indications for DSCT in diagnosing critically ill infants. Effective radiation dose is considerably lower than 0.5 mSv. Extremely rapid image acquisitions with high image quality. Possibility of optimized 3D-based surgical planning
EVALuna2:14590

Application of Next-Generation Sequencing to Enterobacter Hormaechei Subspecies Analysis during a Neonatal Intensive Care Unit Outbreak - Morhart, Patrick; Gerlach, Roman; Kunz, Caroline; Held, Jürgen; Valenza, Giuseppe; Wölfle, Joachim; Reutter, Heiko Martin; Hanslik, Gregor J.; Fahlbusch, Fabian B. (Children, 2023)
Introduction: The Enterobacter cloacae complex (ECC) species are potential neonatal pathogens, and ECC strains are among the most commonly encountered Enterobacter spp. associated with nosocomial bloodstream infections. Outbreaks caused by ECC can lead to significant morbidity and mortality in susceptible neonates. At the molecular level, ECC exhibits genomic heterogeneity, with six closely related species and subspecies. Genetic variability poses a challenge in accurately identifying outbreaks by determining the clonality of ECC isolates. This difficulty is further compounded by the limitations of the commonly used molecular typing methods, such as pulsed field gel electrophoresis, which do not provide reliable accuracy in distinguishing between ECC strains and can lead to incorrect conclusions. Next-generation sequencing (NGS) offers superior resolution in determining strain relatedness. Therefore, we investigated the clinical pertinence of incorporating NGS into existing bundle measures to enhance patient management during an outbreak of ECC in a level-3 neonatal intensive care unit (NICU) in Germany. Methods: As the standard of care, all neonates on the NICU received weekly microbiological swabs (nasopharyngeal and rectal) and analysis of endotracheal secretion, where feasible. During the 2.5-month outbreak, colonisation with ECC was detected in n = 10 neonates. The phylogenetic relationship and potential antimicrobial resistance genes as well as mobile genetic elements were identified via bacterial whole-genome sequencing (WGS) using Illumina MiSeq followed by in silico data analysis. Results: Although all ECC isolates exhibited almost identical antimicrobial susceptibility patterns, the WGS data revealed the involvement of four different ECC clones. The isolates could be characterised as Enterobacter hormaechei subspecies steigerwaltii (n = 6, clonal), subsp. hoffmannii (n = 3, two clones) and subsp. oharae (n = 1). Despite the collection of environmental samples, no source of this diffuse outbreak could be identified. A new standardised operating procedure was implemented to enhance the management of neonates colonised with MRGN. This collaborative approach involved both parents and medical professionals and successfully prevented further transmission of ECC. Conclusions: Initially, it was believed that the NICU outbreak was caused by a single ECC clone due to the similarity in antibiotic resistance. However, our findings show that antibiotic susceptibility patterns can be misleading in investigating outbreaks of multi-drug-resistant ECC. In contrast, bacterial WGS accurately identified ECC at the clonal level, which significantly helped to delineate the nature of the observed outbreak.
CRIS-Team Scopus Importer:2023-11-03
Keywords: ECC; Enterobacter; MRGN; NGS; NICU; WGS

A Prevalence Estimation of Exstrophy and Epispadias in Germany From Public Health Insurance Data - Ebert, Anne Karoline; Zwink, Nadine; Reutter, Heiko Martin; Jenetzky, Ekkehart (Frontiers in Pediatrics, 2021)
Introduction: The prevalence of rare diseases is very important for health care research. According to the European Surveillance of Congenital Anomalies (EUROCAT) registers, the live prevalence for exstrophy and/or epispadias (grades 1–3) is reported with 1:23,255 (95% CI: 1:26,316; 1:20,000). A Europe-wide prevalence evaluation based on reports from excellence centers estimates a prevalence for exstrophies of 1:32,200 and for isolated epispadias of 1:96,800 in 2010. However, the frequency of exstrophy [International Statistical Classification of Diseases and Related Health Problems revision 10 (ICD-10): Q64.1] and epispadias (ICD-10: Q64.0) treated in different age groups in Germany remains unclear. Material and Method: Public health insurance data from 71 million people (approximately 87% of the population) were provided by the German Institute for Medical Documentation and Information (DIMDI) in accordance to the German Social Insurance Code for this research purpose. DIMDI analyzed the data source for the ICD diagnoses exstrophy and epispadias between 2009 and 2011. As provided data were robust over the years, averaged data are mentioned. Detailed subgroup analysis of small numbers was forbidden due to privacy protection. Results: Annually, 126 persons of all ages with epispadias and 244 with exstrophy are treated as inpatients. In the observed population, 34 infants (<1 year of age) with epispadias and 19 with exstrophy (58% male) are treated as outpatients each year. This corresponds to an estimated live prevalence of 1:11,000 (95% CI: 1:14,700; 1:8,400) for EEC (exstrophy–epispadias complex), more specifically a prevalence of 1:17,142 for epispadias and of 1:30,675 for exstrophy. The male-to-female ratio for exstrophy is 1.4:1 for infants and 1.6:1 for all minors. In children and adolescents, 349 epispadias and 393 exstrophies (up to the age of 17) are treated annually, whereas adults with exstrophy and even more with epispadias make comparatively less use of medical care. Conclusion: With the help of DIMDI data, the live prevalence of bladder exstrophy and epispadias in Germany could be estimated. The prevalence of epispadias was higher than in previous reports, in which milder epispadias phenotypes (grade 1 or 2) may not have been included. These analyses might enlighten knowledge about nationwide incidence and treatment numbers of rare diseases such as the EEC.
CRIS-Team Scopus Importer:2021-11-19
Keywords: bladder exstrophy; bladder exstrophy epispadias complex (EEC); epispadias; health insurance; prevalence; public health

Are hypothalamic- pituitary (HP) axis deficiencies after whole brain radiotherapy (WBRT) of relevance for adult cancer patients? - a systematic review of the literature - Mehta, P.; Fahlbusch, Fabian; Rades, D.; Schmid, S. M.; Gebauer, J.; Janssen, S. (BMC Cancer, 2019)
BACKGROUND: Cranial radiotherapy (cRT) can induce hormonal deficiencies as a consequence of significant doses to the hypothalamic-pituitary (HP) axis. In contrast to profound endocrinological follow-up data from survivors of childhood cancer treated with cRT, little knowledge exists for adult cancer patients. METHODS: A systematic search of the literature was conducted using the PubMed database and the Cochrane library offering the basis for our debate of the relevance of HP axis impairment after cRT in adult cancer patients. Against the background of potential relevance for patients receiving whole brain radiotherapy (WBRT), a particular focus was set on the temporal onset of hypopituitarism and the radiation dose to the HP axis. RESULTS: Twenty-eight original papers with a total of 1728 patients met the inclusion criteria. Radiation doses to the HP area ranged from 4 to 97 Gray (Gy). Hypopituitarism incidences ranged from 20 to 93% for adult patients with nasopharyngeal cancer or non-pituitary brain tumors. No study focused particularly on hypopituitarism after WBRT. The onset of hypopituitarism occurred as early as within the first year following cRT (range: 3 months to 25.6 years). However, since most studies started follow-up evaluation only several years after cRT, early onset of hypopituitarism might have gone unnoticed. CONCLUSION: Hypopituitarism occurs frequently after cRT in adult cancer patients. Despite the general conception that it develops only after several years, onset of endocrine sequelae can occur within the first year after cRT without a clear threshold. This finding is worth debating particularly in respect of treatment options for patients with brain metastases and favorable survival prognoses.
CRIS-Team Scopus Importer:2019-12-24
Keywords: Endocrine deficiencies; Hypopituitarism; Hypothalamus; Pituitary; Whole brain radiotherapy

ARE PROTEINS OF THE DEGRANULATION MACHINERY REQUIRED FOR RUBELLA VIRUS CONTROL IN THE SKIN? - Ehl, Stephan; Heizmann, Miriam; Maier, Sarah Lena; Speckmann, Carsten; Tesi, Bianca; Khurana, Claudia; Naumann-Bartsch, Nora; Agaimy, Abbas; Huzly, Daniela; Bryceson, Yenan T.; Schmitt-Graeff, Annette; Lehmberg, Kai (PEDIATRIC BLOOD & CANCER, 2019)
CRIS-Team WoS Importer:2020-02-21

A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption - Assi, Hisham; Cao, Rui; Castelino, Madhura; Cox, Ben; Gilbert, Fiona J.; Gröhl, Janek; Gurusamy, Kurinchi; Hacker, Lina; Ivory, Aoife M.; Joseph, James; Knieling, Ferdinand; Leahy, Martin J.; et al. (Photoacoustics, 2023)
Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.
CRIS-Team Scopus Importer:2023-08-18
Keywords: Clinical translation; Optoacoustic tomography; Phantoms; Photoacoustic imaging; Quality assurance; Standardisation

Arginase 1 functions as anti-resolvin in inflammatory bowel disease - Nuese, B.; Gänsbauer, Maximilian; Baier, J.; Mattner, Jochen; Gerlach, Roman; Wirtz, Stefan; Rauh, Manfred (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Arginase 1 of myeloid cells accounts for disease chronicity in Leishmania mexicana-infected mice - Rai, Baplu; Debus, Andrea; Liang Chunguang,; Kunz, Meik; Rauh, Manfred; Bogdan, Christian; Schleicher, Ulrike (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome - Baier, Julia; Gänsbauer, Maximilian; Giessler, Claudia; Arnold, Harald; Muske, Mercedes; Schleicher, Ulrike; Lukassen, Sören; Ekici, Arif Bülent; Rauh, Manfred; Daniel, Christoph; Hartmann, Arndt; Schmid, Benjamin; et al. (Journal of Clinical Investigation, 2020)
Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from experimental colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells and an accumulation of intraluminal polyamines that promote epithelial healing. The pro-resolving effect of Arg1-deletion was reduced by an L-arginine-free diet, but rescued by simultaneous deletion of other L-arginine-metabolizing enzymes such as Arg2 or Nos2, demonstrating that protection from colitis requires L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wild-type recipients ameliorated intestinal inflammation while transfers from wild-type littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of L-arginine as well as altered intestinal microbiota and metabolic products account for the accelerated resolution from colitis in the absence of Arg1. Consequently, the metabolism of L-arginine may serve as target for clinical intervention in IBD patients.<br

A role for the alpha-8 integrin chain (itga8) in glomerular homeostasis of the kidney. - Marek, Ines; Hilgers, Karl Friedrich; Rascher, Wolfgang; Wölfle, Joachim; Hartner, Andrea (Molecular and Cellular Pediatrics, 2020)
Glomerulonephritis results in a dysregulation of glomerular cells and may end up in chronic alterations and subsequent loss of renal function. Therefore, understanding mechanisms, which contribute to maintain glomerular integrity, is a pivotal prerequisite for therapeutic interventions. The alpha-8 integrin chain seems to be an important player to maintain glomerular homeostasis by conferring mechanical stability and functional support for the renal capillary tuft.
EVALuna2:383426
Keywords: itga8; Glomerular homeostasis; Mesangial cells; Glomerulonephritis

Arterial Hypertension in Children - Rascher, Wolfgang; Paech, Christian (Pediatric Pharmacotherapy, 2020)
Pharmacological treatment of arterial hypertension in children is mainly based on individual experience, but there is evidence that blocking the angiotensin system reduces systolic and diastolic blood when compared to placebo, and these drugs are safe to use for a short duration, also in children under 6 years of age. Blocking the angiotensin system either by angiotensin-converting enzyme inhibitors or by antagonizing the angiotensin 1 receptor is effective, but did not display a consistent dose-response relationship with escalating doses, but the effective doses are known. Calcium channel antagonists are effective antihypertensives in children, but the evidence is limited. Based on small-sized studies, beta-blockers modestly reduce systolic blood pressure, but have no significant effect on diastolic blood pressure compared to placebo. They act in combination to antagonize reflex tachycardia induced by vasodilators. The most commonly used antihypertensive agents are safe to use in short-term studies.
CRIS-Team Scopus Importer:2020-07-31
Keywords: Antihypertensives; Arterial hypertension; Clinical trials; Pediatrics

Arzneimittel bei Kindern sicher einsetzen - Neubert, Antje; Erdlenbruch, Bernhard (Monatsschrift Kinderheilkunde, 2024)
CRIS-Team Scopus Importer:2024-12-06

Arzneimittel für neuartige Therapien. Kurzfassung der Stellungnahme der Deutschen Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ) - Rascher, Wolfgang; Klingebiel, Thomas; Herting, Egbert; Hoffmann, Georg F.; Berner, Reinhard; Krägeloh-Mann, Ingeborg; Gärtner, Jutta; Zepp, Fred; Schara, Ulrike (Monatsschrift Kinderheilkunde, 2020)
CRIS-Team Scopus Importer:2020-12-11

Arzneimittel für neuartige Therapien – Perspektiven, Chancen, Herausforderungen. Stellungnahme der Deutschen Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ) - Rascher, Wolfgang; Klingebiel, Thomas; Herting, Egbert; Hoffmann, Georg F.; Berner, Reinhard; Krägeloh-Mann, Ingeborg; Gärtner, Jutta; Zepp, Fred; Schara, Ulrike (Monatsschrift Kinderheilkunde, 2020)
Advanced therapy medicinal products (ATMP), such as somatic gene therapy and cell therapy, have a high therapeutic potential for diseases that begin very early in life and that were previously untreatable. They are often licensed at a very early stage of development when the efficacy has been shown in a few affected patients and a previously unprecedented therapeutic success is revealed, especially if the therapy is effective before organ damage occurs. This gives rise to new pharmaceutical legal issues and ethical questions for pediatricians. In order to adequately use the new treatment options the diagnosis must be made earlier than before or new screening methods must be available. It is conceivable that the newborn screening will be divided into time-critical diseases in the first 72 h after birth and genetic screening, e.g. in the 4th–5th weeks of life. ATMP were not used in sufficient numbers when they were licensed, so that the necessary knowledge on efficacy and safety is not yet available (benefit-risk ratio). That is why they are used under strict conditions in specialized treatment centers according to quality criteria that the Federal Joint Committee (G-BA) determines after consulting the specialist competent societies. The expenditure of therapy and documentation of the clinical course in registers is considerable and must be reimbursed accordingly. The value of an ATMP becomes clear when it is used more widely after approval, just like the safety of a drug is not fully known with the approval. New challenges and opportunities arise for pediatrics.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Cell therapy; Drug safety; Ethics; Gene therapy; Newborn screening

Arzneimittel-Manipulationen in der Pädiatrie: Eine Untersuchung auf pädiatrischen Stationen eines Universitätsklinikums - Zahn, Julia; Toni, Irmgard; Neubert, Antje (PZ Prisma, 2020)
CRIS-Team Scopus Importer:2021-04-19

A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex - Mammadova, Dilbar; Vecko, Julia; Hofmann, Marlene; Schüssler, Stephanie; Deiters, Ludger; Canda, A.; Wieland, Anna; Gollwitzer, Stephanie; Hamer, Hajo; Trollmann, Regina (Orphanet Journal of Rare Diseases, 2023)
Background: Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods: This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results: Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05). Conclusions: The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.
CRIS-Team Scopus Importer:2023-11-17
Keywords: Antiseizure medication; Autism; Cognition; Rare disease; Refractory epilepsy; Tuberous sclerosis complex

Assessment of cavopulmonary connections by advanced imaging: Value of flat-detector computed tomography - Glöckler, Martin; Koch, Andreas; Halbfass, Julia; Greim, Verena; Rueffer, Andre; Cesnjevar, Robert; Achenbach, Stephan; Dittrich, Sven (Cardiology in the Young, 2013)
Objectives To investigate the impact of flat-detector computed tomography on the clinical assessment of patients with cavopulmonary connections, and to evaluate the obtained diagnostic accuracy and supplementary information, as well as the value of overlaid three-dimensional reconstructions on fluoroscopic images during catheter-based interventions. Methods We analysed 31 consecutive patients retrospectively in whom flat-detector computed tomography was used to visualise the cavopulmonary connection. We investigated patients with cavopulmonary connections either early post-operatively (first group), before converting to a total cavopulmonary connection (second group), and patients with failing total cavopulmonary connection (third group). Flat-detector computed tomography based on a single rotational angiography was used to create a three-dimensional vascular model. The clinical value of flat-detector computed tomography was evaluated using standard categories of diagnostic utility. Used contrast volume and radiation exposure were quantified. Results Within 18 months, flat-detector computed tomography was performed in 31 cases with cavopulmonary connections. The median age was 1.9 years (range 0.3-43 years). In the first group, we found anomalies in 4 out of 8 cases, which led to therapeutic or prophylactic procedures; in the second and third groups, we performed interventions in 14 out of 23 cases. The overall clinical value was always rated superior to conventional biplane angiography. The median dose area product was 91.8 microgray square metres (range 33.0-679.3 microgray square metres). The required contrast medium was 2.08 millilitres per kilogram (range 0.66-4.7 millilitres per kilogram). Conclusion Flat-detector computed tomography improves the diagnostic accuracy in cavopulmonary connections and provides additional diagnostic information, which may lead to therapeutic or prophylactic procedures. Overlaid three-dimensional images on fluoroscopy facilitate and provide security for interventions. © Cambridge University Press 2012.
CRIS-Team Scopus Importer:2023-03-08
Keywords: interventions in congenital heart disease; rotational angiography; Three-dimensional

