Soluble ST2 regulation by rhinovirus and 25(OH)-vitamin D3 in the blood of asthmatic children - Haag, Patricia; Sharma, H.; Rauh, Manfred; Zimmermann, Theodor; Vuorinen, T.; Papadopoulos, N. G.; Weiss, S. T.; Finotto, Susetta (Clinical and Experimental Immunology, 2018)
Paediatric asthma exacerbations are often caused by rhinovirus (RV). Moreover, 25(OH)-vitamin D3 (VitD3) deficiency during infancy was found associated with asthma. Here, we investigated the innate immune responses to RV and their possible modulation by 25(OH)-VitD3 serum levels in a preschool cohort of children with and without asthma. The innate lymphoid cell type 2 (ILC2)-associated marker, ST2, was found up-regulated in the blood cells of asthmatic children with low serum levels of 25(OH)-VitD3 in the absence of RV in their airways. Furthermore, in blood cells from control and asthmatic children with RV in their airways, soluble (s) ST2 (sST2) protein was found reduced. Asthmatic children with low 25(OH)-VitD3 in serum and with RV in vivo in their airways at the time of the analysis had the lowest sST2 protein levels in the peripheral blood compared to control children without RV and high levels of 25(OH)-VitD3. Amphiregulin (AREG), another ILC2-associated marker, was found induced in the control children with RV in their airways and low serum levels of 25(OH)-VitD3. In conclusion, the anti-inflammatory soluble form of ST2, also known as sST2, in serum correlated directly with interleukin (IL)-33 in the airways of asthmatic children. Furthermore, RV colonization in the airways and low serum levels of 25(OH)-VitD3 were found to be associated with down-regulation of sST2 in serum in paediatric asthma. These data indicate a counter-regulatory role of 25(OH)-VitD3 on RV-induced down-regulation of serum sST2 in paediatric asthma, which is relevant for the therapy of this disease.
EVALuna2:35820

Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition - Kapp, Friedrich G.; Bazgir, Farhad; Mahammadzade, Nagi; Mehrabipour, Mehrnaz; Vassella, Erik; Bernhard, Sarah M.; Döring, Yvonne; Holm, Annegret; Karow, Axel; Seebauer, Caroline; Platz Batista da Silva, Natascha; Wohlgemuth, Walter A.; et al. (Angiogenesis, 2024)
Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.
CRIS-Team Scopus Importer:2024-07-12
Keywords: Arteriovenous malformation; RAS-MAPK pathway; RIT1; Trametinib; Vascular anomalies; Vascular malformation

Somatic variant profiling in chronic phase pediatric chronic myeloid leukemia. - Behrens, Yvonne Lisa; Gaschler, Laura; Nienhold, Ronny; Reinkens, Thea; Schirmer, Elke; Knöβ, Sabine; Strasser, Renate; Sembill, Stephanie; Wotschofsky, Zofia; Suttorp, Meinolf; Krumbholz, Manuela; Schlegelberger, Brigitte; et al. (Haematologica, 2024)
EVALuna2:546999

Sonographic and Doppler Sonographic Diagnosis of Necrotizing Enterocolitis in Preterm Infants and Newborns - Deeg, Karl Heinz (Ultraschall in der Medizin, 2019)
Necrotizing enterocolitis (NEC) occurs primarily in immature preterm infants with low birth weight. It has a prevalence of 7-11% with a poor prognosis and a mortality rate of 20-40%. Plain abdominal radiography is still considered the diagnostic method of first choice even though ultrasound can visualize significantly more findings suspicious for NEC. Such as thickened bowel walls, dilated fluid-filled bowel loops, and gas bubbles in the intestinal wall, portal vein. Moreover, it is possible to assess intestinal peristalsis, to differentiate between intraluminal and extraluminal fluid and to assess the location of fluid accumulations and their internal echo pattern. In addition, free intraabdominal gas can be visualized on ultrasound. Increased flow rates in the mesenteric arteries and decreased flow in the portal vein can be detected on Doppler ultrasound in NEC. Color-coded Doppler ultrasound can be used to differentiate between bowel loops with increased and decreased perfusion and thus at risk for perforation. Ultrasound is therefore superior to conventional radiography in many regards and should replace it as the diagnostic method of first choice not least because of its noninvasive nature.
CRIS-Team Scopus Importer:2019-06-25

