Ultra-high-frequency ultrasound in patients with spinal muscular atrophy: A retrospective feasibility study - Regensburger, Adrian; Wagner, Anna; Hanslik, Gregor; Schuessler, Stephanie C.; Fahlbusch, Fabian; Wölfle, Joachim; Juengert, Joerg; Trollmann, Regina; Knieling, Ferdinand (Muscle & Nerve, 2020)
CRIS-Team WoS Importer:2020-01-17

Ultra-long-term human salt balance studies reveal interrelations between sodium, potassium, and chloride intake and excretion - Birukov, Anna; Rakova, Natalia; Lerchl, Kathrin; Engberink, Rik H. G. Olde; Johannes, Bernd; Wabel, Peter; Moissl, Ulrich; Rauh, Manfred; Luft, Friedrich C.; Titze, Jens (American Journal of Clinical Nutrition, 2016)
BACKGROUND: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride. OBJECTIVE: We were able to test the value of 24-h urine collections in a unique, ultra-long-term balance study conducted during a simulated trip to Mars. DESIGN: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intake was maintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily. RESULTS: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland-Altman analyses on the value of urine collections to estimate intake. CONCLUSIONS: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals.
EVALuna2:33935

Ultrasound of the chest and mediastinum in children, interventions and artefacts. WFUMB review paper (part 3) - Fang, Cheng; Jaworska, Joanna; Buda, Natalia; Ciuca, Ioana Mihaiela; Dong, Yi; Feldkamp, Axel; Jüngert, Jörg M.; Kosiak, Wojciech; Mentzel, Hans Joachim; Pienar, Corina; Rabat, Jorge S.; Rafailidis, Vasileios; et al. (Medical Ultrasonography, 2022)
Ultrasound (US) is an ideal diagnostic tool for paediatric patients owning to its high spatial and temporal resolution, realtime imaging, and lack of ionizing radiation and bedside availability. The lack of superficial adipose tissue and favourable acoustic windows in children makes US the first line of investigation for evaluation of pleural and chest wall abnormalities.In the first part of the topic the technical requirements were explained and the use of ultrasound in the lung and pleura in paediatric patients were discussed. In the second part lung parenchymal diseases with their subpleural consolidations are reflected. In the third part, the use of ultrasound for chest wall, mediastinum, diaphragmatic diseases, trachea, interventions and artifacts in paediatric patients are summarized.
CRIS-Team Scopus Importer:2022-02-25

Ultrasound of the pleura in children, WFUMB review paper - Jaworska, Joanna; Buda, Natalia; Ciuca, Ioana Mihaiela; Dong, Yi; Fang, Cheng; Feldkamp, Axel; Jüngert, Jörg M.; Kosiak, Wojciech; Mentzel, Hans Joachim; Pienar, Corina; Rabat, Jorge S.; Rafailidis, Vasileios; et al. (Medical Ultrasonography, 2021)
Ultrasound (US) is an ideal diagnostic tool for paediatric patients owning to its high spatial and temporal resolution ; real-time imaging, and lack of ionizing radiation and bedside availability. The lack of superficial adipose tissue and favorable acoustic windows in children makes US the first line of investigation for the evaluation of pleural and chest wall abnormalities. Lung parenchyma was previously thought to be inaccessible to ultrasound due to the presence of the air and bony thorax. The change in attitude and growing awareness of the diagnostic possibilities has led to lung ultrasound (LUS) being accepted as a valuable point of care method. In addition, the application of LUS has widened with improvements in technology such as higher resolution transducers, harmonic imaging and contrast-enhanced ultrasound.
CRIS-Team WoS Importer:2021-08-27

Umbilical cord blood stem cells: Induction of differentiation into mesenchymal lineages by cell-cell contacts with various mesenchymal cells - Park, Jung; Setter, Viviane; Wixler, Viktor; Schneider, Holm (Tissue Engineering - Part A, 2009)
CD133(+) cells isolated from bone marrow, peripheral blood, or umbilical cord blood (UCB) represent an established source of transplantable hematopoietic progenitors. Further, there is increasing evidence that such CD133(+) cell isolates comprise subpopulations capable of differentiating into several mesenchymal lineages. In this study, we investigated conditions under which mesenchymal differentiation can be induced, particularly the role of cell-cell contacts with mesenchymal cells. A purified, nearly homogeneous CD133(+) population of human UCB cells was expanded by stimulation with platelet-derived growth factor and epidermal growth factor, labeled with the fluorescent marker DiI and cocultivated with rat osteoblasts, C2C12 myoblasts, or rat cardiomyocytes, respectively. In control experiments, the two cell types were separated by microporous membranes to avoid cell-cell contacts. Direct coculture of DiI-labeled UCB cells with the different mesenchymal cell populations resulted in both significant morphological changes and upregulation of lineage-specific markers. Expression of osteocalcin, myosin heavy chain, or α-actinin confirmed differentiation of the UCB cells into an osteoblastic, myoblastic, or cardiomyocytic phenotype, respectively. In contrast, coculture of UCB cells with the respective inducer cells under conditions preventing cell-cell contacts yielded minor, if any, evidence for such differentiation. Our data, thus, indicate that UCB cell expansion in vitro and subsequent direct cell-cell contacts with mesenchymal cells can induce their differentiation into mesenchymal lineages specific to the cell type they are in contact with. This finding has important implications for understanding the homing of adult stem cells and the promise of UCB as a cell source for tissue engineering and regenerative medicine. © 2009, Mary Ann Liebert, Inc.
CRIS-Team Scopus Importer:2020-07-01

Umbilical venous catheter- and peripherally inserted central catheter-associated complications in preterm infants with birth weight < 1250 g: Results from a survey in Austria and Germany Nabelvenenkatheter- und periphere zentrale katheterassoziierte Komplikationen bei Frühgeborenen mit einem Geburtsgewicht < 1250 g: Ergebnisse einer Umfrage in Österreich und Deutschland - Hess, Steffi; Poryo, Martin; Boettger, Ralf; Franz, Axel; Klotz, Daniel; Linnemann, Knud; Ott, Torsten; Poeschl, Johannes; Schroth, Michael; Stein, Anja; Ralser, Elisabeth; Reutter, Heiko Martin; et al. (Wiener Medizinische Wochenschrift, 2022)
Background and objective: Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight < 1250 g and associated rates of catheter-related adverse events. Methods: Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous). Results: In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1–10 days were bacterial infection: 4.2 ± 3.4% (range 0–10%); thrombosis: 7.3 ± 7.1% (0–20%); emboli: 0.9 ± 2.0% (0–5%); organ injury: 1.1 ± 1.9% (0–5%); cardiac arrhythmia: 2.2 ± 2.5% (0–5%); and dislocation: 5.4 ± 8.7% (0–30%); and for PICCs with a dwell time of 1–14 days bacterial infection: 15.0 ± 3.4% (range 2.5–30%); thrombosis; 4.3 ± 3.5% (0–10%); emboli: 0.8 ± 1.6% (0–5%); organ injury: 1.5 ± 2.3% (0–5%); cardiac arrhythmia: 1.5 ± 2.3% (0–5%), and dislocation: 8.5 ± 4.6% (0–30%). Conclusion: The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.
CRIS-Team Scopus Importer:2022-08-19
Keywords: Emboli; Infection; Organ injury; Peripherally inserted central catheter; Survey; Thrombosis; Umbilical venous catheter; Very low birth weight infants

Unbound corneocyte lipid envelopes in 12R-lipoxygenase deficiency support a direct role in lipid-protein crosslinking - Meyer, J. M.; Crumrine, D.; Schneider, Holm; Dick, Angela; Schmuth, M.; Gruber, R.; Radner, F.; Grond, S.; Wakefield, J.; Mauro, T.; Elias, P. (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

Unbound Corneocyte Lipid Envelopes in 12R-Lipoxygenase Deficiency Support a Specific Role in Lipid-Protein Cross-Linking - Meyer, Jason M.; Crumrine, Debra; Schneider, Holm; Dick, Angela; Schmuth, Matthias; Gruber, Robert; Radner, Franz P.W.; Grond, Susanne; Wakefield, Joan S.; Mauro, Theodora M.; Elias, Peter M. (American Journal of Pathology, 2021)
Loss-of-function mutations in arachidonate lipoxygenase 12B (ALOX12B) are an important cause of autosomal recessive congenital ichthyosis (ARCI). 12R-lipoxygenase (12R-LOX), the protein product of ALOX12B, has been proposed to covalently bind the corneocyte lipid envelope (CLE) to the proteinaceous corneocyte envelope, thereby providing a scaffold for the assembly of barrier-providing, mature lipid lamellae. To test this hypothesis, an in-depth ultrastructural examination of CLEs was performed in ALOX12B−/− human and Alox12b−/− mouse epidermis, extracting samples with pyridine to distinguish covalently attached CLEs from unbound (ie, noncovalently bound) CLEs. ALOX12B−−/− stratum corneum contained abundant pyridine-extractable (ie, unbound) CLEs, compared with normal stratum corneum. These unbound CLEs were associated with defective post-secretory lipid processing, and were specific to 12R-LOX deficiency, because they were not observed with deficiency of the related ARCI-associated proteins, patatin-like phospholipase 1 (Pnpla1) or abhydrolase domain containing 5 (Abhd5). These results suggest that 12R-LOX contributes specifically to CLE–corneocyte envelope cross-linking, which appears to be a prerequisite for post-secretory lipid processing, and provide insights into the pathogenesis of 12R-LOX deficiency in this subtype of ARCI, as well as other conditions that display a defective CLE.
CRIS-Team Scopus Importer:2021-05-07