Assessment of educational and social status of survivors of childhood cancer: Data of a single center late effects clinic - Hahn, B.; Schuster, Sonja; Metzler, Markus; Mackensen, Andreas; Meidenbauer, Norbert (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Assessment of genetic defects, baseline characteristics and adverse events reported in the Increlex (R) registry - Polak, Michel; Bang, Peter; Perrot, Valerie; Sert, Caroline; Storr, Helen L.; Wölfle, Joachim (HORMONE RESEARCH IN PAEDIATRICS, 2021)
CRIS-Team WoS Importer:2021-10-08

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US) - Wildner, Dane; Heinzerling, Lucie; Scheulen, Max E.; Kämpgen, Eckhart; Schuler, Gerold; Strobel, Deike; Janka, Rolf Matthias; Neurath, Markus; Sturm, Jörg; Knieling, Ferdinand (Journal of Cancer Research and Clinical Oncology, 2021)
Purpose Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. Methods In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. Results Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. Conclusion An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.
CRIS-Team WoS Importer:2021-06-04

Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA - Schmidkonz, Christian; Krumbholz, Manuela; Atzinger, Armin; Cordes, Michael; Goetz, Theresa Ida; Prante, Olaf; Ritt, Philipp; Schaefer, Christiane; Agaimy, Abbas; Hartmann, Wolfgang; Rössig, Claudia; Fröhlich, Birgit; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2019)
Purpose: The purpose of this study was to perform a prospective integrated analysis of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS). Methods: A total of 20 patients with histologically confirmed EwS underwent multiple 18F-FDG-PET/CT, performed at the time of each patient’s initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 18F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels. Results: Twenty patients underwent a total of 87 18F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8–104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive 18F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%. Conclusion: The combination of 18F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.
CRIS-Team Scopus Importer:2019-12-27
Keywords: Circulating tumor DNA; Ewing sarcoma; Pediatric oncology; Treatment response

Assignment of weight-based antibody units for four additional serotypes to a human anti-pneumococcal standard reference serum 007sp - Goldblatt, David; Mckeen, A.; Burbidge, P.; Mcelhiney, S.; Mclaughlin, L.; Johnson, A.; Rauh, Manfred; Giardina, P. C. (Clinical and Vaccine Immunology, 2017)
The pneumococcal ELISA reference standard serum, Lot 89SF, has been in use since 1990 and was replaced with a new reference standard serum, 007sp in 2013. This serum was generated under an FDA-approved clinical protocol, where 278 adult volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine, Pneumovax II®, and a unit of blood was obtained twice within 120 days following immunization. Pooled serum was prepared from the plasma, filled at 6ml per vial and lyophilised. Five independent laboratories participated in bridging the serotype specific IgG assignments for 89SF to 007sp to establish equivalent reference values for 13 pneumococcal capsular serotypes (1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) using the WHO reference ELISA. A subsequent follow up study established equivalent reference values for an additional seven serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F). In this study three laboratories assigned weight-based IgG concentrations in mcg/mL of serum to 007sp for four additional serotypes; 2, 9N, 17F and 20A. This study completes the assignment of serotypes in 89SF to 007sp. In addition, the IgG antibody assignments for a 12 member WHO QC serum panel were extended to cover the four additional serotypes. Agreement was excellent with a concordance correlation coefficient (rc) > 0.996 when each laboratory was compared to the assigned values for the 12 WHO QC sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantities of 007sp are projected to be available for the next 25 years.
EVALuna2:34239

Association of clinical factors with postoperative complications of esophageal atresia - Besendörfer, Manuel; Müller, Hanna; Weiss, Christel; Wagner, Alexandra; Schellerer, Vera; Hörning, André; Diez, Sonja (Pediatrics and Neonatology, 2020)
Background: Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) remains one of the most common gastrointestinal neonatal malformations. Even though postoperative management is standardized, it differs between hospitals and disease-associated clinical factors that may play a role in outcome have not yet been assessed in detail. Methods: In this monocentric retrospective study, data of 43 patients with EA between 2010 and 2018 were analyzed. Analysis includes assessment of the clinical background, surgical technique, postoperative management including application of continuous muscle relaxation (CMR), influence of coagulation parameters such as factor XIII and incidence of complications. Results: 21 patients (49%) were preterm infants with birth weights between 490 and 2840 g (median 1893 g). Only 35% (n = 15) presented without any concomitant malformations. Within the entire study population, representing Vogt II, IIIb and IIIc, we observed an association between the development of a postoperative pneumothorax and anastomotic failure (AF) (p = 0.0013). Furthermore, pneumothorax was associated with anastomotic stenosis (AS) in Vogt IIIb patients (p = 0.0129). CMR (applied since March 2017 in 7 patients in an attempt to prevent anastomotic problems due to high complication rates) and coagulation factor XIII did not significantly correlate with postoperative outcome. Conclusion: Appearance of pneumothorax was correlated with postoperative complications. These children should be monitored carefully in closer scheduled gastroenterological follow-up esophago-gastro-duodenoscopies. CMR and factor XIII substitution did not reduce anastomotic leakage but should be tested within an enlarged study population.
CRIS-Team Scopus Importer:2020-10-23
Keywords: continuous muscle relaxation; esophageal surgery; neonatal surgery; pneumothorax; postoperative relaxation

Association of Lymphatic Abnormalities with Early Complications after Fontan Operation - Dittrich, Sven; Weise, Anja; Cesnjevar, Robert; Rompel, Oliver; Rüffer, André; Schöber, Martin; Moosmann, Julia; Glöckler, Martin (Thoracic and Cardiovascular Surgeon, 2021)
Background Increased central venous pressure is inherent in Fontan circulation but not strongly related to Fontan complication. Abnormalities of the lymphatic circulation may play a crucial role in early Fontan complications. Methods This was a retrospective, single-center study of patients undergoing Fontan operation from 2008 to 2015. The primary outcome was significant early Fontan complication defined as secondary in-hospital treatment due to peripheral edema, ascites, pleural effusions, protein-losing enteropathy, or plastic bronchitis. All patients received T2-weighted magnetic resonance images to assess abdominal and thoracic lymphatic perfusion pattern 6 months after Fontan completion with respect to localization, distribution, and extension of lymphatic perfusion pattern (type 1-4) and with application of an area score (0-12 points). Results Nine out of 42 patients developed early Fontan complication. Patients with complication had longer chest tube drainage (mean 28 [interquartile range [IQR]: 13-60] vs. 13 [IQR: 2-22] days, p = 0.01) and more often obstructions in the Fontan circuit 6 months after surgery (56 vs. 15%, p = 0.02). Twelve patients showed little or no abnormalities of lymphatic perfusion (lymphatic perfusion pattern type 1). Most frequently magnetic resonance imaging showed lymphatic congestion in the supraclavicular region (24/42 patients). Paramesenteric lymphatic congestion was observed in eight patients. Patients with early Fontan complications presented with higher lymphatic area score (6 [min-max: 2-10] vs. 2 [min-max: 0-8]), p = 0.001) and greater distribution and extension of thoracic lymphatic congestion (type 3-4: n = 5/9 vs. n = 1/33, p = 0.001). Conclusion Early Fontan complication is related to hemodynamic factors such as circuit obstruction and to the occurrence and extent of lymphatic congestion.
CRIS-Team Scopus Importer:2021-01-15
Keywords: cardiovascular magnetic resonance imaging; congenital heart disease; Fontan operation; lymphatic perfusion pattern

Association of Risk of Suicide Attempts With Methylphenidate Treatment - Man, Kenneth K. C.; Coghill, David; Chan, Esther W.; Lau, Wallis C. Y.; Hollis, Chris; Liddle, Elizabeth; Banaschewski, Tobias; Mccarthy, Suzanne; Neubert, Antje; Sayal, Kapil; Ip, Patrick; Schuemie, Martijn J.; et al. (JAMA Psychiatry, 2017)
Importance: Patients with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of attempting suicide. Stimulants, such as methylphenidate hydrochloride, are the most common treatment for ADHD, but the association between their therapeutic use and suicide is unclear. Objective: To investigate the association between methylphenidate and the risk of suicide attempts. Design, Setting, and Participants: A population-based, electronic medical records database from the Hong Kong Clinical Data Analysis & Reporting System was used to identify 25 629 individuals aged 6 to 25 years who were treated with methylphenidate between January 1, 2001, and December 31, 2015. Those who had attempted suicide were included in the analysis. A self-controlled case series design was used to control for time-invariant characteristics of the patients. Main Outcomes and Measures: Relative incidence of suicide attempt during periods when patients were exposed to methylphenidate compared with nonexposed periods. Results: Among 25 629 patients with methylphenidate prescriptions, 154 had their first recorded suicide attempt within the study period; of these individuals, 111 (72.1%) were male; mean (SD) age at baseline was 7.15 (2.19) years. The overall incidence of suicide attempts during methylphenidate treatment was 9.27 per 10 000 patient-years. An increased risk of suicide attempts was detected during the 90-day period before methylphenidate was initiated, with an incidence rate ratio (IRR) of 6.55 (95% CI, 3.37-12.72). The IRR remained elevated during the first 90 days of treatment (IRR, 3.91; 95% CI, 1.62-9.42) before returning to baseline levels during ongoing treatment (IRR, 1.35; 95% CI, 0.77-2.38). When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of suicide attempts was not elevated (IRR, 0.78; 95% CI, 0.26-2.35). Conclusions and Relevance: The incidence of suicide attempts was higher in the period immediately before the start of methylphenidate treatment. The risk remained elevated immediately after the start of methylphenidate treatment and returned to baseline levels during continuation of methylphenidate treatment. The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment. Therefore, this study's results do not support a causal association between methylphenidate treatment and suicide attempts.
EVALuna2:34281

A surrogate cell-based SARS-CoV-2 spike blocking assay - Schuh, Wolfgang; Baus, Lena; Steinmetz, Tobit; Schulz, Sebastian; Weckwerth, Leonie; Roth, Edith; Hauke, Manuela; Krause, Stefan; Morhart, Patrick; Rauh, Manfred; Hoffmann, Markus; Vesper, Niklas; et al. (European Journal of Immunology, 2021)
To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and successful vaccination against coronavirus disease 2019 (COVID-19), the kinetics of neutralizing or blocking anti-SARS-CoV-2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS-CoV-2 blocking assay (SUBA) using immobilized recombinant human angiotensin-converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS-CoV-2 spike protein. Spike protein-expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell-associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2- or 3-approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell-bound SARS-CoV-2 spike protein and can be rapidly adjusted to quickly pre-screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS-CoV-2 variants.
CRIS-Team Scopus Importer:2021-10-08
Keywords: COVID-19; hACE2; SARS-CoV-2; Spike protein; Surrogate blocking assay

Asymmetric Omphalopagus in a Triplet after In Vitro Fertilization: A Rare Case of Conjoined Twinning - Jabari, Samir; Carbon, Roman; Besendörfer, Manuel; Hartmann, Arndt; Rompel, Oliver; Hoerning, Andre; Söder, Stephan (Case Reports in Pediatrics, 2018)
Introduction: Asymmetric omphalopagus is a rare situation of conjoined twinning, in which a grossly defective twin is attached to the thorax and upper abdomen of the main twin. We describe a case of an asymmetric omphalopagus accompanied by a normal triplet after assisted reproductive technology (ART) and tried to further characterize the all aspects of the conjoined twins. Case Presentation: Perioperative diagnostic imaging was carried out followed by an autopsy to evaluate all aspects of the parasite accompanied by histological, immunohistochemical, and molecular biological evaluation. The parasite had well-developed lower extremities as well as upper extremities with a cleft hand syndrome. The sex was nondeterminable, but DNA fingerprinting revealed that both parasite and autosite are monozygotic, so are females. There was no sign of any axial skeleton or central nervous system. We found a rudimentary rectum with a nonpervious anus, a kidney, ureter, urinary bladder, and a blind-ending urethra. The blood supply of the parasite was connected to the vessel system of the autosite. Conclusions: To our knowledge, only two cases of parasitic omphalopagus after ART have been described to date. Altogether, 52 cases have been reported, and in most of them, the parasites were successfully separated.
EVALuna2:34614

A systematic review of magnetic resonance imaging in patients with an implanted vagus nerve stimulation system - Fetzer, S.; Dibue, M.; Nagel, Armin Michael; Trollmann, Regina (Neuroradiology, 2021)
Purpose Vagus nerve stimulation (VNS) is an effective adjunctive treatment for drug-resistant epilepsy (DRE) and difficult-to-treat depression (DTD). More than 125.000 patients have been implanted with VNS Therapy (R) System (LivaNova PLC) since initial approval. Patients with DRE often require magnetic resonance imaging (MRI) of the brain during the course of their disease. VNS Therapy System devices are labeled to allow MRI under certain conditions; however, there are no published comprehensive articles about the real-world experience using MRI in patients with implanted VNS devices. Methods A systematic review in accordance with PRISMA statement was performed using PubMed database. Full-length articles reporting MRI (1.5 T or 3 T scanner) of patients with implanted VNS for DRE or DTD and published since 2000 were included. The primary endpoint was a positive outcome that was defined as a technically uneventful MRI scan performed in accordance with the VNS Therapy System manufacturer guidelines and completed according to the researchers' planned scanning protocol without harm to the patient. Results Twenty-six articles were eligible with 25 articles referring to the VNS Therapy System, and 216 patients were included in the analysis. No serious adverse events or serious device-related adverse events were reported. MRI scan was prematurely terminated in one patient due to a panic attack. Conclusion This systematic review indicates that cranial MRI of patients with an implanted VNS Therapy System can be completed satisfactorily and is tolerable and safe using 1.5 T and 3 T MRI scanners when performed in adherence to the VNS manufacturer's guidelines.
CRIS-Team WoS Importer:2021-05-07

A Temperature-Based Bioimpedance Correction for Water Loss Estimation During Sports - Ring, Matthias; Lohmüller, Clemens; Rauh, Manfred; Mester, Joachim; Eskofier, Björn (IEEE Journal of Biomedical and Health Informatics, 2016)
The amount of total body water (TBW) can be estimated based on bioimpedance measurements of the human body. In sports, TBW estimations are of importance because mild water losses can impair muscular strength and aerobic endurance. Severe water losses can even be life threatening. TBW estimations based on bioimpedance, however, fail during sports because the increased body temperature corrupts bioimpedance measurements. Therefore, this paper proposes a machine learning method that eliminates the effects of increased temperature on bioimpedance and, consequently, reveals the changes in bioimpedance that are due to TBW loss. This is facilitated by utilizing changes in skin and core temperature. The method was evaluated in a study in which bioimpedance, temperature, and TBW loss were recorded every 15 minutes during a two-hour running workout. The evaluation demonstrated that the proposed method is able to reduce the error of TBW loss estimation by up to 71%, compared to the state of art. In the future, the proposed method in combination with portable bioimpedance devices might facilitate the development of wearable devices for continuous and noninvasive TBW loss monitoring during sports.
EVALuna2:15227

ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner - Chen, Daishi; Fan, Zheng; Rauh, Manfred; Buchfelder, Michael; Eyupoglu, I. Y.; Savaskan, Nicolai (Oncogene, 2017)
Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc-). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.
EVALuna2:34242

Athlete's Heart in Elite Sport Climbers: Cardiac Adaptations Determined Using ECG and Echocardiography Data - Schöffl, Isabelle; Wüstenfeld, Jan; Jones, Gareth; Dittrich, Sven; Lutter, Chris; Schöffl, Volker (Wilderness & Environmental Medicine, 2020)
Introduction: Sudden cardiac death in a young athlete is the leading cause of mortality in athletes during sport. Specific knowledge about cardiac adaptations are necessary for a better understanding of the underlying causes of such events. Methods: A retrospective analysis of the electrocardiogram and echocardiographic data obtained during the yearly medical examination of the entire German junior national climbing team was undertaken. First, data from 1 examination were used. In a second step, data from 2 examinations spaced 2 y apart were analyzed for a selected subgroup to gain more knowledge about adaptations to climbing. The data from the subgroup were compared to an age- and sex-matched control group of Nordic skiers from the German junior national Nordic skiing team. Results: Forty-seven young climbers (20 girls, 27 boys) were examined once. There were no pathological findings in the electrocardiogram or echocardiography. The left ventricular (LV) measurements fell between those for athletes and nonathletes. Eight boys and 6 girls from this group were tested twice over a timeframe of 27.5 mo. All LV measurements increased over time. After 2 y, the measurements from the climbers were comparable to those of the Nordic skiers. Conclusions: Hypertrophic cardiomyopathy (hypertrophy of the LV) is the leading cause of sudden cardiac death in athletes. An increase in LV dimensions was observed in the young climbers in this study. LV dimensions being comparable to high-level Nordic skiers after 2 y in the national team imply structural changes over time in this cohort.
CRIS-Team Scopus Importer:2020-11-20
Keywords: adolescent athlete; cardiomyopathy; concentric hypertrophy; eccentric hypertrophy; pediatric cardiology; sports ability test