Sonographic Diagnosis of Neonatal Hypoxic Ischemic Brain Lesions-Part III: Lesions of the Corpus Callosum - Deeg, Karl Heinz (Ultraschall in der Medizin, 2021)
CRIS-Team Scopus Importer:2021-06-25

Sonographic Diagnosis of Neonatal Hypoxic-Ischemic Encephalopathy Part I: Lesions of Deep Nuclear Structures - Basal Ganglia and Thalamus - Deeg, Karl-Heinz (Ultraschall in der Medizin, 2020)
CRIS-Team WoS Importer:2020-11-27

Sonographic Diagnosis of Neonatal Hypoxic-Ischemic Encephalopathy with High-Resolution Sonography-Part II: Cortical and Subcortical Lesions - Deeg, Karl Heinz (Ultraschall in der Medizin, 2021)
CRIS-Team Scopus Importer:2021-06-25
Keywords: cortical and subcortical lesions; high-resolution sonography; hypoxic-ischemic encephalopathy

Sonographic differential diagnosis of duplex kidneys - Deeg, Karl-Heinz (Ultraschall in der Medizin, 2022)
Duplex kidneys have two renal pelvises and two ureters, which can join on the way to the urinary bladder but can also enter the bladder separately. A distinction must be made between normal and pathological duplex kidneys. In normal duplex kidneys, both renal pelvises are normal in width, and the upper and lower poles are approximately the same size. Furthermore, ureters are not dilated, and the upper and lower poles of the kidneys are not cystically altered. In contrast, pathological duplex kidneys, occurring in about 50 % of cases, are characterized by dilation of one or both renal pelvises. Additionally, one or both ureters may be dilated. Megaureters may be obstructive or refluxive. If a megaureter is present, a ureterocele must be ruled out, as well as an ectopically opening ureter. A pathological duplex kidney must always be assumed if one pole of the kidney is hypoplastic. Hypoplasia of the upper renal pole is often associated with an obstructive megaureter. Vesicoureteral reflux into the lower pyelon is common in hypoplasia of the lower pole. In the presence of vesicoureteral reflux, the associated (lower) pyelon is dilated when the bladder is full or during micturition. In addition, there is a dilated ureter. On the other hand, the pyelon can have a normal width when the bladder is empty. In rare cases, one pole may be cystically altered in pathological duplex kidneys. In this instance, segmental multicystic dysplastic duplex kidney must be differentiated from segmental multicystic nephroma.
CRIS-Team WoS Importer:2022-05-13