Under-expression of ?8 integrin aggravates experimental atherosclerosis - Menendez-Castro, Carlos; Cordasic, Nada; Neureiter, Daniel; Amann, Kerstin Ute; Marek, Ines; Volkert, Gudrun; Stintzing, Sebastian; Jahn, Angelika; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea (Journal of Pathology, 2015)
Integrins play an important role in vascular biology. The ?8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of ?8 integrin to atherosclerosis and vascular remodelling. We hypothesized that ?8 integrin expression is reduced in atherosclerotic lesions, and that its under-expression leads to a more severe course of atherosclerosis. ?8 Integrin was detected by immunohistochemistry and qPCR and ?8 integrin-deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross-sections. Second, after crossing into ApoE-deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: ?8 integrin was detected in the media of human and murine vascular tissue and was down-regulated in arteries with advanced atherosclerotic lesions. In ?8 integrin-deficient mice (?8(-/-) ) as well as ?8(+/-) and ?8(+/+) littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated ?8(-/-) and ?8(+/-) compared to ligated ?8(+/+) animals. Carotid artery ligation increased smooth muscle cell number in the media of ?8(+/+) mice and, more prominently, of ?8(-/-) or ?8(+/-) mice. On an ApoE(-/-) background, ?8(+/-) and ?8(-/-) mice developed more atherosclerotic plaques than ?8(+/+) mice. ?8 Integrin expression was reduced in ?8(+/-) animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in ?8(-/-) mice only. Thus, under-expression of ?8 integrin aggravates vascular lesions, while a complete loss of ?8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin ?8?1 has a protective role in arterial remodelling and atherosclerosis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
EVALuna2:3752

Unexpected phenotypic variability in a family with epilepsy explained by independent segregation of biparental CACNA1A loss-of-function variants - Kraus, Cornelia; Mammadova, Dilbar; Leis, T.; Ekici, Arif Bülent; Thiel, C.; Reis, André; Trollmann, Regina (EUROPEAN JOURNAL OF HUMAN GENETICS, 2020)
CRIS-Team WoS Importer:2021-01-22

Unilateral swelling of the lacrimal gland in a 15-year-old female patient - Berta, A. I.; Naumann-Bartsch, N.; Agaimy, Abbas; Metzler, Markus; Kruse, Friedrich; Holbach, L. (Ophthalmologe, 2013)
EVALuna2:6506

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge - Brosens, Erwin; Peters, Nina C.J.; van Weelden, Kim S.; Bendixen, Charlotte; Brouwer, Rutger W.W.; Sleutels, Frank; Bruggenwirth, Hennie T.; van Ijcken, Wilfred F.J.; Veenma, Danielle C.M.; Otter, Suzan C.M.Cochius Den; Wijnen, Rene M.H.; Eggink, Alex J.; et al. (Frontiers in Pediatrics, 2022)
Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck—largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic—and likely mechanistic—variability hampers individual patient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.
CRIS-Team Scopus Importer:2022-02-25
Keywords: congenital; counseling; development; diaphragm; discordant monozygotic twin; foregut; genetics; hernia

Use of Continuous Glucose Monitoring in Pump Therapy Sensor Augmented Pump or Automated Insulin Delivery in Different Age Groups (0.5 to <26 Years) With Type 1 Diabetes From 2018 to 2021: Analysis of the German/Austrian/Swiss/Luxemburg DPV Registry - van den Boom, Louisa; Auzanneau, Marie; Wölfle, Joachim; Sindichakis, Marina; Herbst, Antje; Meraner, Dagmar; Hake, Kathrin; Klinkert, Christof; Gohlke, Bettina; Holl, Reinhard W. (Journal of diabetes science and technology, 2023)
Aim: Insulin pump, continuous glucose monitoring (CGM), and sensor augmented pump (SAP) technology have evolved continuously leading to the development of automated insulin delivery (AID) systems. Evaluation of the use of diabetes technologies in people with T1D from January 2018 to December 2021. Methods: A patient registry (Diabetes Prospective Follow-up Database [DPV]) was analyzed for use of SAP (insulin pump + CGM ≥90 days, no automated dose adjustment) and AID (HCL or LGS/PLGS). In total 46,043 people with T1D aged 0.5 to <26 years treated in 416 diabetes centers (Germany, Austria, Luxemburg, and Switzerland) were included and stratified into 4 groups A-D according to age. Additionally, TiR and HbA1c were analyzed. Results: From 2018 to 2021, there was a significant increase from 28.7% to 32.9% (sensor augmented pump [SAP]) and 3.5% to 16.6% (AID) across all age groups, with the most frequent use in group A (<7 years, 38.8%-40.2% and 10.3%-28.5%). A similar increase in SAP and AID use was observed in groups B (7 to <11 years) and C (11 to <16 years): B: +15.8 PP, C: +15.9 PP. HbA1c improved significantly in groups C and D (16 to <26 years) (both P <.01). Time in range (TiR) increased in all groups (A: +3 PP; B: +5 PP; C: +5 PP; D: +5 PP; P < 0.01 for each group). Insulin pumps (61.0% versus 53.4% male) and SAP (33.5% versus 28.9% male) are used more frequently in females. Conclusion: In recent years, we found an increasing use of new diabetes technologies and an improvement in metabolic control (TiR) across all age groups.
CRIS-Team Scopus Importer:2023-03-10
Keywords: automated insulin delivery; diabetes patient follow up; hybrid closed loop; sensor augmented pump therapy; type 1 diabetes

Use of the WHO Access, Watch, and Reserve classification to define patterns of hospital antibiotic use (AWaRe): an analysis of paediatric survey data from 56 countries - Hsia, Yingfen; Lee, Brian R.; Versporten, Ann; Yang, Yonghong; Bielicki, Julia; Jackson, Charlotte; Newland, Jason; Goossens, Herman; Magrini, Nicola; Sharland, Mike; Teston, L.; Cheung, K.; et al. (Lancet Global Health, 2019)
Background Improving the quality of hospital antibiotic use is a major goal of WHO's global action plan to combat antimicrobial resistance. The WHO Essential Medicines List Access, Watch, and Reserve (AWaRe) classification could facilitate simple stewardship interventions that are widely applicable globally. We aimed to present data on patterns of paediatric AWaRe antibiotic use that could be used for local and national stewardship interventions.
CRIS-Team WoS Importer:2019-06-25

User-Centered Development of an Online Platform for Drug Dosing Recommendations in Pediatrics - Rödle, Wolfgang; Wimmer, Stefan; Zahn, Julia; Prokosch, Hans-Ulrich; Hinkes, Bernward; Neubert, Antje; Rascher, Wolfgang; Kraus, Stefan; Toddenroth, Dennis; Sedlmayr, Brita (Applied Clinical Informatics, 2019)
Background Drug therapy in pediatric patients is a complex process. Children are subject to continuous growth and variation in drug-metabolizing enzyme activity, requiring continuous adaption of dosages. In Germany, currently no publicly available database exists that provides evidence-based information on drug dosages in pediatrics. For local drug dosing support, a prototype database has been developed within the Children's Hospital, Erlangen. A user-centered development process was initiated to establish an online platform for evidence-based dosing recommendations, as well as pharmacological and pharmaceutical drug information in pediatrics. Objectives The objectives of the study were to survey the demand for such a platform and to assess the usability of the different versions of the developed system. Methods The developed prototype was evaluated in a pluralistic walkthrough with prospective end users. After a redesign, the second prototype of the online platform underwent an online usability testing based on a tailored questionnaire and the System Usability Scale (SUS) (n = 12). Results Eleven of 12 participants expressed a demand for an online platform for pediatric dosing recommendations. The majority of the participants requested the integration of extended features, such as drug-drug interaction alerts, or information on adverse effects, pharmacokinetics, and pharmacodynamics. Particularly noteworthy is the demand for an online calculator; 5 of a total of 15 participants explicitly requested a calculator for dosages (based on age, weight, body surface) and glomerular filtration rate. The usability of the second prototype was rated good to excellent with a median SUS of 81.25. Conclusion Local domain experts demand an online platform for pediatric dosing recommendations. The application of the user-centered design approach enabled the development of a prototype suitable for practical use. Multiple additional required functionalities have been identified, whereby the importance of an online calculator for patient-individual dosing recommendations was particularly emphasized.
CRIS-Team Scopus Importer:2019-08-20
Keywords: computer-assisted; decision support techniques; drug therapy; knowledge bases; online systems; pediatric dosages

Using the existing registry Bestehendes Register nutzen - Holl, Reinhard W.; Wölfle, Joachim (Deutsches Ärzteblatt international, 2021)
CRIS-Team Scopus Importer:2021-08-20