Ätiologische Konzepte von gastrointestinalen Fehlbildungen/Atresien - Reutter, Heiko Martin (Monatsschrift Kinderheilkunde, 2023)
The causes of gastrointestinal malformations or atresias are heterogeneous. Most atresias occur sporadically. To date, no environmental factor or genetic defect has been identified that alone could causally explain a large proportion of the various malformations. Due to the capabilities of modern array and exome analyses, numerous new disease genes have been identified in the past 10 years. It is known that a small overlap of individual causative genetic risk factors underlies the co-occurrence of malformations of the esophagus and anorectum, and that a large proportion of duodenal atresias occur in the context of an underlying Down syndrome; however, for the vast majority of intestinal atresias the genetic causes remain unclear. The human genetic counselling should consider epidemiological aspects of the observed recurrence risk for the different atresias and the appearance of each atresia (syndromic or non-syndromic, isolated).
CRIS-Team Scopus Importer:2023-05-19
Keywords: Chromosome disorders; DNA copy number variations; Epidemiology; Pathogenesis; Recurrence risk

A Transmural Path Model Improves the Definition of the Orthotropic Tissue Structure in Heart Simulations - Holz, David; Duong, Minh Tuan; Martonová, Denisa; Alkassar, Muhannad; Leyendecker, Sigrid (Journal of Biomechanical Engineering-Transactions of the Asme, 2021)
In the past decades, the structure of the heart, human as well as other species, has been explored in a detailed way, e.g., via histological studies or diffusion tensor magnetic resonance imaging. Nevertheless, the assignment of the characteristic orthotropic structure in a patient-specific finite element model remains a challenging task. Various types of rule-based models, which define the local fiber and sheet orientation depending on the transmural depth, have been developed. However, the correct assessment of the transmural depth is not trivial. Its accuracy has a substantial influence on the overall mechanical and electrical properties in rule-based models. The main purpose of this study is the development of a finite element-based approach to accurately determine the transmural depth on a general unstructured grid. Instead of directly using the solution of the Laplace problem as the transmural depth, we make use of a well-established model for the assessment of the transmural thickness. It is based on two hyperbolic first-order partial differential equations for the definition of a transmural path, whereby the transmural thickness is defined as the arc length of this path. Subsequently, the transmural depth is determined based on the position on the transmural path. Originally, the partial differential equations were solved via finite differences on structured grids. In order to circumvent the need of two grids and mapping between the structured (to determine the transmural depth) and unstructured (electromechanical heart simulation) grids, we solve the equations directly on the same unstructured tetrahedral mesh. We propose a finite-element-based discontinuous Galerkin approach. Based on the accurate transmural depth, we assign the local material orientation of the orthotropic tissue structure in a usual fashion. We show that this approach leads to a more accurate definition of the transmural depth. Furthermore, for the left ventricle, we propose functions for the transmural fiber and sheet orientation by fitting them to literature-based diffusion tensor magnetic resonance imaging data. The proposed functions provide a distinct improvement compared to existing rules from the literature.<br

Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy - Wahlbuhl, Mandy; Schuepbach-Mallepell, Sonia; Kowalczyk-Quintas, Christine; Dick, Angela; Fahlbusch, Fabian B.; Schneider, Pascal; Schneider, Holm (Journal of Mammary Gland Biology and Neoplasia, 2018)
Hypohidrotic ectodermal dysplasias (HED) are hereditary differentiation disorders of multiple ectodermal structures including the mammary gland. The X-linked form of HED (XLHED) is caused by a lack of the secreted signaling molecule ectodysplasin A1 (EDA1) which is encoded by the gene EDA and belongs to the tumor necrosis factor (TNF) superfamily. Although male patients (hemizygous) are usually more severely affected by XLHED, heterozygous female carriers of an EDA mutation may also suffer from a variety of symptoms, in particular from abnormal development of their breasts. In Tabby mice, a well-studied animal model of XLHED, EDA1 is absent. We investigated the effects of prenatal administration of Fc-EDA, a recombinant EDA1 replacement protein, on mammary gland development in female Tabby mice. Intra-amniotic delivery of Fc-EDA to fetal animals resulted later in improved breastfeeding and thus promoted the growth of their offspring. In detail, such treatment led to a normalization of the nipple shape (protrusion, tapering) that facilitated sucking. Mammary glands of treated female Tabby mice also showed internal changes, including enhanced branching morphogenesis and ductal elongation. Our findings indicate that EDA receptor stimulation during development has a stable impact on later stages of mammary gland differentiation, including lactation, but also show that intra-amniotic administration of an EDA1 replacement protein to fetal Tabby mice partially corrects the mammary gland phenotype in female adult animals.
EVALuna2:35485

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin - Hammersen, Johanna; Neuner, Andrea; Wild, Florian; Schneider, Holm (Dermatology, 2019)
Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.
CRIS-Team Scopus Importer:2019-06-18

Author Correction: The influence of the optical properties on the determination of capillary diameters (Scientific Reports, (2022), 12, 1, (270), 10.1038/s41598-021-04359-5) - Späth, Moritz; Rohde, Maximilian; Ni, Dongqin; Knieling, Ferdinand; Stelzle, Florian; Schmidt, Michael; Klämpfl, Florian; Hohmann, Martin (Scientific Reports, 2023)
The original version of this Article contained errors as the simulation software used for the submission (Monte Carlo extreme, MCX) did not work as anticipated. As a consequence, the optical properties of the first skin layer were taken into account for all seven simulated skin layers. After fixing this bug, all simulations on which the paper is based were re-run. As a result, the Materials and Methods, Results, Discussion and Conclusion sections, tables 1 and 2, figures 2, 4 and 5 were updated.
CRIS-Team Scopus Importer:2023-03-03

Authorized or Off-Label Use? A Structured Analysis of Summaries of Product Characteristics with Regard to Authorization in Pediatrics - Herzig, Markus; Eisenhofer, Simone; Ruschkowski, Meike; Neubert, Antje; Bertsche, Astrid; Bertsche, Thilo; Neininger, Martina Patrizia (Pharmaceutical Medicine, 2024)
Purpose: The Summary of Product Characteristics (SmPC) is required to provide unambiguous information on the authorized use of a medicinal product. Therefore, we performed a structured analysis of the information provided for pediatric patients in current SmPCs. Methods: In the German SmPC of the medicinal products of 452 active substances, we analyzed for each of the listed indications whether information on pediatric use was available in Sects. 4.1–4.4 of the SmPC and, if so, whether it was unambiguous. Information was considered unambiguous if it indicated an exact age- or weight-related specification. The analysis also considered the type of marketing authorization and the date of marketing authorization, either before or after the Pediatric Regulation 2007 came into force. Results: Among the 30,354 identified indications in 8464 SmPCs, unambiguous information was found for 72.4% (21,974/30,354) of the indications. Of these, 45.4% (9967/21,974) disclosed a contraindication for the entire population under 18 years of age. The proportion of unambiguous information was higher for medicinal products with centralized marketing authorization (86.5% [1449/1676]) than for those with a national one (71.6% [20,525/28,678]; p < 0.001). A higher proportion of unambiguous information was found for the marketing authorization period 2007–2021 compared with 1996–2006 (1996–2006: 63.8% [7466/11,694]; 2007–2021: 82.1% [12,349/15,040]; p < 0.001). Conclusion: For about a quarter of all indications, no or only ambiguous information was available for pediatric patients. The measures initiated in recent years to increase pediatric-specific information in SmPCs should be intensified in order to improve drug safety in children and adolescents.
CRIS-Team Scopus Importer:2024-04-05

Autocrine TNF is critical for the survival of human dendritic cells by regulating BAK, BCL-2, and FLIP L - Lehner, Manfred; Kellert, Beate; Proff, Julia; Schmid, Martina A.; Diessenbacher, Philip; Enßer, Armin; Dörrie, Jan; Schaft, Niels; Leverkus, Martin; Kämpgen, Eckhart; Holter, Wolfgang (Journal of Immunology, 2012)
The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIP L. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process. Copyright © 2012 by The American Association of Immunologists, Inc.
CRIS-Team Scopus Importer:2021-10-01

Autoimmune Psychosis as a Differential Diagnosis of Primary Schizophreniform Psychosis in Children and Adolescents - Briegel, Wolfgang; Wößner, Rupert; Trollmann, Regina (Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie, 2024)
Objective: Autoimmune psychosis (AP), defined as an isolated schizophreniform psychosis with no or only minimal neurological abnormalities stemming from autoantibody-associated cerebral processes, is a very rare and potentially underdiagnosed disorder in children and adolescents. Methods: This article reports the case of a 13-year-old boy who became acutely ill with a psychotic disorder following a respiratory infection. We describe the diagnosis and course of treatment in detail. Results: Following an extensive interdisciplinary workup, a probable glutamic acid decarboxylase (GAD)-associated AP was diagnosed that ultimately remitted completely with treatment. Conclusions: Autoimmune psychoses remain a relatively uncharted territory for the specialty of child and adolescent psychiatry. Good interdisciplinary cooperation is essential for patients with somewhat atypical psychotic symptoms, both in terms of diagnosis and treatment.
CRIS-Team Scopus Importer:2025-02-04

Automated production of specific T cells for treatment of refractory viral infections after allogeneic stem cell transplantation - Heinz, Amadeus T.; Calkoen, Friso G.J.; Derbich, Alexander; Miltner, Lea; Seitz, Christian; Doering, Michaela; Braun, Christiane; Atar, Daniel; Schumm, Michael; Heubach, Florian; Arendt, Anne Marie; Schulz, Ansgar; et al. (Haematologica, 2023)
Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods. In this study we describe the in-house production of VST in a closed system (CliniMACS Prodigy® system, Miltenyi Biotec). In addition, we report the efficacy in 26 patients with viral disease following hematopoietic stem cell transplantation in a retrospective analysis (adenovirus, n=7; cytomegalovirus, n=8; Epstein-Barr virus, n=4; multi-viral, n=7). The production of VST was successful in 100% of cases. The safety profile of VST therapy was favorable (n=2 grade 3 and n=1 grade 4 adverse events; all three were reversible). A response was seen in 20 of 26 patients (77%). Responding patients had a significantly better overall survival than patients who did not respond (P<0.001). Virus-specific symptoms were reduced or resolved in 47% of patients. The overall survival of the whole cohort was 28% after 6 months. This study shows the feasibility of automated VST production and safety of application. The scalability of the CliniMACS Prodigy® device increases the accessibility of VST treatment.
CRIS-Team Scopus Importer:2023-08-11

AUTOMATED PUPILLOMETRY FOR PREDICTION OF SPACE-OCCUPYING HEMISPHERIC INFARCTION AFTER ENDOVASCULAR TREATMENT - Köhn, Julia; Kobus, Franca; Kossel, Clara-Sophie; Borutta, Matthias; Kuramatsu, Joji; Schwab, Stefan (JOURNAL OF NEUROTRAUMA, 2022)
CRIS-Team WoS Importer:2022-09-02

Automatic Classification of Neuromuscular Diseases in Children Using Photoacoustic Imaging - Schlereth, Maja; Stromer, Daniel; Breininger, Katharina; Wagner, Alexandra; Tan, Lina; Maier, Andreas; Knieling, Ferdinand (Informatik aktuell, 2022)
Neuromuscular diseases (NMDs) cause a significant burden for both healthcare systems and society. They can lead to severe progressive muscle weakness, muscle degeneration, contracture, deformity and progressive disability. The NMDs evaluated in this study often manifest in early childhood. As subtypes of disease, e.g. Duchenne muscular dystropy (DMD) and spinal muscular atrophy (SMA), are difficult to differentiate at the beginning and worsen quickly, fast and reliable differential diagnosis is crucial. Photoacoustic and ultrasound imaging has shown great potential to visualize and quantify the extent of different diseases. The addition of automatic classification of such image data could further improve standard diagnostic procedures.We compare deep learning-based 2-class and 3-class classifiers based on VGG16 for differentiating healthy from diseased muscular tissue. This work shows promising results with high accuracies above 0.86 for the 3-class problem and can be used as a proof of concept for future approaches for earlier diagnosis and therapeutic monitoring of NMDs.<br
CRIS-Team Scopus Importer:2022-05-06

Automatic recognition of the XLHED phenotype from facial images - Hadj-Rabia, Smail; Schneider, Holm; Navarro, Elena; Klein, Ophir; Kirby, Neil; Huttner, Kenneth; Wolf, Lior; Orin, Melanie; Wohlfart, Sigrun; Bodemer, Christine; Grange, Dorothy K. (American Journal of Medical Genetics Part A, 2017)
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder that affects ectodermal structures and presents with a characteristic facial appearance. The ability of automated facial recognition technology to detect the phenotype from images was assessed . In Phase 1 of this study we examined if the age of male patients affected the technology's recognition. In Phase 2 we investigated how well the technology discriminated affected males cases from female carriers and from individuals with other ectodermal dysplasia syndromes. The system detected XLHED to be the most likely diagnosis in all genetically confirmed affected male patients of all ages, and in 55% of heterozygous females. Interestingly, patients with other ED syndromes were also detected by the XLHED-targeted analysis, consistent with shared developmental features. Thus the automated facial recognition system represents a promising non-invasive technology to screen patients at all ages for a possible diagnosis of ectodermal dysplasia, with greatest sensitivity and specificity for males affected with XLHED.
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Automatic Segmentation of Lymphatic Perfusion in Patients with Congenital Single Ventricle Defects - Stegmaier, Marietta; Schröder, Christian; Müller, Johanna; Day, Thomas; Cuomo, Michela; Dewald, Oliver; Dittrich, Sven; Kainz, Bernhard (Bildverarbeitung für die Medizin 2024. BVM 2024, 2024)
The Fontan circulation is the surgical end-point for a variety of singleventricle congenital heart lesions. While recent decades have witnessed substantial improvements in survival rates, the associated physiology remains susceptible to severe complications such as protein-losing enteropathy and plastic bronchitis. These complications are often indicative of abnormal congestion in the lymphatic system, underscoring their significance as harbingers of impending comorbidities. An accurate assessment of congestion severity requires the detailed annotation of lymphatic perfusion patterns in each volumetric scan slice. The manual labelling of such intricate data is time-consuming and demands a high level of expertise, rendering it unfeasible within the confines of standard clinical protocols. We use a curated database consisting of manually annotated T2-weighted magnetic resonance imaging (MRI) scans from 71 Fontan patients post-surgery. Following the current state-of-the-art method for biomedical image segmentation, we evaluate its performance on multiple independent test sets regarding the degree of severity and imaging quality. Incorporating the best-performing model,we have developed a user-friendly interface for the automatic segmentation of lymphatic malformations, which will be published before the conference starts.
CRIS-Team Scopus Importer:2024-03-29

BAFF 60-mer, and Differential BAFF 60-mer Dissociating Activities in Human Serum, Cord Blood and Cerebrospinal Fluid - Eslami, Mahya; Meinl, Edgar; Eibel, Hermann; Willen, Laure; Donzé, Olivier; Distl, Ottmar; Schneider, Holm; Speiser, Daniel E.; Tsiantoulas, Dimitrios; Yalkinoglu, Ozkan; Samy, Eileen; Schneider, Pascal (Frontiers in Cell and Developmental Biology, 2020)
B cell activation factor of the TNF family (BAFF/BLyS), an essential B cell survival factor of which circulating levels are elevated in several autoimmune disorders, is targeted in the clinic for the treatment of systemic lupus erythematosus (SLE). The soluble form of BAFF can exist as 3-mer, or as 60-mer that results from the ordered assembly of twenty 3-mers and that can be obtained from naturally cleaved membrane-bound BAFF or made as a recombinant protein. However, which forms of soluble BAFF exist and act in humans is unclear. In this study, BAFF 3-mer and 60-mer in biological fluids were characterized for size, activity and response to specific stimulators or inhibitors of BAFF. Human cerebrospinal fluids (CSF) from patients with multiple sclerosis and adult human sera contained exclusively BAFF 3-mer in these assays, also when BAFF concentrations were moderately SLE or highly (BAFFR-deficient individual) increased. Human sera, but not CSF, contained a high molecular weight, saturable activity that dissociated preformed recombinant BAFF 60-mer into 3-mer. This activity was lower in cord blood. Cord blood displayed BAFF levels 10-fold higher than in adults and consistently contained a fair proportion of active high molecular weight BAFF able to dissociate into 3-mer but not endowed with all properties of recombinant BAFF 60-mer. If BAFF 60-mer is produced in humans, it is dissociated, or at least attenuated in the circulation.
CRIS-Team Scopus Importer:2020-11-27
Keywords: 60-mer; atacicept; B-cell activating factor; belimumab; cerebrospinal fluid; cord blood; serum

BCL10 Deficiency Presenting as Severe Combined Immunodeficiency Escaping Newborn Screening - Salou, Sarah; Völkl, Simon; Keller, Baerbel; Ehl, Stephan; Naumann-Bartsch, Nora (Journal of clinical immunology, 2024)
CRIS-Team Scopus Importer:2024-01-12