Sparing the hippocampus and the hypothalamic- pituitary region during whole brain radiotherapy: a volumetric modulated arc therapy planning study - Mehta, P.; Janssen, S.; Fahlbusch, Fabian; Schmid, S. M.; Gebauer, J.; Cremers, F.; Ziemann, C.; Tartz, M.; Rades, D. (BMC Cancer, 2020)
BACKGROUND: Feasibility testing of a simultaneous sparing approach of hippocampus, hypothalamus and pituitary gland in patients undergoing whole-brain radiotherapy (WBRT) with and without a concomitant boost to metastatic sites. INTRODUCTION: Cognitive impairment and hormonal dysfunction are common side effects of cranial radiotherapy. A reduced dose application to the patho-physiologically involved functional brain areas, i.e. hippocampus, hypothalamus and pituitary gland, could reduce these common side effects. While hippocampal sparing is already a common practice to improve cognitive outcome, technical experience of additional combined sparing of the hypothalamus/pituitary gland (HT-P) is insufficient. METHODS: Twenty patients were included in the planning study. In 11 patients, a total dose of 36 Gy of WBRT (2 Gy per fraction) plus a simultaneous integrated boost (SIB) of 9 Gy (0.5 Gy per fraction, total dose: 45 Gy) to the brain metastases was applied. In 9 patients, prophylactic cranial irradiation (PCI) was simulated with a total dose of 30 Gy (2 Gy per fraction). In both patient cohorts, a sparing approach of the hippocampus and the HT-P area was simulated during WBRT. For all treatment plans, volumetric modulated arc therapy (VMAT) was used. Quality assurance included assessment of homogeneity, conformality and target coverage. RESULTS: The mean dose to the hippocampus and HT-P region was limited to less than 50% of the prescribed dose to the planning target volume (PTV) in all treatment plans. Dose homogeneity (HI) of the target volume was satisfying (median HI = 0.16 for WBRT+SIB and 0.1 for PCI) and target coverage (conformation number, CN) was not compromised (median CN = 0.82 for SIB and 0.86 for PCI). CONCLUSION: Simultaneous dose reduction to the hippocampus and the HT-P area did not compromise the PTV coverage in patients undergoing WBRT+SIB or PCI using VMAT. While the feasibility of the presented approach is promising, prospective neurologic, endocrine outcome and safety studies are required.
CRIS-Team Scopus Importer:2020-07-17
Keywords: Brain metastases; Hippocampus sparing; Hypothalamus; Pituitary gland; Volumetric modulated arc therapy (VMAT); Whole brain radiotherapy (WBRT)

Species differences of 11beta-hydroxysteroid dehydrogenase type 2 function in human and rat term placenta determined via LC-MS/MS - Heussner, Kirsten; Rübner, Matthias; Hübner, Hanna; Rascher, Wolfgang; Menendez-Castro, Carlos; Hartner, Andrea; Fahlbusch, Fabian B.; Rauh, Manfred (Placenta, 2016)
INTRODUCTION: Glucocorticoid-induced fetal programming has been associated with negative metabolic and cardiovascular sequelae in the adult. The placental enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) shields the fetus from maternal glucocorticoid excess by catalyzing the conversion of these hormones into biologically inactive derivatives. In vivo experiments addressing placental barrier function are mostly conducted in rodents. Therefore we set out to characterize species-specific differences of rat and human placental 11β-HSD2 steroid turnover, introducing Liquid Chromatography Tandem Mass-Spectrometry (LC-MS/MS) as a tool for rat tissue analysis. MATERIALS AND METHODS: Using LC-MS/MS we determined corticotropin-releasing hormone (CRH), cortisol (F), cortisone (E), corticosterone (B) and 11-dehydrocorticosterone (A) in human and rat placenta at term and measured the enzymatic 11β-HSD glucocorticoid conversion-rates in placental microsomes of both species. In parallel, further glucocorticoid derivatives and sex steroids were determined in the same placental samples. RESULTS: In contrast to the human placenta, we did not detect CRH in the rat placenta. While cortisol (F) and cortisone (E) were exclusively present in human term placenta (E/F-ratio >1), rat placenta showed significant levels of corticosterone (B) and 11-dehydrocorticosterone (A), with an A/B-ratio <1. In line with these species-specific findings, human placenta showed a prominent 11β-HSD2 activity, while in rat placenta higher 11β-HSD1 glucocorticoid turnover rates were determined. DISCUSSION: Placental steroid metabolism of human and rat shows relevant species-specific differences, especially regarding the barrier function of 11β-HSD2 at term. The exclusive expression of CRH in the human placenta further points to relevant differences in the regulation of parturition in rats. Consideration of these findings is warranted when transferring results from rodent placental glucocorticoid metabolism into humans.
EVALuna2:33462