Vaccination With Live Attenuated Vaccines in Four Children With Chronic Myeloid Leukemia While on Imatinib Treatment - Bettoni da Cunha-Riehm, Claudia; Hildebrand, Verena; Nathrath, Michaela; Metzler, Markus; Suttorp, Meinolf (Frontiers in Immunology, 2020)
Chronic myeloid leukemia (CML) in childhood and adolescence is a rare malignancy that can successfully be treated with the tyrosine kinase inhibitor (TKI) imatinib. According to the current experience, treatment is necessary for years and, in the majority of cases, a lifelong approach is required to control the malignant disease. To what extent imatinib causes immunosuppression in different age cohorts is a controversial discussion. According to general medical recommendations, live vaccines are contraindicated in individuals treated with imatinib. However, a recent increase in the number of globally reported cases of measles has been observed and continues to rise. Due to the high contagiousness of the virus, near-perfect vaccination coverage (herd immunity of 93 to 95%) is required to effectively protect against measles resurgence—a scenario that is not realistic in many countries. When four teenagers with CML (median age 13 years, range 12–15) who were enrolled into pediatric trial CML-paed II while on imatinib treatment (median treatment duration 36 months, range 11–84) were identified without protective measles and/or varicella titers, we carefully balanced the risks of a live vaccination under immunosuppressive TKI medication against the benefit of being protected. The patients underwent live vaccination with the live attenuated vaccines M-M-RVAX Pro® and Varivax® simultaneously (Patient #1), Priorix® and Varilix® consecutively (Patient #2), and Priorix® (Patients #3 and #4). While the first three patients were vaccinated while receiving TKI therapy, treatment with imatinib was interrupted in patient #4 for 1 week prior and 2 weeks after vaccination. Patients #1 and #3 reacted with stable long-term seroconversion. In Patient #2, serum titer conversion against measles and varicella could not be demonstrated and thus revaccination with Priorix® and Varilix® was performed 3 years later. However, protective titers did not develop or were lost again. Patient #4 also lost protective titers against measles when assessed 10 months after vaccination, but revaccination resulted in stable seroprotective titers over 12 months after the last vaccination during ongoing imatinib treatment. We conclude that in all patients, the safety of live vaccines could be documented, as no acute or late adverse events were observed. However, in line with observations that memory B-cells are lost under exposure to imatinib, revaccination may become necessary (two out of four patients in this small series lost their seroprotection). Considering that the number of cases is very small, we also suggest some criteria for decision-making regarding live vaccinations of CML patients treated with imatinib.
CRIS-Team Scopus Importer:2020-05-12
Keywords: chronic myeloid leukemia; imatinib; measles; mild immunosuppression; pediatric CML; tyrosine kinase inhibitors; vaccination; varicella

Vaccination with Live Attenuated Virus Vaccines in Four Pediatric Patients with CML While on Imatinib Treatment - Da Cunha-Riehm, Claudia Bettoni; Hildebrand, Verena; Nathrath, Michaela; Metzler, Markus; Suttorp, Meinolf (BLOOD, 2019)
CRIS-Team WoS Importer:2021-10-18

Value of a web-based pediatric drug information system to prevent serious adverse drug reactions in child and adolescent psychiatry - Fekete, Stefanie; Kulpok, Christine; Taurines, Regina; Egberts, Karin; Geissler, Julia; Gerlach, Manfred; Makosi, Dorothee Malonga; Koenig, Jochem; Urschitz, Michael S.; Toni, Irmgard; Neubert, Antje; Romanos, Marcel (Journal of Neural Transmission, 2022)
Psychotropic drugs are frequently prescribed ‘off-label’ to children and adolescents and carry the risk of serious adverse drug reactions (sADR). We examined the frequency of sADRs of psychotropic drugs in pediatric inpatients and explored their potential preventability through following the recommendations of a web-based pediatric drug information system (PDIS). The potential socio-economic impacts of using this online system is also addressed. Routine clinical data from all inpatients treated in a child and adolescent psychiatry department between January 2017 and December 2018 were retrospectively examined for the occurrence of sADRs as defined by the European Medicines Agency. The preventability of the sADRs was assessed based on the information of the PDIS. Furthermore, the expected prolongation of the hospital stay due to sADRs was calculated as well as the associated treatment costs. The study was supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021. In total, 1036 patients were screened of whom 658 (63.5%) received psychopharmacological treatment. In 53 (8.1%) of these patients 54 sADRs were documented, of which 37 sADRs were identified as potentially preventable through PDIS. Mitigating sADR through PDIS would likely have prevented prolonged hospital stays and conferred considerable savings for health insurance companies. PDIS provides systematic and evidence-based information about pediatric psychopharmacotherapy and helps to prevent prescribing errors. Therefore, PDIS is a useful tool to increase drug therapy safety in child and adolescent psychiatry. Further prospective studies are needed to confirm the results.
CRIS-Team Scopus Importer:2022-11-18
Keywords: Adverse effects; Drug safety; Mental health; Pharmacovigilance; Psychotropic drugs

Variable White Matter Atrophy and Intellectual Development in a Family With X-linked Creatine Transporter Deficiency Despite Genotypic Homogeneity - Heussinger, Nicole; Saake, Marc; Mennecke, Angelika; Dörr, Helmuth-Günther; Trollmann, Regina (Pediatric Neurology, 2017)
The X-linked creatine transporter deficiency (CRTD) caused by an SLC6A8 mutation represents the second most common cause of X-linked intellectual disability. The clinical phenotype ranges from mild to severe intellectual disability, epilepsy, short stature, poor language skills, and autism spectrum disorders. The objective of this study was to investigate phenotypic variability in the context of genotype, cerebral creatine concentration, and volumetric analysis in a family with CRTD.The clinical phenotype and manifestations of epilepsy were assessed in a Caucasian family with CRTD. DNA sequencing and creatine metabolism analysis confirmed the diagnosis. Cerebral magnetic resonance imaging (cMRI) with voxel-based morphometry and magnetic resonance spectroscopy was performed in all family members.An SLC6A8 missense mutation (c.1169C>T; p.Pro390Leu, exon 8) was detected in four of five individuals. Both male siblings were hemizygous, the mother and the affected sister heterozygous for the mutation. Structural cMRI was normal, whereas voxel-based morphometry analysis showed reduced white matter volume below the first percentile of the reference population of 290 subjects in the more severely affected boy compared with family members and controls. Normalized creatine concentration differed significantly between the individuals (P < 0.005).There is a broad phenotypic variability in CRTD even in family members with the same mutation. Differences in mental development could be related to atrophy of the subcortical white matter.
EVALuna2:14646

Variants of the ectodysplasin A1 receptor gene underlying homozygous cases of autosomal recessive hypohidrotic ectodermal dysplasia - Wohlfart, Sigrun; Schneider, Holm (Clinical Genetics, 2019)
Hypohidrotic ectodermal dysplasia (HED) is a rare genetic condition resulting from defective development of ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF-kappa B signaling pathway. Here, we describe three cases of AR-HED in families of Turkish, Austrian, and German-American origin (with or without known consanguinity). In these cases, two out-of-frame deletions and a pathogenic missense variant of EDAR were found to be disease-causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non-syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR-Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.
CRIS-Team WoS Importer:2019-03-06

VASCULAR REMODELING OF RETINAL VESSELS IN PATIENTS WITH CONGESTIVE HEART FAILURE - Jung, Susan; Kannenkeril, D.; Ott, Christian; Cifkova, R.; Harazny, J. M.; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Verbesserte Qualität gelagerter Erythrozytenkonzentrate durch maschinelle Autotransfusion - Münch, Frank; Purbojo, Ariawan; Wenzel, F.; Kohl, M.; Dittrich, Sven; Rauh, Manfred; Zimmermann, Rüdiger; Kwapil, Nicola (Die Anaesthesiologie, 2022)
Background The transfusion of packed red blood cells (PRBC) is associated with various side effects, including storage damage to PRBCs. The cells change their structure, releasing potassium as well as lactate. Mechanical rinsing, available in many hospitals, is able to remove toxic substances and possibly minimizes the negative side effects of transfusion. Objective The primary aim of our study was to improve the quality of PRBCs before transfusion. The effects of different washing solutions on PRBC quality were analyzed. Material and methods This in vitro study compares 30 mechanically washed PRBCs. They were either processed with standard normal saline 0.9% (n = 15, N group) or a hemofiltration solution containing 4 mmol/l potassium (n = 15, HF group) by a mechanical rinsing device (Xtra, LivaNova, Munich, Germany). A subgroup analysis was performed based on the storage duration of the processed PRBCs (7, 14, 37 days). Samples were taken before washing (EKpra), immediately after washing (EKpost) and 10 h later (EKpost10h), after storage in the "wash medium" at room temperature. Concentrations of ATP (probability of survival in transfused erythrocytes), lactate, citrate and electrolytes (potassium, sodium, chloride, calcium) were tested. Results and conclusion Mechanical rinsing improves pretransfusion quality of PRBC. Washing with a hemofiltration solution results in a more physiological electrolyte composition. Even 10 h after mechanical rinsing with a hemofiltration solution, the quality of 37-day-old PRBC is comparable to young PRBC that have been stored for 7 days and have not been washed. Washing stored PRBC increases the ATP content, which subsequently leads to an increased probability of survival of red cells after transfusion.
CRIS-Team WoS Importer:2022-08-26

Virtual reality jogging as a novel exposure paradigm for the acute urge to be physically active in patients with eating disorders: Implications for treatment - Paslakis, Georgios; Fauck, Vanessa; Roeder, Kathrin; Rauh, Elisabeth; Rauh, Manfred; Erim, Yesim (International Journal of Eating Disorders, 2017)
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EVALuna2:24045