BDV Syndrome: An Emerging Syndrome with Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome - Bosch, Elisabeth; Hebebrand, Moritz; Popp, Bernt; Penger, Theresa; Behring, Bettina; Cox, Helen; Towner, Shelley; Kraus, Cornelia; Wilson, William G.; Khan, Shagufta; Krumbiegel, Mandy; Ekici, Arif Bülent; et al. (Journal of Clinical Endocrinology and Metabolism, 2021)
Context: CPE encodes carboxypeptidase E, an enzyme that converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, 4 individuals from 2 families with core clinical features including morbid obesity, neurodevelopmental delay, and hypogonadotropic hypogonadism, harboring biallelic loss-of-function (LoF) CPE variants, have been reported. Objective: We describe 4 affected individuals from 3 unrelated consanguineous families, 2 siblings of Syrian, 1 of Egyptian, and 1 of Pakistani descent, all harboring novel homozygous CPE LoF variants. Methods: After excluding Prader-Willi syndrome (PWS), exome sequencing was performed in both Syrian siblings. The variants identified in the other 2 individuals were reported as research variants in a large-scale exome study and in the ClinVar database. Computational modeling of all possible missense alterations allowed assessing CPE tolerance to missense variants. Results: All affected individuals were severely obese with neurodevelopmental delay and other endocrine anomalies. Three individuals from 2 families shared the same CPE homozygous truncating variant c.361Câ€ >â€ T, p.(Arg121∗), while the fourth carried the c.994del, p.(Ser333Alafs∗22) variant. Comparison of clinical features with previously described cases and standardization according to the Human Phenotype Ontology terms indicated a recognizable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes. Conclusion: Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognizable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism, and hypothyroidism. BDV syndrome resembles PWS. Our findings suggest missense variants may also be clinically relevant.
CRIS-Team Scopus Importer:2021-12-24
Keywords: BDV syndrome; carboxypeptidase E; CPE; hypogonadotropic hypogonadism; neurodevelopmental disorder; obesity

Benefit-Risk Assessment of Off-Label Drug Use in Children: The Bravo Framework - Van Der Zanden, Tjitske M.; Mooij, Miriam G.; Vet, Nienke J.; Neubert, Antje; Rascher, Wolfgang; Lagler, Florian B.; Male, Christoph; Grytli, Helene; Halvorsen, Thomas; De Hoog, Matthijs; De Wildt, Saskia N. (Clinical Pharmacology & Therapeutics, 2021)
A drug is granted a license for use after a thorough assessment of risks and benefits based on high-quality scientific proof of its efficacy and safety. Many drugs that are relevant to children are not licensed for use in this population implying that a thorough assessment of risks and benefits in the pediatric population has not been made at all, implying a negative risk-benefit balance in children, or implying insufficient information to establish the risk-benefit balance. Use of drugs without positive assessment of risks and benefits exposes children to potential lack of efficacy, unknown toxicity, and harm. To aid guideline committees and individual prescribers, we here present a tutorial of the Benefit and Risk Assessment for Off-label use (BRAvO) decision framework. This pragmatic framework offers a structured assessment of benefits and risks of off-label drug use, including a clinical pharmacological based approach to age-appropriate dose selection. As proof of concept and to illustrate the practical use, we have applied the framework to assess benefits and risks of off-label use of ondansetron for gastroenteritis-induced nausea and vomiting. The framework could also guide decisions on off-label use in other special populations (e.g., pregnant women, elderly, obese, or critically ill patients) where off-label drug use is frequent, thereby contributing to effective and safe pharmacotherapy.
CRIS-Team WoS Importer:2021-08-13

Benign liver tumors in pediatric patients - Review with emphasis on imaging features - Chiorean, Liliana; Cui, Xin-Wu; Tannapfel, Andrea; Franke, Doris; Stenzel, Martin; Kosiak, Wojciech; Schreiber-Dietrich, Dagmar; Juengert, Joerg; Chang, Jian-Min; Dietrich, Christoph F. (World Journal of Gastroenterology, 2015)
Benign hepatic tumors are commonly observed in adults, but rarely reported in children. The reasons for this remain speculative and the exact data concerning the incidence of these lesions are lacking. Benign hepatic tumors represent a diverse group of epithelial and mesenchymal tumors. In pediatric patients, most benign focal liver lesions are inborn and may grow like the rest of the body. Knowledge of pediatric liver diseases and their imaging appearances is essential in order to make an appropriate differential diagnosis. Selection of the appropriate imaging test is challenging, since it depends on a number of age-related factors. This paper will discuss the most frequently encountered benign liver tumors in children (infantile hepatic hemangioendothelioma, mesenchymal hamartoma, focal nodular hyperplasia, nodular regenerative hyperplasia, and hepatocellular adenoma), as well as a comparison to the current knowledge regarding such tumors in adult patients. The current emphasis is on imaging features, which are helpful not only for the initial diagnosis, but also for pre- and post-treatment evaluation and follow-up. In addition, future perspectives of contrast-enhanced ultrasound (CEUS) in pediatric patients are highlighted, with descriptions of enhancement patterns for each lesion being discussed. The role of advanced imaging tests such as CEUS and magnetic resonance imaging, which allow for non-invasive assessment of liver tumors, is of utmost importance in pediatric patients, especially when repeated imaging tests are needed and radiation exposure should be avoided.
EVALuna2:18922

Beratung nach pränatalen Diagnosen: Sorgen wir für Informationen aus erster Hand! - Schneider, Holm (Zeitschrift für Geburtshilfe und Neonatologie, 2024)

Betreuung von Kindern und Jugendlichen mit M. Basedow in einem endokrinologischen Zentrum - Penger, Theresa; Albrecht, Andrea; Marx, Martin; Jüngert, Jörg M.; Kuwert, Torsten; Dörr, Helmuth-Günther (Monatsschrift Kinderheilkunde, 2019)
Background: Graves’ disease is rare in childhood and adolescence. While the criteria for diagnosis are clearly defined, there are controversial discussions in the literature regarding the optimal treatment modality. Objective: The aim of the study was to retrospectively analyze the treatment and long-term course of patients with Graves’ disease who were under the care of this outpatient department of pediatric endocrinology between 2000 and 2015. Material and methods: The data of 50 children and adolescents (40 female, 10 male) aged between 4.5 and 17.6 years (median 12.4 years) were evaluated. The patient history, height, weight and laboratory values were documented at the initial presentation and at every outpatient visit. The duration to achievement of euthyroidism (remission), the time until attempted withdrawal, the duration of remission, the time of recurrence and the time and type of a final treatment were also documented. To calculate thyroid volume (SDS) values, the data of Kromeyer-Hauschild et al. were used as references for height and BMI and for the sonographically measured thyroid volume the data of the German National Health Examination Survey for Children and Adolescents (KiGGS) were used. Results (median values): The diagnosis was made 6 months after the onset of symptoms at the age of 12.4 years. Serum thyroid-stimulating hormone (TSH) levels were suppressed, free tri-iodothyronine (fT3, 21.6 pmol/l; normal range 3.5–8.1), free thyroxine (fT4, 48.3 pmol/l; 7.6–17.7), and TSH-receptor antibody (TRAB, 9.4 U/l; <1.5) were elevated. At diagnosis 28 children had goiter (+5.9 SDS) and 15 patients developed a goiter during the further course. All patients primarily received thiamazole (n = 34) or carbimazole (n = 16) and 18 patients a beta blocker. During the course 96% received dual therapy (antithyroid drug plus L‑T4) and 9 patients are still receiving primary treatment. Thus, 41 patients could be assessed with respect to the long-term course. The treatment did not affect the size of the thyroid gland. A withdrawal trial was performed in 33 patients at 32 months, including 6 patients receiving treatment for <24 months and 11 patients receiving treatment for more than 36 months. Thyroidectomy was performed in 8 patients on drug treatment without a withdrawal trial due to the increasing goiter. After the end of the thyrostatic therapy, 17 patients achieved full remission (no recurrence of hyperthyroidism after completion of drug treatment) and 8 patients currently have a remission duration ≥12 months. Recurrence treatment was initiated in 7 patients after the first remission and 9 patients underwent thyroidectomy. Conclusion: The high remission rate was positively correlated with the treatment duration. The dual therapy regimen might also affect the outcome. The size of the thyroid gland was unchanged during treatment. The extent of TRAB levels at the time of the withdrawal trial did not affect the long-term outcome. In all cases with a rapid goiter progression, an early thyroidectomy should be performed.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Hyperthyroidism; Long-term outcome; Single center; Therapeutic options

Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 “knock-out” - Vahidnezhad, Hassan; Youssefian, Leila; Daneshpazhooh, Maryam; Mahmoudi, Hamidreza; Kariminejad, Ariana; Fischer, Judith; Christiansen, Julie; Schneider, Holm; Guy, Alyson; Liu, Lu; McGrath, John A.; Has, Cristina; et al. (Matrix Biology, 2019)
Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human “knock-out” of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to perinatal lethal, expanding the genotypic profile of autosomal recessive EBS.
CRIS-Team Scopus Importer:2019-08-02
Keywords: Epidermolysis bullosa simplex; KRT5 homozygosity; Next generation sequencing; Phenotype-genotype correlations

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies - Stegmann, Jil D.; Kalanithy, Jeshurun C.; Dworschak, Gabriel C.; Ishorst, Nina; Mingardo, Enrico; Lopes, Filipa M.; Ho, Yee Mang; Grote, Phillip; Lindenberg, Tobias T.; Yilmaz, Öznur; Channab, Khadija; Seltzsam, Steve; et al. (npj Genomic Medicine, 2024)
CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.
CRIS-Team Scopus Importer:2024-03-15

Bilateral posterior persistent hyperplastic primary vitreous - Hohberger, B.; Knorr, H. L.J.; Mardin, Christian Y.; Trollmann, Regina; von Marchtaler, Philipp; Gusek-Schneider, G. ‑C (Ophthalmologe, 2017)
Bilateral persistent hyperplastic primary vitreous (PHPV) represents a rare entity of a congential malformation. This casuistic presents for the first time in the German literature the case of a 4-month-old child with bilateral posterior PHPV.
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Birth Size in Neonates with Congenital Adrenal Hyperplasia due to 21-hydroxylase Deficiency - Dörr, Helmuth-Günther; Penger, Theresa; Albrecht, Andrea; Marx, Martin; Völkl, Thomas (JCRPE Journal of Clinical Research in Pediatric Endocrinology, 2019)
Objective: Classic congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is characterized by increased prenatal adrenal androgen secretion. There are a small number of reports in the literature showing higher birth weight and length in CAH newborns.
CRIS-Team WoS Importer:2019-03-06

Birthweight Differences in Adolescent Monozygotic Twins Influence Androgens, Psychological Morbidity, and Health-Related Quality of Life - Schmitz, Lioba; Schulte, Sandra; Stoffel-Wagner, Birgit; Bartmann, Peter; Plamper, Michaela; Schreiner, Felix; Wölfle, Joachim; Gohlke, Bettina (Hormone Research in Paediatrics, 2021)
Background: Adverse prenatal conditions can exert a long-lasting impact in later life. Patients and Methods: Thirty-eight post-pubertal monozygotic twin pairs (16 female pairs) with divergent birthweight (bw) due to twin-to-twin transfusion syndrome were examined at a median of 15.1 years. Auxological and endocrine parameters were measured. To evaluate effects of intra-twin bw and hormone differences on mental health, adolescents and their parents completed the Strengths and Difficulties Questionnaire (SDQ), identifying psychological problems. Twins answered the questionnaire on health-related quality of life (HrQoL, KIDSCREEN-52). Results: Parents attributed a higher number of psychological challenges to the formerly smaller twins, for example, total difficulties (8.8 vs. 6.5, p = 0.009). Differences in bw were associated with differences in parental evaluation of problems, for example, peer relationship problems (r = -0.57 and p = 0.0001). In contrast, bw differences did not affect subjects' self-assessment of psychological factors but on physical well-being (r = 0.42, p = 0.017). The formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being (24.9 vs. 26.6, T1,15 = -2.2, and p = 0.043) and moods and emotions (29.8 vs. 32.0, T1,15 = -2.3, p = 0.039). Higher concentrations of androstenedione were linked to greater psychological well-being (r = 0.39 and p = 0.036) in all twin pairs. Conclusion: Our results show that the prenatal environment leading to bw differences exerts a long-lasting impact on diverging parental evaluation of mental health. Formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being and moods and emotions. Higher androstenedione concentrations were linked to greater psychological well-being.
CRIS-Team Scopus Importer:2021-02-26

Blocking counter regulation of unfolded protein response by targeted protein synthesis inhibition produces highly synergistic cell death in several cancer entities - Müller, Fabian; Gsottberger, Franziska; Meier, Clara; Petkovic, S.; Krumbholz, Manuela; Metzler, Markus; Mackensen, Andreas (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23

Block of Counter-Regulation By Inhibition of Protein Synthesis Sensitizes Cancer Cells to IRE1a-Mediated Apoptosis Following Unfolded Protein Response - Gsottberger, Franziska; Meier, Christina; Ammon, Anna-Maria; Parker, Scott; Wendland, Kerstin; George, Rebekka; Petkovic, Srdjan; Mellenthin, Lisa; Emmerich, Charlotte; Lutzny-Geier, Gloria; Metzler, Markus; Mackensen, Andreas; et al. (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-10

Blood circuit reconstruction in an abdominal mouse heart transplantation model - Yin, Decheng; Fu, Jian; Allabauer, Ida; Witzke, Oliver; Rong, Song; Hörning, André (Journal of Visualized Experiments, 2021)
The surgical technique of heterotopic abdominal heart transplantation in mice is a standard model for research in transplantation immunology. Here, the established technique for a modified blood circuit reconstruction in a heterotopic abdominal heart transplantation model is presented. This method uses the intrathoracic inferior vena cava (IIVC) instead of the pulmonary artery of the donor heart for the anastomosis to the inferior vena cava of the recipient. It is facilitating and improving success rates for abdominal heart transplantation in mice.
CRIS-Team Scopus Importer:2021-07-02

Blood counts in adult and elderly individuals: defining the norms over eight decades of life - Zierk, Jakob; Krebs, Alexander; Rauh, Manfred; Metzler, Markus; Löscher, Astrid; Strasser, Erwin; Krause, Stefan (British Journal of Haematology, 2020)
The blood count is one of the most common tests used for health assessment. In elderly individuals, selection of a ‘healthy’ reference population for laboratory assessment is difficult due to the high prevalence of chronic morbidities, leading to uncertainty regarding appropriate reference intervals. In particular, age-specific lower haemoglobin reference limits to define anaemia are controversial. Here, we applied a data mining approach to a large dataset of 3 029 904 clinical routine samples to establish blood count reference intervals. We excluded samples from units/specialists with a high proportion of abnormal blood counts, samples from patients with an unknown or decreased estimated glomerular filtration rate, and samples with abnormal test results in selected other analytes. After sample exclusion, 566 775–572 060 samples from different individuals aged 20–100 years were available for analysis. We then used an established statistical algorithm to determine the distribution of physiological test results and calculated age- and sex-specific reference intervals. Our results show substantial trends with age in haematology analytes' reference intervals. Most notably, haemoglobin and red cell counts decline in men with advanced age, accompanied by increases in red cell volume in both sexes. These findings were confirmed in an independent dataset, and suggest an at least partly physiologic cause.
CRIS-Team Scopus Importer:2020-02-14
Keywords: anaemia; haematology; laboratory haematology

Blood counts in adults and elderly individuals - Zierk, Jakob; Krebs, A.; Rauh, Manfred; Metzler, Markus; Parsch, H.; Strasser, Erwin; Krause, Stefan (ONCOLOGY RESEARCH AND TREATMENT, 2019)
CRIS-Team WoS Importer:2020-10-02

Blood pressure and kidney function in neonates and young infants with intrauterine growth restriction - Heuchel, Katharina Monika; Ebach, Fabian; Alsat, Ebru Aileen; Reutter, Heiko Martin; Mueller, Andreas; Hilger, Alina Christine (Pediatric Nephrology, 2022)
Background: Intrauterine growth restriction (IUGR) has been associated with changes in kidney anatomy, nephrogenesis and the vascular system, resulting in secondary arterial hypertension and kidney damage in adulthood. Here, we compare routine clinical and metabolic parameters between IUGR and non-IUGR study participants in the neonatal and early infant period. Methods: A total of 39 IUGR and 60 non-IUGR neonates were included during an 18-month study period. We compared blood pressure, serum creatinine (SCr), urea nitrogen (BUN), urinary albumin, α-1-microglobulin, transferrin, immunoglobulin G and total protein excretion in spontaneous urine normalized by urine creatinine level during the hospital stay. Results: There were no significant differences in mean values of blood pressure and urinary protein excretion between cases and controls. SCr and BUN levels were lower in the IUGR group compared to the non-IUGR group. Conclusions: The lower levels of SCr and BUN may be attributed to lower liver and muscle mass in IUGR neonates and young infants. Biomarkers currently used in routine clinical care do not allow early postnatal prediction of higher blood pressure or worse kidney function due to IUGR, so further studies are needed. Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information. [Figure not available: see fulltext.]
CRIS-Team Scopus Importer:2022-09-16
Keywords: Blood pressure; Intrauterine growth restriction; Kidney function; Neonates; Proteinuria

Blood Pressure in a Large Cohort of Children and Adolescents With Classic Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency - Bonfig, Walter; Roehl, Friedrich-Wilhelm; Riedl, Stefan; Dörr, Helmuth-Günther; Bettendorf, Markus; Braemswig, Juergen; Schoenau, Eckhard; Riepe, Felix; Hauffa, Berthold; Holl, Reinhard W.; Mohnike, Klaus (American Journal of Hypertension, 2016)
BACKGROUND: Data on blood pressure (BP) in children and adolescents with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are conflicting in the literature. PATIENTS AND METHODS: BP data of n = 716 children and adolescents (aged 3-18 years) from a national CAH database were analyzed. BP data were adjusted for height and compared to contemporary national reference data. A systolic and diastolic BP above the 95th centile was defined as hypertensive. RESULTS: Overall prevalence of hypertension was 12.5%. Prevalence of hypertension was higher in younger children than in adolescents (18.5% vs. 4.9%). Until 8 years of age, fludrocortisone dose/m(2)/day correlated significantly with BP in regression analysis (P < 0.0001). BP correlated significantly with body mass index standard deviation score (BMI-SDS) (P < 0.0001), but not with hydrocortisone dose. In patients with salt-wasting CAH, BMI-SDS and BP were significantly higher compared to patients with simple virilising CAH, P < 0.01. CONCLUSION: Especially young CAH children seem to be at risk for-most likely transient-hypertension, since the prevalence of hypertension decreases with age. In children up to 8 years of age, the used fludrocortisone dose is a significant risk factor for hypertension. Therefore we recommend accurate measurement of BP and careful fludrocortisone dosing in children with CAH.
EVALuna2:34016