Specific Morphology of Coronary Artery Aneurysms in Mainly White Patients With Kawasaki Disease: Initial Data From the Cardiac Catheterization in Kawasaki Disease Registry - Weisser, Julia; Arnold, Leonie; Wällisch, Wolfgang; Quandt, Daniel; Opgen-Rhein, Bernd; Riede, Frank Thomas; Gräfe, Florentine; Michel, Jörg; Arnold, Raoul; Schneider, Heike; Tanase, Daniel; Herberg, Ulrike; et al. (Journal of the American Heart Association, 2024)
BACKGROUND: Patients with Kawasaki disease (KD) with coronary artery involvement require long-term cardiac care. Although respective evidence-based recommendations are missing, cardiac catheterization is still considered the gold standard for diagnosing detailed coronary pathology. Therefore, to better understand coronary artery pathology development, we conducted a survey to document and evaluate cardiac catheterization data in a European population. METHODS AND RESULTS: We retrospectively analyzed cardiac catheterization data from KD children from the year 2010 until April 2023. This registry covers basic acute-phase clinical data, and more importantly, detailed information on morphology, distribution, and the development of coronary artery pathologies. A total of 164 mainly White patients (65% boys) were included. A relevant number of patients had no coronary artery aneurysm (CAA) at the cardiac catheterization, indicating that distal CAAs were almost exclusively detected alongside proximal CAAs. Patients with multiple CAAs revealed a significant positive correlation between the number of CAAs and their dimensions in diameter and in length. Location of the CAA within the coronary artery, age at onset of KD, or natal sex did not significantly influence CAA diameters, but CAAs were longer in older children and in boys. CONCLUSIONS: That distal CAAs were only present together with proximal ones will hopefully reduce diagnostic CCs in patients with KD without echocardiographically detected proximal CAAs. Furthermore, this study gives valuable insights into dimensional specifics of CAAs in patients with KD. As an ongoing registry, future analyses will further explore long-term outcomes and performed treatments, helping to refine clinical long-term strategies for patients with KD. REGISTRATION: URL: https://​drks.​de/​; Unique Identifier: DRKS00031022.
CRIS-Team Scopus Importer:2024-12-06
Keywords: cardiac catheterization; coronary artery pathology; Kawasaki disease; long-term cardiac care; White

Spectrum, Applicability and Diagnostic Capacity of Contrast-Enhanced Ultrasound in Pediatric Patients and Young Adults after Intravenous Application - A Retrospective Trial - Knieling, Ferdinand; Strobel, Deike; Rompel, O.; Zapke, M.; Menendez-Castro, C.; Woelfel, M.; Schulz, J.; Rascher, Wolfgang; Juengert, J. (Ultraschall in der Medizin, 2016)
Purpose: To investigate the spectrum, applicability and diagnostic capacity of intravenous contrast-enhanced ultrasound imaging (CEUS) in a pediatric population. Materials and Methods: From 08/2005 to 11/2015, n = 40 pediatric patients and young adults from 0 - 26 years (Ø 11.4 ± 7.5) and 3.0 - 85.3 kg (Ø 40.8 ± 25.6) with n = 55 investigations received n = 79 IV applications of ultrasound contrast agent (UCA). UCA dose and side effects were documented. Scanned organs were the liver (n = 42), spleen (n = 9), kidney (n = 3), and testis (n = 1). Histology, surgery or reference imaging was compared to CEUS and clinical follow-up. Results: The UCA dose < 20 kg was 0.4 ± 0.3 ml, (0.05 ± 0.02 ml/kg) and > 20 kg was 1.0 ± 0.4 ml (p< 0.0001) (0.02 ± 0.01 ml/kg, p< 0.0001). Adverse effects occurred in 2/79 applications (2.5 %). Agreement CEUS/gold standard resulted in 32/34 investigations. For liver diagnostics (gold standard: MRI, CT, histology, serology), n = 11 malignant and n = 15 benign focal liver lesions were included. The specificity was 100 % (95 % CI: 0.77 - 1.00), the sensitivity was 82 % (95 % CI: 0.48 - 0.98), the positive predictive value was 100 % (95 % CI: 0.69 - 1.00) and the negative predictive value was 88 % (95 % CI: 0.62 - 0.98, p< 0.0001). In n = 2 reference imaging misdiagnosed and CEUS was in accordance with clinical follow-up. All splenic/renal lesions were diagnosed correctly. In n = 1 an insufficient testicular perfusion was ruled out. The observation time was 30.4 ± 30.5 months. Conclusion: CEUS is a well-tolerated and diagnostically equivalent modality in pediatric care, providing fundamental advantages compared to currently approved imaging modalities for these age groups.
EVALuna2:14718