Vitamin D3 resolved human and experimental asthma via B lymphocyte-induced maturation protein 1 in T cells and innate lymphoid cells. - Grund, Janina; Krammer, Susanne; Yang, Zuqin; Mitländer, Hannah; Rauh, Manfred; Zirlik, Sabine; Kiefer, Alexander; Zimmermann, Theodor; Rieker, Ralf; Geppert, Carol-Immanuel; Papadopoulos, Nikolaos G.; Neurath-Finotto, Susetta (Journal of Allergy and Clinical Immunology: Global, 2023)
BACKGROUND: Vitamin D3 (VitD3) is known to have immunomodulatory functions, and VitD3 deficiency is associated with more severe asthma. OBJECTIVE: We aimed to assess the immunoregulatory effects of VitD3 food supplementation on asthma manifestation, with particular focus on T cells and type 2 innate lymphoid cells. METHODS: Preschool children and adult asthmatic cohorts were analyzed in the context of VitD3 supplementation and serum levels. In a murine model of ovalbumin-induced asthma, effects of diet VitD3 sufficiency and deficiency on T cells and type 2 innate lymphoid cells immune mechanisms were investigated. RESULTS: We found less severe and better-controlled asthma phenotypes along with reduced need for steroid medication in preschool children and asthmatic adults with VitD3 supplementation. VitD3 serum levels correlated with B lymphocyte-induced maturation protein 1 (Blimp-1) expression in blood peripheral mononuclear cells. VitD3-supplement-fed mice showed decreased asthmatic traits, with a decrease in IgE serum levels, reduced airway mucus, and increased IL-10 production by lung cells. Furthermore, we discovered an upregulation of effector T cells and Blimp-1+ lung tissue-resident memory T cells as well as induction of anti-inflammatory Blimp-1+ lung innate lymphoid cells producing IL-10. CONCLUSION: Supplementing VitD3 resulted in amelioration of clinical asthma manifestations in human studies as well as in experimental allergic asthma, indicating that VitD3 shifts proinflammatory immune responses to anti-inflammatory immune responses via upregulating Blimp-1 in lung innate lymphoid cells and tissue-resident memory cells.
EVALuna2:544627
Keywords: Allergic asthma; pediatric asthma; adult asthma; vitamin D3; vitamin D3 supplementation; TRM; ILC2s; Blimp-1; resolution of asthma

What to Examine in Youth Climbing Athletes: Yearly Examination of the German Climbing Team and its Consequences - Schöffl, Isabelle; Lutter, Christoph; Schöffl, Volker (Sportverletzung-Sportschaden, 2019)
Objective This article presents the results of the yearly medical examination performed on all our national climbing athletes in 2016 and 2017. Methods Our yearly athlete examination follows the Olympic guidelines and those of the Medical Commission of the International Federation of Sport Climbing. It consists of echocardiography, spiroergometry, a general blood examination, body fat measurement as well as a paediatric and orthopaedic clinical examination. In addition, a yearly ultrasound examination is performed on the fingers to detect pathologies and measure the width of the growth plates. The years 2016/2017 were evaluated. Results Team examinations were undertaken in 17 girls and 23 boys. The mean age was 17.5 years (18.3 years for the boys and 17.4 years for the girls). They had been climbing for 10.9 years on average (the boys for 11.3 and the girls for 10.3 years). Typical findings were susceptibility to infection, musculoskeletal injuries and, in one case, severe headaches. 36% of our athletes had to take a break from climbing due to injury or illness. Most of these breaks were due to infections (7 in total), most of them minor inspiratory or gastrointestinal. One athlete suffered from severe pneumonia during a World Cup in Japan. The other pauses were due to finger injuries (2), foot injuries (2), and injuries to the shoulder and biceps (2). Conclusion The yearly team examination plays an important role in early injury detection. It helps to establish a relationship based on trust, encouraging athletes to approach the team physician openly with questions or concerns.
CRIS-Team Scopus Importer:2019-12-20
Keywords: finger injuries; national team; rock climbing; sport climbing; sports medical exam; team exam

Wie häufig betreffen Gegenanzeigen und Warnhinweise in deutschen Fachinformationen pädiatrische Patienten? - Wimmer, Stefan; Rascher, Wolfgang; Neubert, Antje (Klinische Pädiatrie, 2019)
Background 3.2-3.8% of all medicine prescriptions for minor outpatients are off-label only because of the patients' age group. The younger, the more patients are affected by this issue. Only one fifth of the most commonly used medicines for newborns are licensed for this age group. The aim of this study is to analyse all German SmPCs whether they contain contraindications and warnings that specifically concern paediatric patients. Methods All available SmPCs were processed to search the sections Contraindications and Special warnings and precautions for information on paediatric age groups. Results were evaluated for differences between age groups, ATC classification and routes of application. Results 13547 SmPCs (22863 medicinal products) were evaluated. For 3603 (15.8%) medicinal products the SmPC contained contraindications for at least one paediatric age group. For 9687 (42.4%) medicinal products contraindications or warnings were found, including 2833 (12.4%) where all patients below 18 years were affected. Preterms were particularly affected (n=9581, 41.9%) as well as the ATC therapeutic subgroups contrast media (89.0%), cough and cold preparations (86.2%) and Corticosteroids (topical 88.2%, systemic 86.6%). Concerning liquids for oral use the proportion was higher than average (58.2%). Conclusion It can be assumed that for most medicinal products the contraindications for paediatrics result from a lack of data and age specific formulations rather than from pharmacokinetic or -dynamic differences in paediatric patients. The EU Paediatric Regulation did not significantly stimulate the conduction of paediatric studies in off-patent medicines to this day.
CRIS-Team Scopus Importer:2019-07-26
Keywords: Contraindications; Drug safety; Off-Label-Use; Paediatrics; SmPC

X-chromosomal insertions at a recurrent site causing ectodermal dysplasia - Schneider, Holm; Mühle, Christiane (European Journal of Dermatology, 2009)
CRIS-Team Scopus Importer:2020-07-01

X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems - Kolvenbach, Caroline M.; Felger, Tim; Schierbaum, Luca; Thiffault, Isabelle; Pastinen, Tomi; Szczepanska, Maria; Zaniew, Marcin; Adamczyk, Piotr; Bayat, Allan; Yilmaz, Oeznur; Lindenberg, Tobias T.; Thiele, Holger; et al. (Journal of Medical Genetics, 2022)
BackgroundSHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system. MethodsHere, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development. ResultsIn this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino. ConclusionThe identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.
CRIS-Team WoS Importer:2022-12-16

Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial - Koch, Raphael; Haveman, Lianne; Ladenstein, Ruth; Brichard, Benedicte; Jürgens, Heribert; Cyprova, Sona; van den Berg, Henk; Hassenpflug, Wolf; Raciborska, Anna; Ek, Torben; Baumhoer, Daniel; Egerer, Gerlinde; et al. (Clinical Cancer Research, 2023)
PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.
CRIS-Team Scopus Importer:2023-12-29

Zulassungseinschränkung der Antihistaminika der ersten Generation für Kinder unter 3 Jahren aufgrund eines negativen Nutzen-Risiko-Verhältnisses - Moritz, Katrin; Rascher, Wolfgang; Toni, Irmgard; Zahn, Julia; Neubert, Antje (Monatsschrift Kinderheilkunde, 2020)
First generation H1 antihistamines (e.g. dimenhydrinate, diphenhydramine and doxylamine) have been an essential component in pediatric drug treatment for many years. In recent years there have been an increasing number of reports of serious (including fatalities) side effects in infants following the use of these drugs. For this reason, in 2017 the Federal Institute for Drugs and Medical Devices (BfArM) initiated a risk assessment procedure and reassessed the benefit-risk ratio based on the available data. As a result the oral and rectal use of antiemetics containing dimenhydrinate and diphenhydramine in children below 3 years of age suffering from nausea and vomiting associated with simple gastroenteritis and feverish infections are no longer indicated. In addition, doxylamine became a prescription-only drug. This article illustrates the background to why and how the use of first generation H1 antihistamines is now restricted and the effects which the reporting of adverse drug reactions can have.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Adverse drug reaction; Dimenhydrinate; Histamine H1 antagonist; Pediatrics; Pharmacovigilance

Amplitude-Integrated EEG for Neurological Assessment and Seizure Detection in a German Pediatric Intensive Care Unit - Bruns, Nora; Sanchez-Albisua, Icier; Weiss, Christel; Tschiedel, Eva; Dohna-Schwake, Christian; Felderhoff-Mueser, Ursula; Mueller, Hanna (Frontiers in Pediatrics, 2019)
Objective: The aim of our study was to assess the use of aEEG in our pediatric intensive care unit (PICU), indications for neuromonitoring and its findings, utility for seizure detection, and associations with outcome.
CRIS-Team WoS Importer:2019-09-10

Are Simple Magnetic Resonance Imaging Biomarkers Predictive of Neurodevelopmental Outcome at Two Years in Very Preterm Infants? - Dewan, Monia Vanessa; Herrmann, Ralf; Schweiger, Bernd; Sirin, Selma; Müller, Hanna; Storbeck, Tobias; Dransfeld, Frauke; Felderhoff-Müser, Ursula; Hüning, Britta (Neonatology, 2019)
Background: Preterm infants are at increased risk of neurodevelopmental impairment due to the vulnerability of the immature brain. Early risk stratification is necessary for predicting outcome in the period of highest neuroplasticity. Several biomarkers in magnetic resonance imaging (MRI) at term equivalent age (TEA) have therefore been suggested. Objective: To assess the predictive value of simple brain metrics and the total abnormality score (TAS)- A modified score for brain injury and growth-in relation to neurodevelopmental outcome of very preterm infants in MRI at TEA. Methods: Single-centre cohort study including preterm infants with gestational age (GA) ≤32 weeks and birth weight ≤1,500 g. Biparietal width (BPW), interhemispheric distance, transcerebellar diameter (TCD) and TAS were assessed. To detect subtle haemorrhages, additional susceptibility-weighted imaging (SWI) was used in addition to conventional MRI to evaluate its clinical relevance. Neurodevelopment was tested by the Mental and Psychomotor Developmental Index (MDI/PDI) of the Bayley Scales of Infant Development II at a corrected age of 24 months. Results: One hundred twenty-nine children with median GA of 28.1 weeks and median birth weight of 980 g were included. BPW significantly correlated with PDI (p= 0.01, R2 = 0.06) and TCD with MDI (p < 0.01, R2 = 0.05) and PDI (p < 0.01, R2 = 0.06) but explained variances were low. TAS was not predictive of neurodevelopmental outcome. By using SWI, additional 4 cases of low grade haemorrhages were identified compared to conventional sequences. In one case this additional information was clinically relevant (MDI/PDI below average). Conclusion: Simple brain metrics and TAS did not reliably predict neurodevelopmental outcome in a cohort with low prevalence of high grade brain injury. The additional value of SWI is yet to be determined in larger cohorts. The combination of imaging and functional biomarkers may be advisable for the prediction of neurodevelopmental outcome.
CRIS-Team Scopus Importer:2019-09-17