Blunted transcriptional response to skeletal muscle ischemia in rats with chronic kidney disease: potential role for impaired ischemia-induced angiogenesis - Heiß, Rafael; Fahlbusch, Fabian B.; Jacobi, Johannes; Daniel, Christoph; Ekici, Arif Bülent; Cordasic, Nada; Amann, Kerstin Ute; Hilgers, Karl Friedrich; Hartner, Andrea (Physiological Genomics, 2017)
Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Previous studies indicated an impairment of ischemia-induced angiogenesis in skeletal muscle of rats with CKD. We performed a systematic comparison of early gene expression in response to ischemia in rats with or without CKD to identify potential molecular mechanisms underlying impaired angiogenesis in CKD. CKD was induced in male rats by 5/6 nephrectomy (SNX); control rats were sham operated (sham). Eight weeks later, ischemia of the right limb was induced by ligation and resection of the femoral artery. Rats were sacrificed 24 hours after the onset of ischemia, and RNA was extracted from the musculus soleus of the ischemic and the nonischemic hindlimb. To identify differentially expressed transcripts, RNA was analyzed employing Affymetrix GeneChip Rat Genome 230 2.0 Arrays. RT-PCR analysis of selected genes was performed to validate observed changes. Hindlimb ischemia up-regulated 239 genes in CKD and 299 genes in control rats (66% overlap) whereas only a few genes were down-regulated (14 in CKD and 34 in controls), compared with the non-ischemic limb of the same animals. Comparison between the ischemic limbs of CKD and controls revealed down-regulation of 65 genes in CKD; 37 of these genes were also among the ischemia-induced genes in controls. Analysis of functional groups (other than angiogenesis) pointed to genes involved in leukocyte recruitment and fatty acid metabolism. Transcript expression profiling points to a relatively small number of differentially expressed genes which may underlie the impaired post-ischemic angiogenesis in CKD.
EVALuna2:3946

Blunt renal trauma-induced hypertension in pediatric patients: a single-center experience - Marcou, Marios; Galiano, Matthias; Jüngert, Jörg M.; Rompel, Oliver; Kuwert, Torsten; Wullich, Bernd; Hirsch-Koch, Karin (Journal of Pediatric Urology, 2021)
Purpose: Children have a greater chance of sustaining a renal injury than adults and higher odds of having a high-grade renal injury. Hypertension is a rare complication of blunt renal trauma, with risk being higher in cases of major renal trauma. We reviewed the cases of pediatric blunt renal trauma-induced hypertension in our tertiary referral center in an attempt to better understand this rare condition. Study design: A retrospective evaluation of children under the age of 18 who were admitted to our department during the last 20 years and were diagnosed with blunt renal trauma. Results: Twenty-three children presented with blunt renal trauma, one of whom was treated with emergency nephrectomy. Four children (18%) developed post-traumatic hypertension. All four cases were associated with a reduction in blood flow to the kidney, either through injury to the renal artery (in three cases) or through extrinsic compression of the kidney by a large perirenal hematoma (Page kidney; in one case). The Page kidney case developed hypertension during the initial hospitalization, and it resolved spontaneously after five months through the gradual resorption of the perirenal hematoma. Among the three cases of renal artery injury, hypertension during the initial hospitalization was only observed in one case, with hypertension in the other two cases manifesting after two months and four years, respectively. All three cases of renal artery injury resulted in a complete loss of function of the injured kidney, and two cases were treated with nephrectomy. Following nephrectomy, the blood pressure level returned to normal within a few days. Discussion: Development of hypertension following a blunt renal trauma can be heterogenous, with the time of manifestation stretching between days after the accident and years thereafter. Children have a higher risk of renal trauma and, according to published data out of the National Trauma Data Bank, a 20-times higher risk of renal artery injury in comparison to the adult population. Large multicenter studies are required to answer the question of whether children are therefore more prone to blunt renal trauma-induced hypertension than adults. Conclusions: Our study highlights the importance of blood pressure monitoring in children following blunt renal trauma, as post-traumatic hypertension can develop even years after the accident. In cases of a poorly functioning kidney, nephrectomy may be regarded as a curative therapy.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Accidents; Blood pressure; Child; Renal artery; Renovascular hypertension

Bone Fractures in Children and Young Adults With Type 1 Diabetes: Age Distribution, Fracture Location, and the Role of Glycemic Control - Eckert, Alexander J.; Semler, Oliver; Schnabel, Dirk; Köstner, Katharina; Wurm, Donald; Bechtold-Dalla Pozza, Susanne; Schaaf, Katja; Hörtenhuber, Thomas; Hammersen, Johanna; Holl, Reinhard W. (Journal of Bone and Mineral Research, 2021)
Type 1 diabetes (T1D) is a known risk factor for fractures, but the underlying pathophysiology is still not fully understood. This study aims to define age peaks and frequent fracture sites of children and young adults with T1D. Additionally, associations of fractures with metabolic and lifestyle factors as well as with additional complications in individuals with T1D were analyzed. A total of 750 individuals with T1D aged ≤25 years with fractures were matched to 3750 patients with T1D without fractures by demographics and insulin regimen. Hemoglobin A1c (HbA1c) values were compared using linear regression, and logistic regression was used to calculate odds ratios (OR) for fractures in individuals with acute complications and diseases. Median (Q1–Q3) age was 12.7 (9.9 to 14.9) years in individuals with fractures and 16.3 (12.6 to 17.8) years in the entire control group with 65% versus 53% males. Peak age for fractures was 7 to <15 years in males and 9 to <11 years in females, which is earlier than reported for the general population. HbA1c (%) was significantly higher in individuals with fractures than in controls (difference of estimated means: 0.26%; 95% confidence interval [CI] 0.07–0.46), especially in postpubertal females (0.68; 0.10–1.26). Significantly higher odds for fractures were observed in individuals with severe hypoglycemia (OR = 1.90; 95% CI 1.47–2.47), especially in prepubertal females (OR = 2.81; 1.21–6.52]) and postpubertal males (2.44; 1.11–5.38), celiac disease (2.02; 1.67–2.45), and with a history of smoking (1.38; 1.02–1.88). The age peak of fractures seems to be earlier in T1D than in the general population. Poor glycemic control is related to fractures, even before puberty. Associations of HbA1c and severe hypoglycemia with fractures highly depend on age and sex. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
CRIS-Team Scopus Importer:2021-10-29
Keywords: CELIAC DISEASE; DISEASES AND DISORDERS OF/RELATED TO BONE; FRACTURE RISK ASSESSMENT; HEALTH SERVICES RESEARCH; HEMOGLOBIN A1c; HYPOGLYCEMIA

Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia - Verma, Divij; Zanetti, Costanza; Godavarthy, Parimala Sonika; Kumar, Rahul; Minciacchi, Valentina R.; Pfeiffer, Jakob; Metzler, Markus; Lefort, Sylvain; Maguer-Satta, Véronique; Nicolini, Franck E.; Burroni, Barbara; Fontenay, Michaela; et al. (Leukemia, 2020)
Specific and reciprocal interactions with the bone marrow microenvironment (BMM) govern the course of hematological malignancies. Matrix metalloproteinase-9 (MMP-9), secreted by leukemia cells, facilitates tumor progression via remodeling of the extracellular matrix (ECM) of the BMM. Hypothesizing that leukemias may instruct the BMM to degrade the ECM, we show, that MMP-9-deficiency in the BMM prolongs survival of mice with BCR-ABL1-induced B-cell acute lymphoblastic leukemia (B-ALL) compared with controls and reduces leukemia-initiating cells. MMP-9-deficiency in the BMM leads to reduced degradation of proteins of the ECM and reduced invasion of B-ALL. Using various in vivo and in vitro assays, as well as recipient mice deficient for the receptor for tumor necrosis factor (TNF) α (TNFR1) we demonstrate that B-ALL cells induce MMP-9-expression in mesenchymal stem cells (MSC) and possibly other cells of the BMM via a release of TNFα. MMP-9-expression in MSC is mediated by activation of nuclear factor kappa B (NF-κB) downstream of TNFR1. Consistently, knockdown of TNF-α in B-ALL-initiating cells or pharmacological inhibition of MMP-9 led to significant prolongation of survival in mice with B-ALL. In summary, leukemia cell-derived Tnfα induced MMP-9-expression by the BMM promoting B-ALL progression. Inhibition of MMP-9 may act as an adjunct to existing therapies.
CRIS-Team Scopus Importer:2020-01-21

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921. - Brivio, Erica; Pennesi, Edoardo; Willemse, Marieke E.; Huitema, Alwin D.R.; Jiang, Yilin; Van Tinteren, Harm D.R.; Van Der Velden, Vincent H.J.; Beverloo, Berna H.; Den Boer, Monique L.; Rammeloo, Lukas A.J.; Hudson, Chad; Heerema, Nyla; et al. (Journal of Clinical Oncology, 2024)
PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 μg h/mL, 2.52 μg h/mL, and 2.66 μg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.
EVALuna2:550441

Brain Abnormalities in Patients with Germline Variants in H3F3: Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors - Alves, C. A.P.F.; Sherbini, O.; D’Arco, F.; Steel, D.; Kurian, M. A.; Radio, F. C.; Ferrero, G. B.; Carli, D.; Tartaglia, M.; Balci, T. B.; Powell-Hamilton, N. N.; Schrier Vergano, S. A.; et al. (American Journal of Neuroradiology, 2022)
BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.
CRIS-Team Scopus Importer:2022-08-19

Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience - Pfaff, Elke; El Damaty, Ahmed; Balasubramanian, Gnana Prakash; Blattner-Johnson, Mirjam; Worst, Barbara C.; Stark, Sebastian; Witt, Hendrik; Pajtler, Kristian W.; van Tilburg, Cornelis M.; Witt, Ruth; Milde, Till; Jakobs, Martin; et al. (European Journal of Cancer, 2019)
Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome. The Individualised Therapy For Relapsed Malignancies In Childhood (INFORM) registry study offers comprehensive molecular profiling of high-risk tumours to identify target alterations for potential precision therapy. We analysed molecular characteristics and clinical data after brainstem biopsy of all enrolled newly diagnosed DIPGs. Patients and methods: From –February 2015 to February 2018, 21 subsequent primary DIPG cases were enrolled in the nation-wide multicentre INFORM registry study after brainstem biopsy. Whole-genome, whole-exome sequencing and DNA methylation analysis were performed, and RNA-sequencing was added in case of sufficient material. Clinical data were obtained from standardised questionnaires and the INFORM clinical data bank. Results: Tumour material obtained from brainstem biopsy was sufficient for DNA analysis in all cases and RNA analysis in 16 of 21 cases. In 16 of 21 cases (76%), potential targetable alterations were identified including highly relevant MET and NTRK1 fusions as well as an EZH2 alteration not previously described in DIPG. In 5 of 21 cases, molecular information was used for initiation of targeted treatment. The majority of patients (19/21) presented with neurological deficits at diagnosis. Newly arising or worsening of neurological deficits post-biopsy occurred in nine patients. Symptoms were reversible or improved notably in eight cases. Conclusion: In this multicentre study setting, brainstem biopsy of DIPG was feasible and yielded sufficient material for comprehensive molecular profiling. Relevant molecular targets were identified impacting clinical management in a substantial subset. Death or severe bleeding occurred in none of the cases. One of 20 patients experienced unilateral paraesthesia possibly related to biopsy.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Brainstem biopsy; Molecular profiling; Pediatric diffuse intrinsic pons glioma; Targeted therapy

Brittle-Cornea-Syndrom Typ 1 durch Compound-Heterozygotie zweier Mutationen im ZNF469-Gen - Menzel-Severing, Johannes; Meiller, Ralph; Kraus, Cornelia; Trollmann, Regina; Atalay, Deniz (Ophthalmologe, 2019)
We report the case of a 3-year-old boy presenting with bilateral keratoglobus and blue sclera in addition to hallux valgus, arachnodactyly, small joint hypermobility, mitral valve dysfunction and a history of generalized muscular hypotonia in early infancy. Molecular genetics provided evidence of two pathogenic mutations in the ZNF469 gene (compound heterozygosity) leading to the diagnosis of brittle cornea syndrome type 1. In addition to neuropediatric care, spectacles were prescribed to correct refractive error and for ocular protection. Owing to the thin cornea and sclera, eye injuries are the main cause for irreversible visual loss in this disease.
CRIS-Team Scopus Importer:2019-08-20
Keywords: Blue sclera; Connective tissue disease; Hereditary eye disease; Keratoglobus; Pediatric ophthalmology

Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: A prospective, multicenter study from Germany - Strzelczyk, Adam; Kalski, Malin; Bast, Thomas; Wiemer-Kruel, Adelheid; Bettendorf, Ulrich; Kay, Lara; Kieslich, Matthias; Kluger, Gerhard; Kurlemann, Gerhard; Mayer, Thomas; Neubauer, Bernd A.; Polster, Tilman; et al. (European Journal of Paediatric Neurology, 2019)
Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany. Methods: A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany. Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis. Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
CRIS-Team Scopus Importer:2019-05-21
Keywords: Costs; Depression; Epilepsy; Quality of life; Seizure

C1 Esterase Inhibitor Reduces BBB Leakage and Apoptosis in the Hypoxic Developing Mouse Brain - Jung, Susan; Topf, Hans Georg; Boie, Gudrun; Trollmann, Regina (Neuromolecular Medicine, 2019)
Inflammatory pathways involved in blood–brain barrier (BBB) vulnerability and hypoxic brain oedema in models of perinatal brain injury seem to provide putative therapeutic targets. To investigate impacts of C1-esterase inhibitor (C1-INH; 7.5–30 IU/kg, i.p.) on functional BBB properties in the hypoxic developing mouse brain (P7; 8% O2 for 6 h), expression of pro-apoptotic genes (BNIP3, DUSP1), inflammatory markers (IL-1ß, TNF-alpha, IL-6, MMP), and tight junction proteins (ZO-1, occludin, claudin-1, -5), and S100b protein concentrations were analysed after a regeneration period of 24 h. Apoptotic cell death was quantified by CC3 immunohistochemistry and TUNEL staining. In addition to increased apoptosis in the parietal cortex, hippocampus, and subventricular zone, hypoxia significantly enhanced the brain-to-plasma albumin ratio, the cerebral S100b protein levels, BNIP3 and DUSP1 mRNA concentrations as well as mRNA expression of pro-inflammatory cytokines (IL-1ß, TNF-alpha). In response to C1-INH, albumin ratio and S100b concentrations were similar to those of controls. However, the mRNA expression of BNIP3 and DUSP1 and pro-inflammatory cytokines as well as the degree of apoptosis were significantly decreased compared to non-treated controls. In addition, occludin mRNA levels were elevated in response to C1-INH (p < 0.01). Here, we demonstrate for the first time that C1-INH significantly decreased hypoxia-induced BBB leakage and apoptosis in the developing mouse brain, indicating its significance as a promising target for neuroprotective therapy.
CRIS-Team Scopus Importer:2019-08-23
Keywords: BNIP3; DUSP1; Hypoxia; Matrix metalloproteinases; Neonatal brain injury; Neuroprotection; Occludin; S100b protein; Tight junctions

c4c: Paediatric pharmacovigilance: Methodological considerations in research and development of medicines for children - A c4c expert group white paper - Aurich, Beate; Apele-Freimane, Dina; Banaschewski, Tobias; Chouchana, Laurent; Day, Simon; Kaguelidou, Florentia; Kelly, Lauren E.; Kindblom, Jenny M.; Neubert, Antje; Wong, Ian C. K. (British Journal of Clinical Pharmacology, 2021)
Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population-specific factors (e.g., more frequent use of off-label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life-cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post-marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record-linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit-risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life-cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs.
CRIS-Team WoS Importer:2021-12-31