Spontaneous postnatal growth is reduced in children with CHARGE syndrome - Dörr, Helmuth-Günther; Madeja, Julia; Junghans, Claudia (Acta Paediatrica, 2015)
There is a scarcity of data on postnatal growth in children with CHARGE syndrome, a genetic disorder. This study analysed spontaneous growth and weight in German children with CHARGE from birth to the age of 6 years.This was a retrospective analysis of 19 children, nine females and 10 males, using data from child health records. Standard deviation scores (SDS) were calculated based on Swiss references.The median birthweight was 2950 g (-0.78 SDS), and the birth length was 49 cm (-0.5 SDS). There was a significant loss of median body length, at around 4 weeks of age from -0.5 to -2.3 SDS (p < 0.05). At 1 year, the median length was -2.6 SDS and it remained low until 5 years of age when the lowest value was found to be -2.8 SDS. There was a significant increase in median body mass index (BMI) from -1.15 SDS at 1 year to -0.15 SDS at 5 years (p < 0.01).Children with CHARGE syndrome displayed almost normal length and weight data at birth, with just one of the 19 infants having below average length for gestational age. However, postnatal growth was retarded during infancy and childhood, and the increase in BMI-SDS did not correlate with growth.
EVALuna2:18914

Sports despite masks: no negative effects of FFP2 face masks on cardiopulmonary exercise capacity in children - Weigelt, Annika; Schöffl, Isabelle; Rottermann, Kathrin; Wällisch, Wolfgang; Müller, Susanna; Dittrich, Sven; Hübner, Matthias (European Journal of Pediatrics, 2023)
Face masks were recognized as one of the most effective ways to prevent the spread of the COVID-19 virus in adults. These benefits were extended to children and adolescents. However, the fear of negative consequences from wearing a face mask during physical exercise led to cancellations of physical education lessons. This further decreased the amount of physical activity available to children and adolescents during the pandemic. However, there is little published data on the potential adverse effects of wearing the most effective and partially mandatory FFP2/N95 face masks during PE or physical activity (PA) in this age. Even though the pandemic has been declared as passed by the WHO, the rise of a new pandemic and thus the use of face masks for limiting its spread is inevitable, so we need to be better prepared for alternative options to lockdown and limitation of PA in such a scenario. Twenty healthy children aged 8–10 years performed two identical cardiopulmonary exercise tests as an incremental step test on a treadmill within an interval of 2 weeks, one time without wearing a protective mask and one time wearing an FFP2 mask. The cardiopulmonary exercise parameter and especially the end-expiratory gas exchange for oxygen and carbon dioxide (petO2 and petCO2) were documented for each step, at rest and 1 min after reaching physical exhaustion. Twelve boys (mean age 8.5 ± 1.4 years) and 8 girls (mean age 8.8 ± 1.4 years) showed no adverse events until maximal exertion. The mean parameters measured at peak exercise did not differ significantly between both examinations (mean peak VO2 = 42.7 ± 9.5 vs 47.8 ± 12.9 ml/min/kg, p = 0.097, mean O2pulse 7.84 ± 1.9 ml/min vs. 6.89 ± 1.8, p = 0.064, mean VE/VCO2slope 33.4 ± 5.9 vs. 34.0 ± 5.3, p = 0.689). The only significant difference was the respiratory exchange rate (RER, 1.01 ± 0.08 vs 0.95 ± 0.08, p = 0.004). The measured respiratory gases (end-tidal O2 and CO2) decreased and respectively increased significantly in almost every step when wearing an FFP2 mask. However, these levels were well below hypercapnia and above hypoxia. Conclusion: In this study, no significant differences in the cardiorespiratory function at peak exercise could be discerned when wearing an FFP2/N95 face mask. While the end-tidal values for CO2 increased significantly and the end-tidal values for O2 decreased significantly, these values did never reach levels of hypercapnia or hypoxia. Furthermore, the children terminated the exercise at a lower RER and heart rate (HR) suggesting a subconscious awareness of the higher strain. Since the detrimental effects of limiting sports during the pandemic are well documented, stopping PE lessons altogether because of the minor physiological effects of wearing these masks instead of simply stopping pushing children to perform at their best seems premature and should be reconsidered in the future. What is Known: • Wearing a face mask has an influence on psychological, social, and physiological functions in adults. • Because of the observed effects of wearing face masks in adults, physical activity in children was limited during the pandemic. What is New: • Wearing an FFP2/N95 mask during physical activity did not lead to hypercapnia or hypoxia in children in this study. • Even though end-tidal CO2 values were significantly higher and end-tidal O2 values significantly lower when wearing an FFP2/N95 face mask, no pathological values were reached.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Coronavirus; COVID-19; End-tidal CO; End-tidal O; Oxygen saturation; Treadmill testing; VO