Arterial hypertension in children with hemolytic uremic syndrome after kidney transplantation - Hoenecke, Johannes; Hartmann, Hans; Melk, Anette (Pediatric Transplantation, 2015)
The development of arterial hypertension after KTX is a well-known complication. HUS is a systemic disease associated with arterial hypertension during long-term follow-up. Our goal was to report on the severity of arterial hypertension after KTX in patients with typical and atypical HUS. We analyzed the course of 197 patients with HUS, of which 22 (n = 10 with typical HUS; n = 12 with atypical HUS) developed ESRF and received KTX as renal replacement therapy. We analyzed data from 1766 casual BP and 85 24-h ABPM measurements. In addition, we evaluated the used antihypertensive strategy. Comparison between the two patient groups revealed that patients with atypical HUS had significantly higher casual SBP-SDS and DBP-SDS values after KTX despite similar intensity of antihypertensive treatment. These data were supported by analysis of ABPM profiles showing comparable results for the interval 1-5 yr after KTX. Patients with atypical HUS had a greater severity of arterial hypertension despite similar treatment strategies and intensity of treatment. Our observation, even though in a small cohort, supports recent genetic studies showing arterial hypertension closely associated with HUS-causing mutations in patients with atypical HUS.
EVALuna2:18935

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset - Langer, Thorsten; Clemens, Eva; Broer, Linda; Maier, Lara; Uitterlinden, André G.; de Vries, Andrica C.H.; van Grotel, Martine; Pluijm, Saskia F.M.; Binder, Harald; Mayer, Benjamin; von dem Knesebeck, Annika; Byrne, Julianne; et al. (Data in Brief, 2020)
Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Adverse drug reaction; Cancer survivors; Childhood cancer; Cisplatin: carboplatin; Drug-induced ototoxicity; Genetic markers; Multicenter cohort study; Pharmacogenetics

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life - Odenwald, Brigitte; Nennstiel-Ratzel, Uta; Dörr, Helmuth-Günther; Schmidt, Heinrich; Wildner, Manfred; Bonfig, Walter (European Journal of Endocrinology, 2016)
OBJECTIVE: To evaluate adrenal crises after the start of treatment up to the age of 6 years in children with classic congenital adrenal hyperplasia (CAH). DESIGN: Analysis of data extracted from a population-based prospective long-term follow-up study of children detected in neonatal screening. METHODS: Data of 102 Bavarian children with classic CAH due to 21-hydroxylase deficiency were analyzed, using parental questionnaires and medical reports. Parent-reported hospital admissions of children diagnosed with acute health impairment were included in the analysis if salt loss (hyponatremia) or hypoglycemia was documented in the discharge summary. RESULTS: A total of 74 children (72.5%) had no report of hospital admissions with salt loss or hypoglycemia during the observational period. However, in 27.5% of the children, 22 salt-wasting crises (seven of these also with low blood glucose) and 16 hypoglycemic episodes without salt loss were reported. Furthermore, the cumulative incidence for seizures was elevated; 13 children experienced seizures during hyponatremia or hypoglycemia. Most adrenal crises were triggered by infections, often with inappropriate emergency management, but in 11 cases hypoglycemia occurred unexpectedly, without evidence of severe illness and without any management errors. Frequency of adrenal crises was 6.5 per 100 patient years (95% CI: 4.6-8.8). CONCLUSIONS: Crisis prevention remains a permanent challenge for families and physicians caring for children with classic CAH. Expert care and compliance with emergency recommendations are crucial. Further research on the interactions among glucocorticoid deficiency, adrenomedullary dysfunction, and glucose metabolism is necessary for the prevention of hypoglycemia, especially in young CAH patients.
EVALuna2:33872

Clinical correlates of rhinovirus infection in preschool asthma - Jartti, Tuomas; Liimatainen, Unna; Xepapadaki, Paraskevi; Vahlberg, Tero; Bachert, Claus; Finotto, Susetta; Kowalski, Marek L.; Sobanska, Anna; Lukkarinen, Heikki; Pasioti, Maria; Vuorinen, Tytti; Zhang, Nan; et al. (Allergy, 2020)
Background: Investigation of preschool asthma is important since not all children outgrow their illness during this age. Data are scarce on the role of rhinovirus (RV) infections in this patient group. Objectives: To investigate the role of RV infections in preschool asthma: (i) susceptibility factors, (ii) clinical course, and (iii) medium-term outcome. Methods: A total of 130 asthmatic children aged 4-6 years from the multinational PreDicta cohort were prospectively followed for a 12-month period. Allergy tests and a standard health questionnaire were carried out at study entry. Respiratory virus presence in nasopharyngeal washes was studied at illness visits and at 3 scheduled visits. Results: At study entry, mean age of the children was 5.3 years. Of 571 visits, 54% were positive for any virus and 39% for RV. Patient characteristics were only assessed with RV infection due to low number of other viruses. The use of supplementary vitamin D was inversely associated with RV infection (P <.05). RV infection was associated with more severe course of acute illness in terms of more severe nighttime coughing, more sleep disturbances, and more days with runny nose (all P <.05). RV infection was also associated with more severe disease course during the 12-month follow-up in terms of more nights with awakenings and more days of exercise-related symptoms (both P <.05). Conclusions: Vitamin D supplementation may have an anti-rhinovirus effect. Both short- and medium-term outcomes suggest RV infection to be an important clinical marker of instable preschool asthma.
CRIS-Team Scopus Importer:2020-07-31
Keywords: asthma; child; preschool; rhinovirus; vitamin D

Correlation of lateral ventricular size and deep gray matter volume in MRI at term equivalent age with neurodevelopmental outcome at a corrected age of 24 months and with handedness in preterm infants - Storbeck, Tobias; Bruns, Nora; Weiss, Christel; Felderhoff-Müser, Ursula; Müller, Hanna (European Journal of Pediatrics, 2019)
The aim of this study was to correlate ventricular size and volumes of deep gray matter (DGM) in MRI at term equivalent age (TEA) with outcome at a corrected age of 24 months in preterm infants and with handedness. Seventy-three infants born before 32 weeks of gestation or with birth weight < 1500 g were included in this retrospective analysis and measurement of lateral ventricles, and DGM was performed on MRI scans. The left lateral ventricle was significantly larger than the right lateral ventricle (p = 0.001). There was no correlation between volumes of the right and left ventricles and the DGM volume (p = 0.207 and p = 0.597, respectively), nor with the head circumference at TEA (p = 0.177 and p = 0.976, respectively). The total volume of both lateral ventricles did not correlate with Mental Develomental Index (MDI, p = 0.336) or Psychomotor Developmental Index (PDI, p = 0.650) score (Bayley Scales of Infant Development, BSID II). However, a correlation of total DGM volume with birth weight (p = 0.0001; r = 0.437), head circumference at TEA (p < 0.0001; r = 0.640), MDI (p = 0.029; r = 0.310), and PDI (p = 0.002; r = 0.456) was observed. No significant difference between right- and left-handed infants was seen in relation to volumes of both lateral ventricles and of DGM. Conclusion: DGM volume at TEA was significantly associated with the outcome at a corrected age of 24 months. Handedness did not correlate with DGM or lateral ventricle size.What is Known:• White matter injury as well as altered development of deep gray matter is associated with neurodevelopmental disability in preterm infants.• No study analyzed the association between deep gray matter volume or volumes of lateral ventricle and handedness in former preterm infants so far.What is New:• Volume of deep gray matter, but not lateral ventricular size was significantly associated with outcome at a corrected age of 24 months in preterm infants.• There was no correlation of handedness with volumes of lateral ventricular size or with deep gray matter volumes.
CRIS-Team Scopus Importer:2019-11-26
Keywords: Deep gray matter; Handedness; Immature preterm infants; MRI; Neurodevelopmental outcome; Ventricular size