Candidate reference measurement procedure based on isotope dilution-two dimensional-liquid chromatography-tandem mass spectrometry for the quantification of androstenedione in human serum and plasma - Ott, Myriam; Bauland, Friederike; Fischer, Vanessa; Köppl, Daniel; Gaudl, Alexander; Geistanger, Andrea; Ceglarek, Uta; Rauh, Manfred; Taibon, Judith (Clinical Chemistry and Laboratory Medicine, 2025)
Objectives: Androstenedione (ASD) is a biomarker used in the diagnosis of hyperandrogenism and adrenal hyperplasia. Therefore, accurate measurement of serumASD is pivotal in clinical settings. We aimed to develop a novel highly selective reference measurement procedure (RMP) based on isotope dilution-two dimensional-liquid chromatographytandem mass spectrometry (ID-2D-LC-MS/MS) for the quantification of ASD in human serum/plasma. Methods: To achieve high selectivity and sensitivity, a twodimensional heart-cut LC approach for LC-MS/MS and a supported liquid extraction sample preparation protocol were employed. Matrix effects were evaluated through a post-column infusion experiment and comparison of standard line slopes. Precision and accuracy were determined via a multi-day validation experiment. Reproducibility was assessed by comparing results from two independent laboratories, and measurement uncertainty (MU) was evaluated in compliance with current guidelines. Results: Our novel RMP proved effective for measuring ASD concentrations ranging from 0.00800 ng/mL to 12.0 ng/mL (0.0279 nmol/L to 41.9 nmol/L) and demonstrated matrixindependence. The relative mean bias varied between 0.6 and 2.2 %across different matrices and concentration levels. Intermediate precision was observed to be between 1.2 and 1.9 %. The expanded measurement uncertainty for ASD target value assignment ranged from 1.7 to 2.5 %, irrespective of sample concentration. Equivalence to the JCTLMlisted RMP was evaluated through a method comparison study, revealing a high degree of agreement (r≥0.997). Additionally, by comparing results from two independent laboratories, the transferability and reproducibility of the RMP were confirmed. Conclusions: This isotope dilution two-dimensional LC-MS/ MS method can be used for the evaluation and standardization of routine assays and for measuring individual patient samples, ensuring traceability.
CRIS-Team Scopus Importer:2025-06-06
Keywords: androstenedione; isotope dilution-liquid chromatography-tandem mass spectrometry; qNMR characterization; reference measurement procedure; SI units; traceability

Can we starve leukemia? Metabolic needs of MLL - Garcia-Cuellar, Maria-Paz; Lawlor, Jennifer; Böttcher, Martin; Mougiakakos, Dimitrios; Metzler, Markus; Slany, Robert (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23

Cardiac MRI in Children and Adolescents Who Have Undergone Surgical Repair of Right-Sided Congenital Heart Disease: Automated Left Ventricular Volumes and Function Analysis and Effects of Different Manual Adjustments - Rompel, O.; Janka, Rolf Matthias; May, Matthias; Glöckler, Martin; Cesnjevar, Robert; Dittrich, Sven; Lell, Michael; Uder, Michael; Hammon, Matthias (Röfo-Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren, 2015)
Purpose: To evaluate automated segmentation and the effects of different manual adjustments regarding left ventricular parameter quantification in cardiac magnetic resonance (MR) data on children and adolescents who have undergone surgical repair of right-sided congenital heart disease (CHD). Materials and Methods: Dedicated software (syngo.via, Siemens AG) was used to automatically segment and/or manually adjust the end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), myocardial mass (MM) and ejection fraction (EF) before/after manual apex/base adjustment (ADJ-step 1) and after manual apex/base/myocardial contour adjustment (ADJ-step 2; reference standard). MR data of 40 patients (13.1 ± 3.1y, 4 - 17y) with repaired CHD with decreased pulmonary blood flow (CHD-DPBF) were evaluated. Intra- and inter-rater reliability was determined for 10 randomly selected patients. Results: The software correctly detected the left ventricle in 38/40 (95 %) patients. EDV after automated segmentation: 119.1 ± 44.0ml; after ADJ-step 1: 115.8 ± 39.5ml; after ADJ-step 2: 116.2 ± 39.4 ml. The corresponding results for ESV were 52.0 ± 18.5/49.6 ± 16.9/49.7 ± 16.4ml; for SV 67.1 ± 28.5/66.2 ± 25.4/66.5 ± 25.5ml; for EF 55.5 ± 7.3/56.7 ± 6.6/56.7 ± 6.3 %; for MM 83.7 ± 35.9/76.2 ± 28.3/74.6 ± 27.2 g. Significant differences were found for ESV/MM/EF comparing the automated segmentation results with these after ADJ-step 1 and ADJ-step 2. No significant differences were found when comparing all results of ADJ-step 1 and ADJ-step 2 or when comparing EDV/SV results. Intra- and inter-rater reliability was excellent. The mean time effort was 63.4 ± 6.9 s for the automated segmentation, 74.2 ± 8.9 s for ADJ-step 1 and 269.5 ± 39.4 s for ADJ-step 2. Conclusion: Automated left ventricular volumes and function analysis in children and adolescents with surgically treated CHD proved to be feasible with excellent intra- and inter-rater reliability. Automated segmentation with manual apex/base adjustment provided clinically acceptable results. Key Points: o?Automated left ventricular volume and function analysis in children and adolescents with surgically treated right-sided heart disease is feasible with excellent intra- and inter-rater reliability.o?Automated segmentation with manual apex/base adjustment provides clinically acceptable results.o?Additional manual myocardial contour adjustment does not significantly improve the results. Citation Format: o?Rompel O, Janka R, May MS et al. Cardiac MRI in Children and Adolescents Who Have Undergone Surgical Repair of Right-Sided Congenital Heart Disease: Automated Left Ventricular Volumes and Function Analysis and Effects of Different Manual Adjustments. Fortschr Röntgenstr 2015; 187: 1099 - 1107.
EVALuna2:14516

Cardiomyopathy in Duchenne Muscular Dystrophy: Current Value of Clinical, Electrophysiological and Imaging Findings in Children and Teenagers - Dittrich, Sven; Türk, Matthias; Haaker, G.; Greim, V.; Buchholz, A.; Burkhardt, B.; Fujak, A.; Trollmann, Regina; Schmid, Andrea; Schröder, Rolf (Klinische Pädiatrie, 2015)
Progressive cardiomyopathy (CMP) is one main cause of death in DMD. This cross-sectional assessment of different cardiac diagnostic procedures focusses on preterm diagnosis of cardiac dysfunction.39 male DMD patients aged 6-20 years were included. 6 patients were still ambulatory, 21 patients received corticosteroid therapy.All patients were investigated by ECG, Holter ECG and heart rate variability (HRV), B-type natriuretic peptide (BNP), echocardiography (TTE), tissue Doppler Imaging (TD) and magnetic resonance imaging (MRI) with Late Gadolinium enhancement (LE) and segmental wall motion analysis (WMA).56% of the patients showed repolarization abnormalities and 76% altered HRV. Subnormal ventricular function was found in 25% by TTE and in 34% by MRI. TD differed from normal controls only in the apical septum. In MRI 89% of the patients showed different distribution and intensity of LE and WM restriction. The extent of LE was less in patients after steroid treatment (p<0.05).MRI with segmental LE- and WM-analysis seems to be superior to TTE and TD in exploring regional distribution and severity of damage of the myocardium. ECG and HRV abnormalities are common in DMD-patients but not tightly predictive for segmental and global left ventricular dysfunction. Targeted treatment of CMP in DMD needs prospective evaluation.A timely cardiac MRI is the most sensitive investigation for the identification of early myocardial changes in DMD which is a prerequisite for early interventions and therapeutic strategies.
EVALuna2:7289

Cardiopulmonary function in paediatric post-COVID-19: a controlled clinical trial - Schöffl, Isabelle; Raming, Roman; Tratzky, Jan Philipp; Regensburger, Adrian; Kraus, Calvin; Wällisch, Wolfgang; Trollmann, Regina; Wölfle, Joachim; Dittrich, Sven; Heiß, Rafael; Knieling, Ferdinand; Weigelt, Annika (European Journal of Pediatrics, 2024)
Recently, the importance of post-COVID-19 in children has been recognized in surveys and retrospective chart analysis. However, objective data in the form of cardiopulmonary exercise test as performed in adults suffering from this condition are still lacking. This study aimed to investigate the cardiopulmonary effects of post-COVID-19 on children and adolescents. In this cross-sectional study (the FASCINATE study), children fulfilling the criteria of post-COVID-19 and an age- and sex-matched control group underwent cardiopulmonary exercise testing on a treadmill and completed a questionnaire with regard to physical activity before, during and after the infection with SARS-CoV-2. We were able to recruit 20 children suffering from post-COVID-19 (mean age 12.8 ± 2.4 years, 60% females) and 28 control children (mean age 11.7 ± 3.5 years, 50% females). All participants completed a maximal treadmill test with a significantly lower V ˙ O 2peak in the post-COVID-19 group (37.4 ± 8.8 ml/kg/min vs. 43.0 ± 6.7 ml/kg/min. p = 0.019). This significance did not persist when comparing the achieved percentage of predicted V ˙ O 2peak . There were no significant differences for oxygen pulse, heart rate, minute ventilation or breathing frequency. Conclusion: This is the first study to investigate post-COVID-19 in children using the cardiopulmonary exercise test. Although there was a significantly reduced V ˙ O 2peak in the post-COVID-19 group, this was not true for the percent of predicted values. No pathological findings with respect to cardiac or pulmonary functions could be discerned. Deconditioning was the most plausible cause for the experienced symptoms. Trial registration: clinicaltrials.gov, NCT054445531, Low-field Magnetic Resonance Imaging in Pediatric Post Covid-19—Full Text View—ClinicalTrials.gov. What is Known: • The persistence of symptoms after an infection with SARS-CoV 2, so-called post-COVID-19 exists also in children. • So far little research has been conducted to analyze this entity in the pediatric population. What is New: • This is the first study proving a significantly lower cardiopulmonary function in pediatric patients suffering from post-COVID-19 symptoms. • The cardiac and pulmonary function appear similar between children suffering from post-COVID-19 and those who don’t, but the peripheral muscles seem affected.
CRIS-Team Scopus Importer:2024-01-19
Keywords: Cardiopulmonary exercise testing; Exercise capacity; Fitness; Physical activity; Post-COVID; VO

Cardiovascular Outcome of Pediatric Patients With Bi-Allelic (Homozygous) Familial Hypercholesterolemia Before and After Initiation of Multimodal Lipid Lowering Therapy Including Lipoprotein Apheresis - Taylan, Christina; Driemeyer, Joenna; Schmitt, Claus P.; Pape, Lars; Büscher, Rainer; Galiano, Matthias; König, Jens; Schürfeld, Carsten; Spitthöver, Ralf; Versen, Axel; Koziolek, Michael; Marsen, Tobias A.; et al. (American Journal of Cardiology, 2020)
Twenty-four patients with bi-allelic familial hypercholesterolemia commencing chronic lipoprotein apheresis (LA) at a mean age of 8.5 ± 3.1 years were analysed retrospectively and in part prospectively with a mean follow-up of 17.2 ± 5.6 years. Mean age at diagnosis was 6.3 ± 3.4 years. Untreated mean LDL-C concentrations were 752 mg/dl ± 193 mg/dl (19.5 mmol/l ± 5.0 mmol/l). Multimodal lipid lowering therapy including LA resulted in a mean LDL-C concentration of 184 mg/dl (4.8 mmol/l), which represents a 75.5% mean reduction. Proprotein convertase subtilisin/kexin type 9-antibodies contributed in 3 patients to LDL-C lowering with 5 patients remaining to be tested. After commencing chronic LA, 16 patients (67%) remained clinically stable with only subclinical findings of atherosclerotic cardiovascular disease (ASCVD), and neither cardiovascular events, nor need for vascular interventions or surgery. In 19 patients (79%), pathologic findings were detected at the aortic valve (AV), which in the majority were mild. AV replacement was required in 2 patients. Mean Lipoprotein(a) concentration was 42.4 mg/dl, 38% had >50 mg/dl. There was no overt correlation of AV pathologies with other ASCVD complications, or Lipoprotein(a) concentration. Physicochemical elimination of LDL particles by LA appears indispensable for patients with bi-allelic familial hypercholesterolemia and severe hypercholesterolemia to maximize the reduction of LDL-C. In conclusion, in this rare patient group regular assessment of both the AV, as well as all arteries accessible by ultrasound should be performed to adjust the intensity of multimodal lipid lowering therapy with the goal to prevent ASCVD events and aortic surgery.
CRIS-Team Scopus Importer:2020-11-20

Caring for a Child with Congenital Adrenal Hyperplasia Diagnosed by Newborn Screening: Parental Health-Related Quality of Life, Coping Patterns, and Needs - Rautmann, Laura; Witt, Stefanie; Theiding, Christoph; Odenwald, Birgit; Nennstiel-Ratzel, Uta; Dörr, Helmuth-Günther; Quitmann, Julia Hannah (International Journal of Environmental Research and Public Health, 2023)
Diagnosing a child by newborn screening with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) causes multiple challenges for the affected parents and the whole family. We aimed to examine the health-related Quality of Life (HrQoL), coping, and needs of parents caring for a child with CAH to develop demand-responsive interventions for improving the psychosocial situation of affected families. In a retrospective cross-sectional design, we assessed HrQoL, coping patterns, and the needs of parents caring for a CAH-diagnosed child using specific questionnaires. Data of 59 families with at least one child diagnosed with CAH were analyzed. The results show that mothers and fathers in this study reached significantly higher HrQoL scores compared to reference cohorts. Decisive for the above-average parental HrQoL were effective coping behaviors and the parental needs being met. These findings verify the importance of helpful coping patterns and rapid fulfillment of parental needs for maintaining a good and stable HrQoL of parents with a child diagnosed with CAH. It is crucial to strengthen the parental HrQoL to build a reasonable basis for a healthy upbringing and improve the medical care of CAH-diagnosed children.
CRIS-Team Scopus Importer:2023-03-24
Keywords: 21-hydroxylase deficiency; congenital adrenal hyperplasia; newborn screening; parental coping; parental needs; psychological stress; rare disease

CAR-T cells for the treatment of pediatric chronic myeloid leukemia in repeatedly relapsed lymphoid blast phase - Kramp, Laura Jane; Heydrich-Karsten, Christiane; Sembill, Stephanie; Karow, Axel; Lion, Thomas; Chitadze, Guranda; Suttorp, Meinolf; Cario, Gunnar; Metzler, Markus (Annals of Hematology, 2024)
Chronic myeloid leukemia presenting de novo in the blast phase (CML-BP) is a rare diagnosis among pediatric malignancies. We report on a 16-year-old male who presented with CML-BP lymphoid at diagnosis. He was treated with shortened acute lymphoblastic leukemia induction plus the tyrosine kinase inhibitor (TKI) imatinib followed by dasatinib. After achieving molecular remission (MR), hematopoietic stem cell transplantation (HSCT) was performed early after diagnosis. Despite prophylactic dasatinib, he relapsed 3 months later with the kinase domain mutation T315I. Multiple therapeutic approaches including ponatinib, blinatumomab, a 2nd HSCT from a different donor, donor lymphocyte infusions, and high-dose asciminib all resulted in subsequent relapse. Another molecular response was achieved by combining ponatinib plus asciminib with chemotherapy. In this situation, CD19-directed CAR-T cells (Kymriah®) were administered for compassionate use and tolerated without adverse events. Compared to all prior therapies, CAR T-cells maintained remission. After 12 months of follow-up, complete B-cell aplasia and low numbers of CAR-T cells are detectable in the peripheral blood, potentially mediating long-term disease control.
CRIS-Team Scopus Importer:2024-09-27
Keywords: Blast phase; CD19 CAR-T cells; Chronic myeloid leukemia; Refractory leukemia

CAR T-cell therapy rescues adolescent with rapidly progressive lupus nephritis from haemodialysis - Krickau, Tobias; Naumann-Bartsch, Nora; Aigner, Michael; Kharboutli, Soraya; Kretschmann, Sascha; Spörl, Silvia; Vasova, Ingrid; Völkl, Simon; Wölfle, Joachim; Mackensen, Andreas; Schett, Georg; Metzler, Markus; et al. (Lancet, 2024)
CRIS-Team Scopus Importer:2024-05-03

Case report: Tension pneumoperitoneum after diagnostic colonoscopy in an 11 y/o boy with Crohns disease - Seitz, Sigurd; Rückel, Aline; Siebenlist, Gregor; Besendörfer, Manuel; Schellerer, Vera (International Journal of Surgery Case Reports, 2020)
Introduction: Endoscopy is an established diagnostic and therapeutic tool in paediatric gastroenterology and a save method with rare complications. Presentation of case: We present the case of an 11-year-old Caucasian boy with a long history of inflammatory bowel disease. Three years prior an ileostomy was created and is still in position. After diagnostic panendoscopy (colonoscopy, gastroscopy, endoscopy of small intestine via ileostomy) the patient showed progressive abdominal distension and pain. After diagnosis of tension pneumoperitoneum by radiological proof of massive intraabdominal air and altered vital signs, we initiated emergency laparotomy. Surgical intervention ruled out a free gastrointestinal perforation as well as peritonitis. There was a gaseous insufflation of the mesenteric tissue of the sigmoid and upper rectum most likely according to microperforations to the mesentery. Due to the pre-existing ileostomy, we took no further surgical action. The abdomen was lavaged and drains inserted. Upon further conservative treatment with intravenous antibiotics, the patient showed quick recovery and was discharged on postoperative day 6. Discussion: With an incidence of 0.01%, perforation after diagnostic colonoscopy in children is very uncommon. The zone most frequently affected is the sigmoid colon due to direct penetration or indirect force due to flexure, or insufflation. Even without macroscopic perforation, the development of a tension pneumoperitoneum seems to be possible. Conclusion: Even though Colonoscopy in children is a safe tool, the treating physician must never underestimate the risks of such an intervention. Especially chronically altered intestine as in long-time persisting chronic inflammatory bowel disease demand special care and intensive observation of the patient after intervention.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Child; Colonoscopy; Crohns disease; Pneumoperitoneum