Sports-Medical Supervision of Competition Climbers and Climbing Competitions - Schöffl, Volker; Schöffl, Isabelle (Springer International Publishing, 2022)
Conducting yearly team examinations and serving as a medical officer at climbing competitions are central elements in taking care of competitive climbers. The team examination plays an important role in early injury detection and is an opportunity to establish a trusting relationship so that the athletes approach the team physician openly with questions or concerns. It is based on the recommendations of the national Olympic Committees and the Medical Commission of the IFSC, which recommend performing a sports-medical and an orthopedic exam, a resting ECG, a spiroergometry with stress ECG, a cardiac echography, a laboratory analysis, and body fat measurement. In climbers, we also always perform an ultrasound examination of the hand and fingers. During climbing competitions, the most frequent treatments are the care of acute traumata need and many superficial skin bleeds. Nevertheless, the occasional internal medical condition also occurs. A central part in being an effective medical supervisor in competitions is organization and coordination of the whole medical team and the communication with athletes, judges, and other officials—it is always teamwork. To achieve this, specific insight into climbing medicine is essential.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Anti-doping; Cardiac echography; Competition; Spiroergometry; Team examination

Stammzellen aus Nabelschnurblut - ein besonderes Gut: Informationen für eine fachärztliche Beratung der Schwangeren - Goecke, Tamme W.; Jud, Sebastian; Weisbach, Volker Günter; Bender, A. W.; Schneider, Holm (Geburtshilfe und Frauenheilkunde, 2010)
CRIS-Team Scopus Importer:2020-07-01

STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis - Heichler, Christina; Scheibe, Kristina; Schmied, Anabel; Geppert, Carol-Immanuel; Schmid, Benjamin; Wirtz, Stefan; Thoma, Oana Maria; Kramer, Viktoria; Waldner, Maximilian; Büttner, Christian; Farin, Henner; Pešić, Marina; et al. (Gut, 2019)
Objective: Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood. Design: We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI-) on STAT3 activation (IL-6 vs IL-11). Results: The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts. Conclusion: Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.
CRIS-Team Scopus Importer:2019-11-19
Keywords: colorectal cancer

Stem Cell Mobilization by Plerixafor Has an Affirmatory Effect on the Development of Transplant Vasculopathy in a Murine Aortic Allograft Model - Theil, F.; Kuckhahn, A.; Hörning, André; Ramsperger-Gleixner, Martina; Weyand, Michael; Heim, Christian (JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-05-20