Correlation of lateral ventricular size and deep gray matter volume in MRI at term equivalent age with neurodevelopmental outcome at a corrected age of 24 months and with handedness in preterm infants - Storbeck, Tobias; Bruns, Nora; Weiss, Christel; Felderhoff-Mueser, Ursula; Mueller, Hanna (European Journal of Pediatrics, 2020)
The aim of this study was to correlate ventricular size and volumes of deep gray matter (DGM) in MRI at term equivalent age (TEA) with outcome at a corrected age of 24 months in preterm infants and with handedness. Seventy-three infants born before 32 weeks of gestation or with birth weight < 1500 g were included in this retrospective analysis and measurement of lateral ventricles, and DGM was performed on MRI scans. The left lateral ventricle was significantly larger than the right lateral ventricle (p = 0.001). There was no correlation between volumes of the right and left ventricles and the DGM volume (p = 0.207 and p = 0.597, respectively), nor with the head circumference at TEA (p = 0.177 and p = 0.976, respectively). The total volume of both lateral ventricles did not correlate with Mental Develomental Index (MDI, p = 0.336) or Psychomotor Developmental Index (PDI, p = 0.650) score (Bayley Scales of Infant Development, BSID II). However, a correlation of total DGM volume with birth weight (p = 0.0001; r = 0.437), head circumference at TEA (p < 0.0001; r = 0.640), MDI (p = 0.029; r = 0.310), and PDI (p = 0.002; r = 0.456) was observed. No significant difference between right- and left-handed infants was seen in relation to volumes of both lateral ventricles and of DGM.Conclusion: DGM volume at TEA was significantly associated with the outcome at a corrected age of 24 months. Handedness did not correlate with DGM or lateral ventricle size.What is Known:• White matter injury as well as altered development of deep gray matter is associated with neurodevelopmental disability in preterm infants.• No study analyzed the association between deep gray matter volume or volumes of lateral ventricle and handedness in former preterm infants so far.What is New:• Volume of deep gray matter, but not lateral ventricular size was significantly associated with outcome at a corrected age of 24 months in preterm infants.• There was no correlation of handedness with volumes of lateral ventricular size or with deep gray matter volumes.
EVALuna2:210492

DMBT1 amount in amniotic fluid depends on gestational age - Blickwedel, Jana; Bagci, Soyhan; Alsat, Ebru Ailen; Strizek, Brigitte; Renner, Marcus; Mueller, Andreas; Mueller, Hanna (Journal of Maternal-Fetal & Neonatal Medicine, 2021)
Objective Amniotic fluid is a mixture containing many different proteins as immunomodulatory peptides and growth factors. The glycoprotein Deleted in Malignant Brain Tumors 1 (DMBT1) is participated in innate immunity, angiogenesis and epithelial differentiation. We analyzed the DMBT1 concentration in amniotic fluid during gestation. Methods DMBT1 concentration was quantified by ELISA. Amniotic fluid samples were collected from preterm and term neonates. Effects of maternal or neonatal parameters were analyzed. To evaluate the source of DMBT1 we examined RNA of fetal tissue in relation to DMBT1 expression. Results The median DMBT1 concentration in amniotic fluid was 54.4 ng/ml. Amniotic fluid obtained <28 weeks of gestation revealed significantly lower DMBT1 concentrations compared to >= 28 weeks. We found a positive correlation between DMBT1 concentration and gestational age (p = .026). The fetal DMBT1 expression was pronounced in the gastrointestinal tract. Conclusions The results showed that DMBT1 concentrations in amniotic fluid correlate with the gestational age during gestation and that the fetal gastrointestinal tract is a potential source of DMBT1. BRIEF RATIONALE Amniotic fluid contains not only nutrients, but also many immunomodulatory peptides and growth factors. Deleted in Malignant Brain Tumors 1 (DMBT1) is an innate immunity protein with functions in epithelial differentiation and angiogenesis. The aim of this research was to study the DMBT1 content and the factors affecting its concentration in amniotic fluid during gestation. In summary, the results obtained in this study showed that DMBT1 is a component of amniotic fluid and that DMBT1 concentrations in amniotic fluid correlate with gestational age. In addition to this, the fetal gastrointestinal tract is a potential source of DMBT1 detected in amniotic fluid.
CRIS-Team WoS Importer:2021-06-25

Glukokortikoide bei nichtendokrinen Erkrankungen, bei Kortisolmangel und bei endogenem Exzess – der Einfluss therapeutischer Strategien auf das kindliche Wachstum - Hauffa, B. P.; Binder, G.; Bonfig, W.; Bettendorf, M.; Dörr, Helmuth-Günther (Monatsschrift Kinderheilkunde, 2019)
Background: Adrenocortical hormones can influence the growth of children and adolescents. Objective: How does chronic glucocorticoid treatment of nonendocrine diseases and endogenous Cushing’s syndrome affect growth? What has to be considered during the treatment of patients with central adrenal cortex insufficiency under growth hormone substitution and patients with congenital adrenal hyperplasia with respect to growth? Material and methods: This article is based on the results of a workshop held by pediatric endocrinologists. Each author conducted a recent literature research on growth under the specific aspects of adrenal cortex physiology and pathology and the respective treatment procedures. Results: The therapeutic use of high doses of synthetic glucocorticoids for nonendocrine disorders (pharmacological treatment) inhibits the growth of children and adolescents. Long-term use should therefore be avoided and glucocorticoid-sparing treatment regimens (biologicals etc.) should be preferred. High endogenous cortisol levels in Cushing’s syndrome cause growth retardation; however, if the secretion of androgens predominates, longitudinal growth can also be increased. In patients with growth hormone deficiency, the possibility of a delayed failure of the hypothalamus-pituitary-adrenal cortex axis has to be considered and a re-evaluation should be scheduled. High doses of hydrocortisone during substitution should be avoided so as not to compromise the effect of the growth hormone therapy (substitution therapy). Patients with congenital adrenal hyperplasia and 21-hydroxylase deficiency show specific growth characteristics in the different phases of life. It is therefore a therapeutic challenge to achieve a normal final body height by individually adapting glucocorticoid treatment. Conclusion: The adequate diagnosis, treatment and monitoring of disorders of adrenal cortex function are important to minimize the negative effects on the growth of children and adolescents.
CRIS-Team Scopus Importer:2019-06-07
Keywords: Adrenal glands; Congenital adrenal hyperplasia; Cushing’s syndrome; Hydrokortisone; Synthetic Glucocorticoids

Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4 - Loos, Sebastian; Aulbert, Wiebke; Hoppe, Bernd; Ahlenstiel-Grunow, Thurid; Kranz, Birgitta; Wahl, Charlotte; Staude, Hagen; Humberg, Alexander; Benz, Kerstin; Krause, Martin; Pohl, Martin; Liebau, Max C.; et al. (Clinical Infectious Diseases, 2017)
Background.: In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking. Methods.: Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak. Results.: Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes. Conclusions.: The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.
EVALuna2:34003

Isolation of a unique hepatic stellate cell population expressing integrin α8 from embryonic mouse livers - Ogawa, Tomohiro; Li, Yuchang; Lua, Ingrid; Hartner, Andrea; Asahina, Kinji (Developmental Dynamics, 2018)
BACKGROUND: Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. However, little is known about their phenotype and role in liver development. The aim of this study is to identify specific markers for embryonic HSCs. RESULTS: Using antibodies against ALCAM and PDPN, we separated mesothelial cells (MCs) and HSCs from developing livers and identified integrin α8 (ITGA8) as a marker for embryonic desmin+ HSCs that are preferentially localized near the developing liver surface and α-smooth muscle actin+ perivascular mesenchymal cells around the vein. A cell lineage-tracing study revealed that upon differentiation, MC-derived HSCs or perivascular mesenchymal cells express ITGA8 during liver development. Using anti-ITGA8 antibodies, we succeeded in isolating MC-derived HSCs and perivascular mesenchymal cells from embryonic livers. In direct co-culture, ITGA8+ mesenchymal cells promoted the expression of hepatocyte and cholangiocyte markers in hepatoblasts. In the normal adult liver, expression of ITGA8 was restricted to portal fibroblasts in the portal triad. Upon liver injury, myofibroblasts increased the expression of ITGA8. CONCLUSIONS: ITGA8 is a specific cell surface marker of MC-derived HSCs and perivascular mesenchymal cells in the developing liver. Our data suggest that ITGA8+ mesenchymal cells maintain the phenotype of hepatoblast in liver development. Developmental Dynamics 247:867-881, 2018. © 2018 Wiley Periodicals, Inc.
EVALuna2:35482

Longitudinal Cytokine Profiling Identifies GRO-alpha and EGF as Potential Biomarkers of Disease Progression in Essential Thrombocythemia - Obro, Nina F.; Grinfeld, Jacob; Belmonte, Miriam; Irvine, Melissa; Shepherd, Mairi S.; Rao, Tata Nageswara; Karow, Axel; Riedel, Lisa M.; Harris, Oliva B.; Baxter, E. Joanna; Nangalia, Jyoti; Godfrey, Anna; et al. (HemaSphere, 2020)
Myeloproliferative neoplasms (MPNs) are characterized by deregulation of mature blood cell production and increased risk of myelofibrosis (MF) and leukemic transformation. Numerous driver mutations have been identified but substantial disease heterogeneity remains unexplained, implying the involvement of additional as yet unidentified factors. The inflammatory microenvironment has recently attracted attention as a crucial factor in MPN biology, in particular whether inflammatory cytokines and chemokines contribute to disease establishment or progression. Here we present a large-scale study of serum cytokine profiles in more than 400 MPN patients and identify an essential thrombocythemia (ET)-specific inflammatory cytokine signature consisting of Eotaxin, GRO-alpha and EGF. Levels of 2 of these markers (GRO-alpha and EGF) in ET patients were associated with disease transformation in initial sample collection (GRO-alpha) or longitudinal sampling (EGF). In ET patients with extensive genomic profiling data (n=183) cytokine levels added significant prognostic value for predicting transformation from ET to MF. Furthermore, CD56(+)CD14(+) proinflammatory monocytes were identified as a novel source of increased GRO-alpha levels. These data implicate the immune cell microenvironment as a significant player in ET disease evolution and illustrate the utility of cytokines as potential biomarkers for reaching beyond genomic classification for disease stratification and monitoring.
CRIS-Team WoS Importer:2020-07-24