Case Report: Trans-axillary Artery Access for Rescue Stent Implantation in an Infant With Retrograde Non-passable Aortic Coarctation - Moosmann, Julia; Purbojo, Ariawan; Eder, Susanne; Dittrich, Sven (Frontiers in Pediatrics, 2021)
Primary surgical repair remains the traditional treatment for patients with critical duct-dependent coarctation of the aorta (CoA). Initial surgical repair might not be possible or associated with higher risks if additional comorbidities arise in small infants and neonates. Balloon angioplasty (BA) has been described as a rescue strategy for these children. We describe the feasibility of a palliative BA and rescue stent implantation via an alternative antegrade right-axillary artery approach in an initially inoperable infant with pneumonia and respiratory failure and severe CoA, where the stenosis was not passable by traditional retrograde femoral access. This case adds new aspects to the therapy of critical CoA: Stent implantation provides a bridge to surgery in critically ill infants and does not preclude successful surgical repair. Further, if the classic retrograde approach is not possible, the right axillary artery access should be considered as an alternative to pass the stenosis.
CRIS-Team Scopus Importer:2021-05-07
Keywords: axillary artery access; coarctation of aorta; congenital heart defect; stent implantation; vascular access

Cavernous sinus thrombosis as a rare cause of exophthalmos in childhood : A case report - Kamawal, A.; Schmidt, M. A.; Rompel, O.; Gusek-Schneider, G. C.; Mardin, C. Y.; Trollmann, Regina (Ophthalmologe, 2016)
Complications of acute bacterial sinusitis mostly occur in children and adolescents. In particular, intracranial spread of the infection can lead to severe even fatal courses of the disease. This article is a case report about a 13-year-old boy suffering from left-sided headache, meningismus and exophthalmos as presenting symptoms. Cranial magnetic resonance imaging (MRI) showed merely right-sided sphenoid sinusitis; however, the diffusion-weighted MRI sequence indicated a left-sided cavernous sinus thrombosis, which could be confirmed by computed tomography (CT) angiography. Cerebrospinal fluid diagnostics showed significant leukocytosis confirming secondary meningitis. Finally, exophthalmos was explained by parainfectious cavernous sinus thrombosis and periorbital edema. This case report highlights the importance of extended and specific diagnostic imaging in cases of clinically suspected complications in children and adolescents with sinusitis and the diagnostic significance of diffusion-weighted MRI.
EVALuna2:21321

CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series - Auth, Janina; Müller, Fabian; Völkl, Simon; Bayerl, Nadine; Distler, Jörg H.W.; Tur, Carlo; Raimondo, Maria Gabriella; Chenguiti Fakhouri, Sara; Atzinger, Armin; Coppers, Birte; Eckstein, Markus; Liphardt, Anna-Maria; et al. (The Lancet Rheumatology, 2024)
Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis. Methods: Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 106 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months. Findings: Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36–53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342–585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100–100) at 6 months. Median mRSS decreased by 31% (IQR 29–38), corresponding to a median of 8 points (IQR 7–13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3–4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18–275) at the latest observational timepoint. Interpretation: We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis. Funding: Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung.
CRIS-Team Scopus Importer:2024-12-13

Cell-based resurfacing of large cartilage defects: Long-term evaluation of grafts from autologous transgene-activated periosteal cells in a porcine model of osteoarthritis - Gelse, Koja; Muehle, Christiane; Franke, Oliver; Park, Jung; Jehle, Marc; Durst, Karsten; Göken, Mathias; Hennig, Friedrich; Mark, Klaus; Schneider, Holm (Arthritis & Rheumatism-Arthritis Care & Research, 2008)
WW1::753

Cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways by CD101 - Wrage, Marius; Holland, Tim; Nüse, Björn; Kaltwasser, Johanna; Fröhlich, Jessica; Arnold, Harald; Gießler, Claudia; Flamann, Cindy; Bruns, Heiko; Berges, Johannes; Daniel, Christoph; Hoffmann, Markus; et al. (Mucosal Immunology, 2024)
T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101−/− mice, animals with a regulatory T cell-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101−/− x interferon-g−/− mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.
CRIS-Team Scopus Importer:2024-07-19

Centralization as the key survival benefit in acute neonatal surgery - Besendörfer, Manuel; Günster, Simone; Linz, Katja; Reutter, Heiko Martin; Diez, Sonja (Frontiers in Pediatrics, 2024)
Introduction: Centralization of neonatal surgical care for congenital malformations is already under discussion. Acute care of neonatal emergencies in perinatal centers with affiliated hospitals is not uniformly regulated in Germany. Materials and methods: Analyses are based on acute pediatric surgical care at four affiliated hospitals of a perinatal center. Epidemiologic data and outcome parameters “survival”, “intracerebral hemorrhage”, and “revision of surgical indication” are assessed. Comparison is made between patients receiving surgical treatment at affiliated hospitals (group A) and patients with transfer to the university center for therapy in case of surgical indication for gastrointestinal diseases (group B). Results: 17 group A-patients are compared to 40 group B-patients. Comparison of epidemiological data reveals no significant differences. There is a survival advantage with transfer to the university center (mortality of 29% in group A vs. 2% in group B, p = 0.007). Intracerebral hemorrhage occurred more frequently in externally treated patients (group A 24% vs. group B 2%, p = 0.024). Surgical indication was revised in 30% of group B at the university center (p = 0.011) with consecutive successful conservative treatment. Conclusion: Transfer of patients at the beginning of the acute phase of gastrointestinal diseases is key to optimize the quality of neonatal surgical care. However, larger population studies should confirm the presented results, discuss restricting factors of real care structures and should rule out bias in triage of patients.
CRIS-Team Scopus Importer:2024-04-05
Keywords: centralization; German medical system; neonatal emergency; neonatal surgery; perinatal center

Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children? - Plamper, Michaela; Born, Mark; Gohlke, Bettina; Schreiner, Felix; Schulte, Sandra; Splittstößer, Vera; Wölfle, Joachim (Cells, 2020)
BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. METHODS: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. RESULTS: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. CONCLUSION: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood.
CRIS-Team Scopus Importer:2020-07-24
Keywords: children; cMRI; enlarged perivascular spaces; macrocephaly; PHTS; PTEN; Virchow–Robin spaces; white matter abnormalities

Cervical intraepithelial neoplasia grade 3: development during pregnancy and postpartum - Stübs, Frederik; Mergel, Franziska; Koch, Martin; Dietl, Anna; Schulmeyer, Carla; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Gaß, Paul; Mehlhorn, Grit (Archives of Gynecology and Obstetrics, 2022)
Purpose: The aims of the present study were to evaluate the development of untreated cervical intraepithelial neoplasia (CIN) 3 during pregnancy and to assess persistence, progression, and regression rates postpartum to identify factors associated with regression. Methods: In a tertiary gynecology and obstetrics department, a total of 154 pregnant women with CIN 3 were treated in the dysplasia unit. The follow-up findings were analyzed retrospectively on the basis of histological, cytological, and human papillomavirus (HPV) testing of 154 pregnant women confirmed as having CIN 3 in colposcopically guided biopsies. Results: The rates of persistence, regression, and progression of CIN 3 in these women were 76.1%, 20% and 3.2%, respectively. Data for the delivery mode was available for 126 women. The rate of regression was almost twice as high with vaginal delivery as with cesarean section, at 27.4 vs. 15.2%, whereas the rate of progression was lower with vaginal delivery, at 2.7 vs. 6.5%. Conclusion: The rate of persistence of CIN observed in this study is comparable to that reported in other studies. The study provides strong evidence for greater regression among women who have vaginal deliveries. Careful work-up is recommended postpartum for this group of women in order to rule out persistent CIN 3 or invasive disease.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Cervical dysplasia; High-grade squamous intraepithelial lesion (HSIL); Mode of delivery; Pregnancy; Treatment

CFAP74-mutations as cause of Primary Ciliary Dyskinesia (PCD): Clinical presentation and diagnostic challenges - Biebach, L.; Cindric, S.; Koenig, J.; Aprea, I.; Dougherty, G.; Raidt, J.; Bracht, D.; Ruppel, Renate; Schreiber, J.; Hjeij, R.; Olbrich, H.; Omran, H. (EUROPEAN RESPIRATORY JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

Change of the metabolomic profile during short-term mononuclear cell storage - Steininger, Philipp; Strasser, Erwin; Ziehe, Bettina; Eckstein, Reinhold; Rauh, Manfred (Vox Sanguinis, 2017)
BACKGROUND AND OBJECTIVES: Short-term storage of leukapheresis products used for immunotherapeutic mononuclear cell (MNC) products is a frequent event. The analysis of time-related metabolic patterns enables the characterization of storage-related effects in MNCs and the hypothesis-based optimization of the MNC medium. MATERIALS AND METHODS: The MNC products from seven leukapheresis procedures were stored within a closed bag system for 48 h. Concentrations of amino acids, biogenic amines, phospho- and sphingolipids and hexoses in the medium were measured by targeted metabolomics. The viability of MNC subpopulations was assayed by Annexin V (AnV) and JC-1 staining. RESULTS: Glucose depletion and a significant change of the acylcarnitine profile are early events within the first 24 h of storage. In contrast, for most amino acids, the maximum increase was observed at 48 h of storage as mirrored by an increase in the amino acid levels by a mean factor of 1·2 (1·3, 2·0) after 6 h (24 h, 48 h, respectively). This was except for the concentrations of glutamine and lysine, which did not change significantly. The taurine concentration showed a twofold increase within the first 24 h and remained constant thereafter. The steepest increase in AnV+and 7-AAD+CD4+T cells was found between 24 and 48 h. CONCLUSION: The time-course of apoptosis and metabolic patterns in the MNC products demonstrate that 24 h of storage is a decisive time-point, as afterwards key metabolic pathways showed nonlinear detrimental changes. Optimization of storage by supplementation of specific substrates demands therefore an early intervention.
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Changes in behavior and quality of life in German young children during the COVID-19 pandemic—results from the COVID kids bavaria study - Schillok, Hannah; Coenen, Michaela; Rehfuess, Eva A.; Kuhlmann, Pia H.; Matl, Stefan; Kindermann, Hannah; Maison, Nicole; Eckert, Jana; von Both, Ulrich; Behrends, Uta; Frühwald, Michael C.; Neubert, Antje; et al. (Frontiers in Pediatrics, 2023)
Introduction: The COVID-19 pandemic with its containment measures such as closures of schools and daycare facilities led to numerous restrictions in daily life, putting developmental opportunities and health-related quality of life in children at risk. However, studies show that not every family was impacted equally by the pandemic and that this exceptional health and societal situation reinforced pre-existing health inequalities among the vulnerable. Our study aimed at analyzing changes in behavior and health-related quality of life of children attending elementary schools and daycare facilities in Bavaria, Germany in spring 2021. We also sought to identify associated factors contributing to inequalities in quality of life. Methods: Data from a multi-center, open cohort study (“COVID Kids Bavaria”) conducted in 101 childcare facilities and 69 elementary schools across all electoral districts of Bavaria were analyzed. Children attending these educational settings (aged 3-10 years) were eligible for participation in a survey on changes in behavior and health-related quality of life. The KINDLR questionnaire (based on children’s self-report and parental report) was administered about one year after the onset of the pandemic (spring 2021). Descriptive and logistic regression analyses and comparisons to pre-pandemic KiGGS (German Health Interview and Examination Survey for Children and Adolescents) data were undertaken. Results: Among respondents, a high percentage of parents reported changes in their children's eating and sleeping behavior, sports and outdoor activities as well as altered screen time. Health-related quality of life in KINDLR analyses compared to pre-pandemic population averages were lower in all age groups (for 3–6-year-old KINDLR-total score: COVID Kids Bavaria MD 74.78 ± 10.57 vs KiGGS data 80.0 ± 8.1; 7-10 years-old KINDLR-total score: COVID Kids Bavaria MD 73.88 ± 12.03 vs KiGGS data 79.30 ± 9.0). No significant differences were detected with regard to associated factors, namely type of institution, sex of the child, migration background, household size and parental education. Conclusion: These findings suggest a relevant impact of the COVID-19 pandemic on children’s behavior and health-related quality of life one year after the onset of the pandemic. Further analyses in large-scale longitudinal studies are needed to determine the effects of specific pandemic or crisis associated factors contributing to health inequalities.
CRIS-Team Scopus Importer:2023-06-02
Keywords: behavior change; COVID-19; health inequalities in children; health-related quality of life (HRQL); mental health—related quality of life; pandemic

Characterisation of passive mechanical properties in healthy and infarcted rat myocardium - Martonová, Denisa; Alkassar, Muhannad; Seufert, Julia; Holz, David; Duong, Minh Tuan; Reischl, Barbara; Friedrich, Oliver; Leyendecker, Sigrid (conference, GAMM Annual Meeting, 2021)

Characterization and diagnostic application of genomic NPM-ALK fusion sequences in anaplastic large-cell lymphoma - Krumbholz, Manuela; Woessmann, Wilhelm; Zierk, Jakob; Seniuk, David; Ceppi, Paolo; Zimmermann, Martin; Singh, Vijay Kumar; Metzler, Markus; Damm-Welk, Christine (Oncotarget, 2018)
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.
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Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool - Dahlmanns, Marc; Yakubov, Eduard; Chen, Daishi; Sehm, Tina; Rauh, Manfred; Savaskan, Nicolai; Wrosch, Jana Katharina (Cell Death Discovery, 2017)
In the search for new potential chemotherapeutics, the compounds' toxicity to healthy cells is an important factor. The brain with its functional units, the neurons, is especially endangered during the radio- and chemotherapeutic treatment of brain tumors. The effect of the potential compounds not only on neuronal survival but also neuronal function needs to be taken into account. Therefore, in this study we aimed to comprehend the biological effects of chemotherapeutic xCT inhibition on healthy neuronal cells with our synaptic optogenetic function analysis tool (SOFA). We combined common approaches, such as investigation of morphological markers, neuronal function and cell metabolism. The glutamate-cystine exchanger xCT (SLC7A11, system Xc-) is the main glutamate exporter in malignant brain tumors and as such a relevant drug target for treating deadly glioblastomas (WHO grades III and IV). Recently, two small molecules termed sorafenib (Nexavar) and erastin have been found to efficiently block xCT function. We investigated neuronal morphology, metabolic secretome profiles, synaptic function and cell metabolism of primary hippocampal cultures (containing neurons and glial cells) treated with sorafenib and erastin in clinically relevant concentrations. We found that sorafenib severely damaged neurons already after 24 h of treatment. Noteworthy, also at a lower concentration, where no morphological damage or metabolic disturbance was monitored, sorafenib still interfered with synaptic and metabolic homeostasis. In contrast, erastin-treated neurons displayed mostly inconspicuous morphology and metabolic rates. Key parameters of proper neuronal function, such as synaptic vesicle pool sizes, were however disrupted following erastin application. In conclusion, our data revealed that while sorafenib and erastin effectively inhibited xCT function they also interfered with essential neuronal (synaptic) function. These findings highlight the particular importance of investigating the effects of potential neurooncological and general cancer chemotherapeutics also on healthy neuronal cells and their function as revealed by the SOFA tool.
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Cherry-red spot in a 13-month-old child - Hohberger, B.; Stenger, Nico; Trollmann, Regina; Mardin, C. Y.; Gusek-Schneider, G-C. (Ophthalmologe, 2016)
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Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology - Ripperger, Tim; Bielack, Stefan S.; Borkhardt, Arndt; Brecht, Ines B.; Burkhardt, Birgit; Calaminus, Gabriele; Debatin, Klaus-Michael; Deubzer, Hedwig; Dirksen, Uta; Eckert, Cornelia; Eggert, Angelika; Erlacher, Miriam; et al. (American Journal of Medical Genetics Part A, 2017)
Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.
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Choice of basal insulin therapy is associated with weight and height development in type 1 diabetes: A multicenter analysis from the German/Austrian DPV registry in 10 338 children and adolescents - Vollbach, Heike; Auzanneau, Marie; Reinehr, Thomas; Wiegand, Susanna; Schwab, Karl-Otfried; Oeverink, Rudolf; Froehlich-Reiterer, Elke; Wölfle, Joachim; De Beaufort, Carine; Kapellen, Thomas; Gohlke, Bettina; Holl, Reinhard W. (Journal of Diabetes, 2021)
Background Available basal insulin regimes differ in pharmacokinetic profiles, which may be related to subsequent changes in anthropometry in patients with type 1 diabetes. This analysis elucidates the standardized height and body mass index development (height and BMI standard deviation score [height-SDS and BMI-SDS]) in pediatric type 1 diabetes patients depending on the choice of basal insulin. Methods Longitudinal data of 10 338 German/Austrian patients from the Diabetes Prospective Follow-up (DPV, Diabetes Patienten Verlaufsdokumentation) database were analyzed. Patients aged 5.0 to 16.9 years were treated exclusively with neutral protamine Hagedorn (NPH), insulin detemir (IDet), insulin glargine (IGla), or continuous subcutaneous insulin infusion (CSII) for at least 3 years. Population-based German reference data were used to calculate height-SDS and BMI-SDS. Multiple linear regression was conducted. Results BMI-SDS increased significantly in all regimes (NPH P = .0365; IDet P = .0003; IGla P < .0001; and CSII P < .0001). Direct comparison of the therapies revealed a favorable association only for NPH vs IGla. A rise in BMI-SDS was observed for all insulins in females, but only for IGla in males. BMI-SDS increment was not observed before 8 years of age. Initially and at the end of the observation period, mean height was above the 50th percentile of the reference population. Across the cohort, height-SDS declined during the observation period, except for CSII. Apart from the 5.0- to 7.9-year-old subgroup, long-acting insulin analogues were associated with a significant loss of height-SDS. Conclusions Choice of basal insulin regimen might influence height development. CSII appeared to have a favorable effect on growth trajectories. All therapies were associated with an increase of BMI-SDS, most evident in females.
CRIS-Team WoS Importer:2021-07-23