Strategies for mitral valve disease in children: What, how and when - Cesnjevar, Robert; Cuomo, Michela; Purbojo, Ariawan; Dittrich, Sven (European Journal of Cardio-Thoracic Surgery, 2021)
CRIS-Team Scopus Importer:2021-09-03
Keywords: Congenital mitral valve disease; Mitral valve replacement; Small mitral annulus

Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury - Sieckmann, Tobias; Schley, Gunnar; Ögel, Neslihan; Kelterborn, Simon; Boivin, Felix J.; Fähling, Michael; Ashraf, Muhammad I.; Reichel, Martin; Vigolo, Emilia; Hartner, Andrea; Lichtenberger, Falk Bach; Breiderhoff, Tilman; et al. (Kidney International, 2023)
The polyamines spermidine and spermine and their common precursor molecule putrescine are involved in tissue injury and repair. Here, we test the hypothesis that impaired polyamine homeostasis contributes to various kidney pathologies in mice during experimental models of ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. We found a remarkably similar pattern in most kidney pathologies with reduced expression of enzymes involved in polyamine synthesis together with increased expression of polyamine degrading enzymes. Transcript levels of amine oxidase copper-containing 1 (Aoc1), an enzyme which catalyzes the breakdown of putrescine, were barely detectable by in situ mRNA hybridization in healthy kidneys. Aoc1 was highly expressed upon various experimental kidney injuries resulting in a significant reduction of kidney putrescine content. Kidney levels of spermine were also significantly reduced, whereas spermidine was increased in response to ischemia-reperfusion injury. Increased Aoc1 expression in injured kidneys was mainly accounted for by an Aoc1 isoform that harbors 22 additional amino acids at its N-terminus and shows increased secretion. Mice with germline deletion of Aoc1 and injured kidneys showed no decrease of kidney putrescine content; although they displayed no overt phenotype, they had fewer tubular casts upon ischemia-reperfusion injury. Hyperosmotic stress stimulated AOC1 expression at the transcriptional and post-transcription levels in metanephric explants and kidney cell lines. AOC1 expression was also significantly enhanced after kidney transplantation in humans. These data demonstrate that the kidneys respond to various forms of injury with down-regulation of polyamine synthesis and activation of the polyamine breakdown pathway. Thus, an imbalance in kidney polyamines may contribute to various etiologies of kidney injury.
CRIS-Team Scopus Importer:2023-05-26
Keywords: Aoc1; kidney injury; mRNA in situ hybridization; osmotic stress; polyamines; putrescine

Stroke in Duchenne Muscular Dystrophy: A Retrospective Longitudinal Study in 54 Patients - Winterholler, Martin; Hollaender, Christian; Kerling, Frank; Weber, Irina; Dittrich, Sven; Türk, Matthias; Schröder, Rolf (Stroke, 2016)
Duchenne muscular dystrophy (DMD) is the most frequent skeletal muscle myopathy. Nearly all patients develop cardiomyopathy in their second decade of life. The purpose of this study was to evaluate the frequency, cause, and outcome of stroke in a German cohort of patients with DMD.Retrospective analysis of medical records of 54 DMD patients, who lived in a regional facility for handicapped people (Wichernhaus Altdorf, Germany) between 1963 and 2013.Fifty-four DMD patients were followed up for 7.4 years on average. Mean age at admission and discharge from the long-term care facility or death were 11.4 and 18.8 years, respectively. Covering a total observation period of 400 patient-years, we identified 4 DMD patients with juvenile arterial ischemic strokes. Off-label systemic thrombolysis in 2 patients resulted in a nearly complete regression of stroke-related symptoms, but 1 patient died of septic pneumonia and cardiac failure 24 days after thrombolysis therapy. In the other 2 patients, who had their ischemic strokes in 1994 and 1998, severe infarction-related symptoms persisted, and 1 patient died 13 days later. DMD-associated cardiomyopathy without evidence of atrial fibrillation was the only risk factor for ischemic stroke in all patients.This study indicates an increased risk for ischemic strokes in DMD patients. Regular cardiological assessment of all DMD patients is mandatory to evaluate the individual risk profile for cardioembolic events and to adapt therapeutic strategies.
EVALuna2:7328