Malformationen des Zentralnervensystems: Seltene Ursachen eines organischen Wachstumshormonmangels bei Kindern - Dörr, Helmuth-Günther; Bettendorf, M.; Binder, G.; Hauffa, B.; Mohnike, K.; Mueller, H. L.; Reinehr, T.; Stalla, G. K.; Woelfle, J. (Padiatrie und Padologie, 2020)
Background Growth hormone (GH) deficiency is a rare endocrine disease. Diagnosis using laboratory investigations must be followed by contrast agent-enhanced magnetic resonance imaging of the central nervous system (CNS). Objective Overview of rare CNS malformations associated with GH deficiency in children and adolescents. Material and methods This article was prepared based on lectures held within the framework of a workshop of pediatric endocrinologists in Frankfurt/Main in March 2017. During script preparation, the authors came to a consensus regarding the key statements in the present publication. Results Malformations of the CNS are extremely rare. Among these malformations, pituitary hypoplasia has been most frequently described, followed by the empty sella syndrome and the pituitary stalk interruption syndrome. Ectopic neurohypophysis has been reported in patients with isolated GH deficiency. Septum pellucidum agenesia, corpus callosum defects, ectopic pituitary gland and optic nerve hypoplasia have been found in patients with septo-optic dysplasia. Pharmacological tests of GH secretion revealed markedly lower maximum GH concentrations in patients with CNS anomalies. As a rule, patients with combined CNS anomalies show better response to GH treatment than patients with only a single anomaly. Conclusion The availability of data on CNS malformations in children with GH deficiency is unsatisfactory. The data from patients under GH treatment should continue to be documented and analyzed on a systematic basis.
CRIS-Team WoS Importer:2020-05-15

Medizinische Betreuung von jungen Frauen mit Ullrich-Turner-Syndrom in Deutschland - Dörr, Helmuth-Günther; Bettendorf, Markus; Binder, Gerhard; Braemswig, Juergen; Hauffa, Berthold P.; Holterhus, Paul-Martin; Mohnike, Klaus; Schmidt, Heinrich; Stalla, Guenter K.; Wabitsch, Martin; Woelfle, Joachim (Deutsche Medizinische Wochenschrift, 2020)
BACKGROUND: Many recommendations for medical care for women with Turner syndrome (TS) have been published in the past. There are no studies that analyse the care situation of the women in Germany until now. METHODS: The study was performed in 2015 based on a questionnaire that was completed by TS women (aged ≥ 18 years; median: 25 years). The questionnaire was devised by a French team and used with their permission. All women had received growth hormone treatment during childhood. The women were identified and addressed in writing through eleven cooperating centers and the support group. In all, 130 questionnaires were evaluated. RESULTS: 79 of the 130 women (61 %) stated that they had health problems. 38 % of the women were under medical care by only one physician and 42 % by two physicians. The gynecologist was mentioned most often (by 80.3 %), followed by the family physician (53.8 %). ENT was mentioned as a problem system by 35 %, but only 3 % of the women attended an ENT physician. The question as to whether at least one of the following examinations (measurements of blood pressure, blood sugar, blood fats, liver function and/or thyroid hormones, echocardiographic and/or audiogram examination) had been performed during a period of 4 years was answered as follows: blood pressure (85 %), blood sugar (47 %), blood fats (41 %), liver function (46 %), thyroid hormones (44 %), echocardiography (57 %) and audiogram (35 %). A comprehensive examination was performed in 9.8 % of the women. 103 women (80.5 %) received sexual hormone replacement therapy. 76 women were on further drugs; thyroid hormones (44 %) and antihypertensive drugs (11 %) were stated most often. CONCLUSIONS: This is the first study which analyses the current situation of medical care of TS women in Germany. Our data show that medical care of young adult TS women is not optimal. The study cannot clarify the reasons. Due to the numerous and different comorbidities, the medical care of TS women is complex and should therefore be provided multidisciplinarily by different specialists under the direction of one physician.
CRIS-Team Scopus Importer:2020-03-13

Postnatal serum creatinine is elevated in preterm infants with PPROM-induced anhydramnios - Bruns, Nora; Stähling, Ann Christin; Greve, Sandra; Weiss, Christel; Köninger, Angela; Felderhoff-Müser, Ursula; Müller, Hanna (Pediatrics and Neonatology, 2020)
Background: The reason for increased serum creatinine levels in preterm infants often remains unclear. We aimed to determine whether postnatal serum creatinine in preterm infants correlates with intake of amniotic fluid, represented by the amount of amniotic fluid after preterm premature rupture of membranes (PPROM). Methods: 74 preterm infants with PPROM > 48 h duration were retrospectively studied. Postnatal creatinine concentration was determined at day 2–5, 10–17 and 26–33 of life and compared between infants with normal intrauterine amniotic volumes, oligohydramnios and anhydramnios. Results: Mean gestational age of included patients was 29.7 weeks (range: 24.0–36.1 weeks) and mean birth weight was 1452 g (range: 560–2940 g). Serum creatinine concentration was similar at day 2–5 and day 10–17 of life between the three groups. We observed a significant decrease in creatinine concentration from day 2–5 to day 26–33 in infants with normal amniotic fluid volume and oligohydramnios (p = 0.0001 and p = 0.0071, respectively), but not in anhydramnios. On day 26–33 of life, infants with anhydramnios showed significantly higher creatinine levels compared to infants with normal amniotic fluid volume and oligohydramnios (p = 0.0211). Conclusion: Postnatal serum creatinine of preterm infants at day 26–33 of life is elevated in infants with PPROM-induced anhydramnios, but not in oligohydramnios.
CRIS-Team Scopus Importer:2020-04-17
Keywords: amniotic fluid; anhydramnios; preterm infant; preterm premature rupture of membranes; serum creatinine

Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL - Babor, Florian; Peters, Christina; Manser, Angela R.; Glogova, Evgenia; Sauer, Martin; Pötschger, Ulrike; Ahlmann, Martina; Cario, Gunnar; Feuchtinger, Tobias; Gruhn, Bernd; Güngör, Tayfun; Horn, Peter A.; et al. (Bone Marrow Transplantation, 2019)
Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.
CRIS-Team Scopus Importer:2019-05-28

Prospective Clinical Phase II Results on Treosulfan-Based Conditioning Treatment of 70 Paediatric Patients with Haematological Malignancies - Kalwak, Krzysztof; Bader, Peter; Styczynski, Jan; Gruhn, Bernd; Patrick, Katharine; Sedlacek, Petr; Stachel, Daniel; Sykora, Karl-Walter; Corbacioglu, Selim; Drabko, Katarzyna; Fagioli, Franca; Greil, Johann; et al. (BLOOD, 2018)
CRIS-Team WoS Importer:2019-02-27

Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients - Grebe, Sören Jendrik; Malzahn, Uwe; Donhauser, Julian; Liu, Dan; Wanner, Christoph; Krane, Vera; Hammer, Fabian (Cardiovascular Ultrasound, 2020)
BACKGROUND: Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients. METHODS: TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR. RESULTS: LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34-0.62); Th: r = 0.44 (0.32-0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean ∆LVMI (ASE-CMR): 19.5 ± 19.48 g/m2, p < 0.001; mean ∆LVMI (Th-CMR): 15.9 ± 15.89 g/m2, p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in ∆LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737-0.901) and 0.808 (0.723-0.892) for Th and ASE, respectively). CONCLUSIONS: The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients. TRIAL REGISTRATION: The data was derived from the following clinical trial: NCT01691053 , registered on 19 September 2012 before enrollment of the first participant.
CRIS-Team Scopus Importer:2020-09-25
Keywords: ASE formula; Echocardiography; Hemodialysis; Left ventricular hypertrophy; Left ventricular mass index; Teichholz formula

Reduced inflammatory activity of RAW 264.7 macrophages on titania nanotube modified Ti surface - Neacsu, Patricia; Mazare, Anca Valentina; Cimpean, Anisoara; Park, Jung Hyun; Costache, Marieta; Schmuki, Patrik; Demetrescu, Ioana (International Journal of Biochemistry & Cell Biology, 2014)
Macrophages play a pivotal role in the hosts response to biomaterials being considered as an essential cell type during both optimal tissue-implant integration and pathologic process of implant failure. Hence, understanding of their cellular activity on biomaterials is important for improving evaluation and design of biomaterials for biomedical applications. In the present study, we have comparatively investigated the interactions of titania nanotubes (78 nm diameter) and commercial pure Ti with RAW 264.7 macrophages in both standard and pro-inflammatory (stimulation with lipopolysaccharide, LPS) culture conditions. In vitro tests showed that TiO2 nanotubes exhibited significantly decreased inflammatory activity of macrophages with respect to cytokine and chemokine gene expression/protein secretion, induction of foreign body giant cells (FBGCs) and nitric oxide (NO) release thereby mitigating the inflammatory response induced by LPS as compared to flat Ti surface. Therefore, our results suggest a novel role of TiO2 nanotubes in modulating macrophage response in biomaterial-associated bacterial infections. Overall, the current study provides new insight into how TiO2 nanotubes can be involved in macrophage activation and supports the great promise of such surface modifications for biomedical applications.
EVALuna2:18899