Chronic antipsychotic treatment targets GIRK current suppression, loss of long-term synaptic depression and behavioural sensitization in a mouse model of amphetamine psychosis - Groos, Dominik; Zheng, Fang; Rauh, Manfred; Quinger, Benedikt; Kornhuber, Johannes; Müller, Christian P.; Alzheimer, Christian (Journal of Psychopharmacology, 2018)
BACKGROUND:: Antipsychotic drugs (APDs) are the mainstay of the pharmacological treatment of psychotic disorders like schizophrenia. While the clinical efficacy of APDs has long since been established, the neurobiological mechanisms underlying their therapeutic benefits are still not well understood. METHODS:: Here, we used an escalating amphetamine regimen to induce a psychosis-like state in mice. To achieve clinically relevant drug concentrations in amphetamine-pretreated mice, the typical APD haloperidol or the atypical APD olanzapine were chronically administered via subcutaneously implanted osmotic mini-pumps. RESULTS:: Demonstrating their therapeutic efficacy, both drugs dampened amphetamine-induced hyperlocomotion and restored normal behaviour in the light-induced activity test. Whole-cell recordings from dopaminergic neurons of the ventral tegmental area (VTA) in ex vivo brain slices revealed two pronounced aberrations associated with the psychosis-like state: Strongly enhanced spontaneous firing and a substantial loss of G protein-gated inwardly rectifying potassium (GIRK) current upon activation of GABAB receptors with baclofen. Chronic haloperidol and olanzapine restored normal firing and partially rescued the GIRK current response to baclofen. In ex vivo slices containing the nucleus accumbens, which receives a dopaminergic projection from the VTA, abrogation of long-term synaptic depression (LTD) and enhanced excitatory drive onto medium spiny neurons were identified as synaptic consequences of amphetamine-induced psychosis. Again, both alterations proved amenable to chronic APD treatment. CONCLUSION:: Our data provide evidence for aberrant neuronal function and plasticity in the mesolimbic dopamine system during an induced psychotic state and identify these alterations as targets of chronic APD treatment.
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Chronic recurrent multifocal osteomyelitis in association with pyoderma gangraenosum - Wurm, Matthias; Brecht, Ines; Lell, Michael; Brunner, Kathrin; Mitsimponas, Konstantinos Theodorou; Chada, Martin; Jahn, Julia; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (BMC Oral Health, 2016)
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare acquired inflammatory skeletal disorder of unknown origin. CRMO was first described by Gideon in 1972 and mainly affects children and young adults of female gender. The CRMO is part of the clinical picture of non-bacterial Osteomyelitis (NBO) and typically presents a relapsing recurring course with both remission and spontaneous exacerbation. CRMO is typically encountered in the limbs and the metaphysis of long bones in particular. Usually the clinical symptoms include painful swellings of the affected regions. This case report describes the rare case of a CRMO of the mandible in association with pyoderma gangraenosum.A 14-year old female caucasian patient, residing in the south of Germany, presented in the oncological outpatient clinic of our Department of Paediatrics and Adolescent Medicine in June 2014 complaining of increasing neck pain and progressive swelling at her left cheek ongoing for about 6 weeks. These symptoms had been occurring quarterly for 4 years, but had never been as pronounced. Blood biochemistry showed a moderately elevated CRP (35 mg/l) and a significantly increased blood sedimentation rate (BSR 48/120 mm). The panoramic radiograph, however, revealed a bone alteration in the left mandibular region. Further investigations confirmed the diagnosis of CRMO.The present case underlines the fact that rare diseases might occasionally present with even more rare symptoms. These occasions can obviously be considered to present a considerable diagnostic challenge.
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Cinematic Rendering in Mixed-Reality Holograms: A New 3D Preoperative Planning Tool in Pediatric Heart Surgery - Gehrsitz, Pia; Rompel, Oliver; Schoeber, Martin; Cesnjevar, Robert; Purbojo, Ariawan; Uder, Michael; Dittrich, Sven; Alkassar, Muhannad (Frontiers in Cardiovascular Medicine, 2021)
Cinematic rendering (CR) is based on a new algorithm that creates a photo-realistic three-dimensional (3D) picture from cross-sectional images. Previous studies have shown its positive impact on preoperative planning. To date, CR presentation has only been possible on 2D screens which limited natural 3D perception. To depict CR-hearts spatially, we used mixed-reality technology and mapped corresponding hearts as holograms in 3D space. Our aim was to assess the benefits of CR-holograms in the preoperative planning of cardiac surgery. Including 3D prints allowed a direct comparison of two spatially resolved display methods. Twenty-six patients were recruited between February and September 2019. CT or MRI was used to visualize the patient's heart preoperatively. The surgeon was shown the anatomy in cross-sections on a 2D screen, followed by spatial representations as a 3D print and as a high-resolution hologram. The holographic representation was carried out using mixed-reality glasses (HoloLens (R)). To create the 3D prints, corresponding structures were segmented to create STL files which were printed out of resin. In 22 questions, divided in 5 categories (3D-imaging effect, representation of pathology, structure resolution, cost/benefit ratio, influence on surgery), the surgeons compared each spatial representation with the 2D method, using a five-level Likert scale. The surgical preparation time was assessed by comparing retrospectively matched patient pairs, using a paired t-test. CR-holograms surpassed 2D-monitor imaging in all categories. CR-holograms were superior to 3D prints in all categories (mean Likert scale 4.4 +/- 1.0 vs. 3.7 +/- 1.3, P < 0.05). Compared to 3D prints it especially improved the depth perception (4.7 +/- 0.7 vs. 3.7 +/- 1.2) and the representation of the pathology (4.4 +/- 0.9 vs. 3.6 +/- 1.2). 3D imaging reduced the intraoperative preparation time (n = 24, 59 +/- 23 min vs. 73 +/- 43 min, P < 0.05). In conclusion, the combination of an extremely photo-realistic presentation via cinematic rendering and the spatial presentation in 3D space via mixed-reality technology allows a previously unattained level of comprehension of anatomy and pathology in preoperative planning.
CRIS-Team WoS Importer:2021-03-12

Citrullination licenses calpain to decondense nuclei in neutrophil extracellular trap formation - Goesswein, Stefanie; Lindemann, Aylin; Mahajan, Aparna; Maueröder, Christian; Martini, Eva; Patankar, Jay; Schett, Georg; Becker, Christoph; Wirtz, Stefan; Naumann-Bartsch, Nora; Bianchi, Marco E.; Greer, Peter A.; et al. (Frontiers in Immunology, 2019)
Neutrophils respond to various stimuli by decondensing and releasing nuclear chromatin characterized by citrullinated histones as neutrophil extracellular traps (NETs). This achieves pathogen immobilization or initiation of thrombosis, yet the molecular mechanisms of NET formation remain elusive. Peptidyl arginine deiminase-4 (PAD4) achieves protein citrullination and has been intricately linked to NET formation. Here we show that citrullination represents a major regulator of proteolysis in the course of NET formation. Elevated cytosolic calcium levels trigger both peptidylarginine deiminase-4 (PAD4) and calpain activity in neutrophils resulting in nuclear decondensation typical of NETs. Interestingly, PAD4 relies on proteolysis by calpain to achieve efficient nuclear lamina breakdown and chromatin decondensation. Pharmacological or genetic inhibition of PAD4 and calpain strongly inhibit chromatin decondensation of human and murine neutrophils in response to calcium ionophores as well as the proteolysis of nuclear proteins like lamin B1 and high mobility group box protein 1 (HMGB1). Taken together, the concerted action of PAD4 and calpain induces nuclear decondensation in the course of calcium-mediated NET formation.
CRIS-Team Scopus Importer:2019-11-15
Keywords: Calpain; Cell death; Chromatin; Citrullination; Neutrophil; Nucleus; PAD4

Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase-Deficiency: 13 Years of Neonatal Screening and Follow-up in Bavaria - Odenwald, B.; Dörr, Helmuth-Günther; Bonfig, W.; Schmidt, H.; Fingerhut, R.; Wildner, M.; Nennstiel-Ratzel, U. (Klinische Pädiatrie, 2015)
21-Hydroxylase deficient (21-OHD) classic congenital adrenal hyperplasia (CAH) is a potentially lethal inherited endocrine disorder. It is included in many neonatal screening programs to prevent morbidity and mortality from salt-wasting and to reduce long-term health problems. This paper presents a population-based evaluation of CAH screening quality and outcome in Bavaria between 1999 and 2011 including long-term follow-up of patients.Screening process quality, clinical complications during the neonatal period, treatment and development of patients up to the age of 4 years were analysed.Among 1 420 102 screened infants, 114 cases of 21-OHD classic CAH were detected (prevalence 1:12 457). Mean age at start of treatment was 7 days. However, in 29 cases (25.4%), age at start of treatment was 12 days or more. The frequency of neonatal salt-wasting increased with age at start of treatment, but all neonatal salt-wasting episodes and crises were managed successfully. Up to the age of 4 years, developmental assessment of the CAH cohort yielded normal results.Epidemiological and screening effectiveness results are in keeping with other publications. For the most part, screening process times were compliant with guidelines. The Bavarian CAH screening and tracking system proved successful, but there were process delays and complications which might have been avoidable. The outcome supports the benefits of CAH screening, but further research is necessary to increase CAH screening effectiveness and to evaluate long-term effects.
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Clean Intermittent Catheterization in Children under 12 Years Does Not Have a Negative Impact on Long-Term Graft Survival following Pediatric Kidney Transplantation - Marcou, Marios; Galiano, Matthias; Tzschoppe, Anja; Sauerstein, Katja; Wach, Sven; Taubert, Helge; Wullich, Bernd; Hirsch-Koch, Karin; Apel, Hendrik (Journal of Clinical Medicine, 2024)
Background: Congenital anomalies of the kidneys and urinary tract (CAKUTs) are one of the most prevalent primary causes of end-stage renal disease (ESRD) in young children, and approximately one-third of these children present with lower urinary tract dysfunction (LUTD). Many children with LUTD require therapy with clean intermittent catheterization (CIC). CIC commonly leads to bacteriuria, and considerations have arisen regarding whether CIC in immunosuppressed children is safe or whether repeated febrile urinary tract infections (UTIs) may lead to the deterioration of kidney graft function. Material and Methods: We retrospectively reviewed all cases of primary kidney transplantation performed in our center between 2001 and 2020 in recipients aged less than twelve years. The number of episodes of febrile UTIs as well as the long-term kidney graft survival of children undergoing CIC were compared to those of children with urological causes of ESRD not undergoing CIC, as well as to those of children with nonurological causes of ESRD. Results: Following successful kidney transplantation in 41 children, CIC was needed in 8 of these patients. These 8 children undergoing CIC had significantly more episodes of febrile UTIs than did the 18 children with a nonurological cause of ESRD (p = 0.04) but not the 15 children with a urological cause of ESRD who did not need to undergo CIC (p = 0.19). Despite being associated with a higher rate of febrile UTIs, CIC was not identified as a risk factor for long-term kidney graft survival, and long-term graft survival did not significantly differ between the three groups at a median follow-up of 124 months. Conclusions: Our study demonstrates that, under regular medical care, CIC following pediatric transplantation is safe and is not associated with a higher rate of long-term graft loss.
CRIS-Team Scopus Importer:2024-01-19
Keywords: CAKUT; catheterization; child; kidney transplantation; LUTD

Climbing Medicine: A Practical Guide - Schöffl, Volker; Schöffl, Isabelle; Lutter, Christoph; Hochholzer, Thomas (Springer International Publishing, 2022)
This book comprehensively discusses the medical aspects of sports climbing, a still young but emerging sport, which will be one of the disciplines at the Tokyo Olympics. Its rapid development from niche to popular sport has been accompanied by an increase in the number of climbing-sports-specific injuries and has attracted growing interest within the sports medicine community. Gathering expertise from around the globe, the book covers all aspects related to this discipline – from physiology, biomechanics and anatomy through upper and lower extremity injuries to cardiology, gynecology, pediatric and adolescent conditions. Following a coherent structure, each chapter equips readers with evidence-based diagnostic and therapeutic guidelines. Enriched by a wealth of pictures, this manual offers a timely and up-to-date resource for sports physicians, orthopedic surgeons and traumatologists, as well as trainers, physiotherapists and other health professionals involved in climbing.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Hand injuries; Mountain sports; Physiology of climbing; Rock climbing; Sports climbing

Clinical Characteristics and Courses of Patients With Autosomal Recessive Polycystic Kidney Disease-Mimicking Phenocopies - Halawi, Abdul A.; Burgmaier, Kathrin; Buescher, Anja K.; Dursun, Ismail; Erger, Florian; Galiano, Matthias; Gessner, Michaela; Gökce, Ibrahim; Mekahli, Djalila; Mir, Sevgi; Obrycki, Lukasz; Shroff, Rukshana; et al. (Kidney International Reports, 2023)
CRIS-Team Scopus Importer:2023-05-26
Keywords: ciliopathies; PKD1; PKD2; PKHD1; polycystic kidney disease; TMEM67

Clinical characteristics and outcome of 60 pediatric patients with malignant melanoma registered with the German Pediatric Rare Tumor Registry (STEP) - Offenmüller, Sonja; Leiter, Ulrike; Bernbeck, Benedikt; Garbe, Claus; Eigentler, Thomas; Borkhardt, Arndt; Classen, Carl Friedrich; Corbacioglu, Selim; Dirksen, Uta; Ebetsberger-Dachs, Georg; Heinzerling, Lucie; Jorch, Norbert; et al. (Klinische Pädiatrie, 2017)
Background Malignant melanoma (MM) is a common malignancy in adults while it is rare in children. Thus, information on clinical behavior of pediatric MM is incomplete. Patients The German Pediatric Rare Tumor Registry (STEP) presents a prospective analysis of 60 childhood MM cases diagnosed between June 2006 and December 2014. Method Patients' ages ranged between 0 and 17 years at initial diagnosis (median age 9.6 years). Information on patient's and tumor characteristics was obtained by standardized documentation. Three-year overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier test. Results Follow-up ranged from 0 to 116 months with a median of 36.5 months, however, univariate analysis was performed for 46 cases with a follow-up > 3 months, only. Cases with spitzoid histotype (40%) did not show a significantly different outcome compared to cases with non-spitzoid MM. Breslow thickness ≤ 2.00 mm was identified in 30% of the cases and 18% were Clark level I to III. Adjuvant therapy was used in 45% of cases. OS at 3 years was 100%, EFS 95.2%. Conclusion We present a series of cases with a high number of spitzoid malignant melanoma and advanced pediatric melanoma, but surprisingly good overall survival rates. Spitzoid and non-spitzoid MM do not differ in clinical behavior and survival.
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Clinical characteristics and outcome of biopsy-proven myocarditis in children – Results of the German prospective multicentre registry “MYKKE” - Seidel, Franziska; Opgen-Rhein, Bernd; Rentzsch, Axel; Boehne, Martin; Wannenmacher, Bardo; Boecker, Dorotheé; Reineker, Katja; Grafmann, Maria; Wiegand, Gesa; Hecht, Tobias; Kiski, Daniela; Fischer, Marcus; et al. (International Journal of Cardiology, 2022)
Background: Heart failure (HF) due to myocarditis might not respond in the same way to standard therapy as HF due to other aetiologies. The aim of this study was to investigate the value of endomyocardial biopsies (EMB) for clinical decision-making and its relation to the outcome of paediatric patients with myocarditis. Methods: Clinical and EMB data of children with myocarditis collected for the MYKKE-registry between 2013 and 2020 from 23 centres were analysed. EMB studies included histology, immunohistology, and molecular pathology. The occurrence of major adverse cardiac events (MACE) including mechanical circulatory support (MCS), heart transplantation, and/or death was defined as a combined endpoint. Results: Myocarditis was diagnosed in 209/260 patients: 64% healing/chronic lymphocytic myocarditis, 23% acute lymphocytic myocarditis (AM), 14% healed myocarditis, no giant cell myocarditis. The median age was 12.8 (1.4–15.9) years. Time from symptom-onset to EMB was 11.0 (4.0–29.0) days. Children with AM and high amounts of mononuclear cell infiltrates were significantly younger with signs of HF compared to those with healing/chronic or healed myocarditis. Myocardial viral DNA/RNA detection had no significant effect on outcome. The worst event-free survival was seen in patients with healing/chronic myocarditis (24%), followed by acute (31%) and healed myocarditis (58%, p = 0.294). A weaning rate of 64% from MCS was found in AM. Conclusions: EMB provides important information on the type and stage of myocardial inflammation and supports further decision-making. Children with fulminant clinical presentation, high amounts of mononuclear cell infiltrates or healing/chronic inflammation and young age have the highest risk for MACE.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Endomyocardial biopsy; Myocarditis; Outcome; Paediatric; Registry

Clinical Characteristics and Outcome of Children With Wagr Syndrome and Wilms Tumor Identified through SIOP-RTSG Registries - Hol, J. A.; Jongmans, M. C. J.; Sudour-Bonnange, H.; Ramirez-Villar, G. L.; Chowdhury, T.; Rechnitzer, C.; Pal, N.; Schleiermacher, G.; Karow, A.; Kuiper, R. P.; De Camargo, B.; Avcin, S.; et al. (PEDIATRIC BLOOD & CANCER, 2020)
CRIS-Team WoS Importer:2020-12-04