Relationship between brain function (aEEG) and brain structure (MRI) and their predictive value for neurodevelopmental outcome of preterm infants - Huening, Britta; Storbeck, Tobias; Bruns, Nora; Dransfeld, Frauke; Hobrecht, Julia; Karpienski, Julia; Sirin, Selma; Schweiger, Bernd; Weiss, Christel; Felderhoff-Mueser, Ursula; Mueller, Hanna (European Journal of Pediatrics, 2018)
To improve the prediction of neurodevelopmental outcome in very preterm infants, this study used the combination of amplitude-integrated electroencephalography (aEEG) within the first 72 h of life and cranial magnetic resonance imaging (MRI) at term equivalent age. A single-center cohort of 38 infants born before 32 weeks of gestation was subjected to both investigations. Structural measurements were performed on MRI. Multiple regression analysis was used to identify independent factors including functional and structural brain measurements associated with outcome at a corrected age of 24 months. aEEG parameters significantly correlated with MRI measurements. Reduced deep gray matter volume was associated with low Burdjalov Score on day 3 (p < 0.0001) and day 1-3 (p = 0.0012). The biparietal width and the transcerebellar diameter were related to Burdjalov Score on day 1 (p = 0.0111; p = 0.0002). The final multiple regression analysis revealed independent predictors of neurodevelopmental outcome: intraventricular hemorrhage (p = 0.0060) and interhemispheric distance (p = 0.0052) for mental developmental index; Burdjalov Score day 1 (p = 0.0201) and interhemispheric distance (p = 0.0142) for psychomotor developmental index. CONCLUSION: Functional aEEG parameters were associated with altered brain maturation on MRI. The combination of aEEG and MRI contributes to the prediction of outcome at 24 months. What is Known: • Prematurity remains a risk factor for impaired neurodevelopment. • aEEG is used to measure brain activity in preterm infants and cranial MRI is performed to identify structural gray and white matter abnormalities with impact on neurodevelopmental outcome. What is New: • aEEG parameters observed within the first 72 h of life were associated with altered deep gray matter volumes, biparietal width, and transcerebellar diameter at term equivalent age. • The combination of aEEG and MRI contributes to the prediction of neurodevelopmental outcome at 2 years of corrected age in very preterm infants.
EVALuna2:35724

Renal Transplant Recipients Treated with Calcineurin-Inhibitors Lack Circulating Immature Transitional CD19+CD24hiCD38hi Regulatory B-Lymphocytes - Tebbe, Bastian; Wilde, Benjamin; Ye, Zeng; Wang, Junyu; Wang, Xinning; Jian, Fu; Dolff, Sebastian; Schedlowski, Manfred; Hoyer, Peter F.; Kribben, Andreas; Witzke, Oliver; Hoerning, Andre (PLoS ONE, 2016)
BACKGROUND: CD19+CD24hiCD38hi transitional immature B-lymphocytes have been demonstrated to play an important role in regulating the alloimmune response in transplant recipients. Here, we analyzed the effect of calcineurin inhibition on these peripherally circulating regulatory B-cells (Breg) in renal transplant recipients receiving cyclosporine A (CsA) or tacrolimus. METHODS: PBMCs from healthy subjects (HS) (n = 16) and renal transplant recipients (n = 46) were isolated. Flow cytometry was performed for CD19, CD24, CD38 and IL-10 either after isolation or after 72 hours of co-culture in presence of PMA/Ionomycin and TLR9-ligand in presence or absence of increasing concentrations of tacrolimus or CsA. RESULTS: The amount of CD19+ B-cells among lymphocytes was ∼9.1% in HS, ∼3.6% in CsA (n = 11, p<0.05) and ∼6.4% in TAC (n = 35, p<0.05) treated patients. Among B-cells, a distinct subset of Breg was found to be 4.7% in HS, 1.4% in tacrolimus treated patients and almost blunted in patients receiving CsA. Similarily, ∼4% of B-cells in HS and even fewer in CsA or tacrolimus treated patients produced IL-10 (0.5% and 1.5%, p<0.05) and this was confirmed both in non-transplanted CsA-treated healthy subjects and in in vitro co-culture experiments. Among 29 patients with <1% of Breg, 9 cases (31%) displayed an allograft rejection in contrast to only one case of rejection (6%) among 17 patients with >1%. CONCLUSION: Calcineurin inhibitors reduce number and IL-10 production of Bregs in the peripheral circulation of both renal transplant recipients and non-transplanted healthy subjects. CNI induced Breg reduction is not restricted to a solid organ transplant setting and is not mediated by co-medication with steroids or MPA. A low proportion of Breg cells is associated with an elevated frequency of allograft rejection events.
EVALuna2:33928

Severity of asthma symptoms, lung function and airway inflammation in the PreDicta cohort of preschool-age children with asthma - Roumpedaki, E.; Karantoumanis, D.; Xepapadaki, P.; Sintobin,; Bachert, C.; Lukkarinen, H.; Jartti, T.; Zimmermann, Theodor; Finotto, Susetta; Sobanska, Anna; Kowalski, M.; Papadopoulos, N. G. (2015)
EVALuna2:33298

The Development of Integrin Alpha-8 Deficient Lungs Shows Reduced and Altered Branching and a Correction of the Phenotype During Alveolarization - Cremona, Tiziana P.; Hartner, Andrea; Schittny, Johannes C. (Frontiers in Physiology, 2020)
Lung development involves epithelial-mesenchymal interactions and integrins represent one of the key elements. These extracellular matrix receptors form hetero-dimers of alpha and beta subunits. The integrin alpha 8 beta 1 is highly expressed in mouse tissues, including lung. It forms a cellular receptor for fibronectin, vitronectin, osteopontin, nephronectin, and tenascin-C. This study aims to investigate the role of the integrin alpha 8-subunit (alpha 8) during lung development. Wild type and alpha 8-deficient lungs were explanted at embryonic days 11.5/12.5. After 24-73 h in culture alpha 8-deficient lung explants displayed reduced growth, reduced branching, enlarged endbuds, altered branching patterns, and faster spontaneous contractions of the airways as compared to wild type. Postnatally, a stereological investigation revealed that lung volume, alveolar surface area, and the length of the free septal edge were significantly reduced in alpha 8-deficient lungs at postnatal days P4 and P7. An increased formation of new septa in alpha 8-deficient lungs rescued the phenotype. At day P90 alpha 8-deficient lungs were comparable to wild type. We conclude that alpha 8 beta 1 takes not only part in the control of branching, but also possesses a morphogenic effect on the pattern and size of the future airways. Furthermore, we conclude that the phenotype observed at day P4 is caused by reduced branching and is rescued by a pronounced formation of the new septa throughout alveolarization. More studies are needed to understand the mechanism responsible for the formation of new septa in the absence of alpha 8 beta 1 in order to be of potential therapeutic benefit for patients suffering from structural lung diseases.
CRIS-Team WoS Importer:2021-01-22

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis - Lehmberg, Kai; Albert, Michael H.; Beier, Rita; Beutel, Karin; Gruhn, Bernd; Kröger, Nicolaus; Meisel, Roland; Schulz, Ansgar; Stachel, Daniel; Woessmann, Wilhelm; Janka, Gritta; Müller, Ingo (Haematologica, 2014)
In hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis, high transplant-related mortality after busulfan-based myeloablative regimens has been observed. Conditioning regimens with reduced toxicity based on melphalan or treosulfan are promising alternatives. We retrospectively analyzed hematopoietic stem cell transplantations in 19 hemophagocytic lymphohistiocytosis patients after conditioning with fludarabine, treosulfan, alemtuzumab, with or without thiotepa. Overall and disease-free survivals were 100% (follow up 7-31 months). Two patients required second transplant (1 after haploidentical transplantation). In 6 patients, overall donor chimerism dropped below 75% and prompted donor lymphocyte infusions. Administration of donor lymphocytes or second transplantation were significantly more frequent after transplantation from a human leukocyte antigen mismatched (9/10) versus matched (10/10) donor (P=0.018). The toxicity profile was favorable, with one veno-occlusive disease, one grade 3 graft-versus-host disease after donor lymphocyte infusion, and 2 severe viral infections (1 influenza, 1 Epstein Barr virus). In conclusion, the treosulfan-based regimen in hemophagocytic lymphohistiocytosis is effective with low toxicity and gives excellent overall and disease-free survival rates. In the future, the incidence of mixed chimerism, particularly after human leukocyte antigen mismatched donor transplants, needs to be addressed.
EVALuna2:18905

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies - Kalwak, Krzysztof; Mielcarek, Monika; Patrick, Katharine; Styczynski, Jan; Bader, Peter; Corbacioglu, Selim; Burkhardt, Birgit; Sykora, Karl Walter; Drabko, Katarzyna; Gozdzik, Jolanta; Fagioli, Franca; Greil, Johann; et al. (Bone Marrow Transplantation, 2020)
Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m(2)/day (7.7%), 12 g/m(2)/day (35.4%), or 14 g/m(2)/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.
CRIS-Team WoS Importer:2020-04-07

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study - Langer, Thorsten; Clemens, Eva; Broer, Linda; Maier, Lara; Uitterlinden, André G.; de Vries, Andrica C.H.; van Grotel, Martine; Pluijm, Saskia F.M.; Binder, Harald; Mayer, Benjamin; von dem Knesebeck, Annika; Byrne, Julianne; et al. (European Journal of Cancer, 2020)
Background: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. Results: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. Conclusions: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Adverse drug reaction; Anti-neoplastic drugs; Cancer survivors; Childhood cancer; Cisplatin: carboplatin; Drug-induced ototoxicity; Genetic markers; Multicenter cohort study; Pharmacogenetics