Strong hypoxia reduces leptin synthesis in purified primary human trophoblasts - Nuesken, E.; Herrmann, Y.; Wohlfarth, M.; Goecke, Tamme W.; Appel, S.; Schneider, Holm; Doetsch, J.; Nuesken, K. D. (Placenta, 2015)
Introduction Oxygen availability severely affects placental function. During placental hypoxia, stabilization of hypoxia inducible factors (HIFs) affects transcription, and leptin gene expression concomitantly increases in vivo and in vitro. However, a causal relationship is uncertain.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Hypoxia; Leptin/leptin receptor; Placenta; Trophoblast

Subcortical Lacerations, a Significant Sign of Shaken Baby Syndrome Diagnosis with High-Resolution Duplex Sonography - Deeg, Karl-Heinz (Ultraschall in der Medizin, 2022)
CRIS-Team WoS Importer:2022-05-27
Keywords: shaken infant syndrome; subcortical lacerations; high-resolution sonography

Successful eradication of newly acquired MRSA in six of seven patients with cystic fibrosis applying a short-term local and systemic antibiotic scheme - Kiefer, Alexander; Bogdan, Christian; Melichar, Volker O. (BMC Pulmonary Medicine, 2018)
BACKGROUND: In individuals with cystic fibrosis (CF), colonization with methicillin-resistant Staphylococcus aureus (MRSA) was reported to be associated with a deterioration of pulmonary disease as reflected by an accelerated decline in lung function. Thus, an early eradication of MRSA could be beneficial in these patients. Here, we report on an intensified MRSA eradication protocol. METHODS: Since 2012 a protocol for the eradication of newly acquired MRSA has been used in our CF Clinic, combining oral rifampicin and fusidic acid, inhaled vancomycin, nasal mupirocin, local antiseptic treatment and hygienic directives all of which are applied for only 7 days during an inpatient hospital stay. RESULTS: Since 2012 seven patients (3 male, 4 female; age range 4 to 30 years) newly acquired MRSA. In 6 of the 7 patients (86%) successful eradication of MRSA was achieved upon first treatment using the protocol described above. In one patient a second course of treatment was performed which, however, also failed to eliminate the colonizing MRSA. CONCLUSIONS: Our protocol led to an eradication rate of 86%. The impact of each individual component of the protocol remains to be determined.
EVALuna2:33304

Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines - Ruggieri, L.; Giannuzzi, V.; Baiardi, P.; Bonifazi, Fedele; Davies, E. H.; Giaquinto, C.; Bonifazi, D.; Felisi, M.; Chiron, Catherine; Pressler, R.; Rabe, H.; Whitaker, M. J.; et al. (European Journal of Pediatrics, 2015)
The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres.Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.
EVALuna2:18911

Surgical treatment of congenital heart defects in adulthood Special surgical and interdisciplinary challenge - Cesnjevar, Robert; Dittrich, Sven (Zeitschrift für Herz-, Thorax- und Gefäßchirurgie, 2019)
Successful treatment of congenital heart defects by pediatric cardiac surgeons and pediatric cardiologists is responsible for survival rates above 90% in the current era. Long-term survival into adulthood, even for newborns with complex cardiac conditions has become very common. It is estimated that there are around 250,000-350,000 patients in this relatively heterogeneous patient group in Germany, which nowadays exceeds the number of pediatric patients with congenital heart defects (approximately 120,000 patients). The constantly increasing number of grown-ups with congenital heart (GUCH) defects need to be classified according to the underlying cardiac disease and the individual treatment history. Systematic categorization helps to determine each patient's individual risk and treatment complexity. Non-corrected cardiac malformations, residual cardiac problems after correction or palliation and clinically relevant heart failure are the most important surgical treatment indications for adults with congenital heart defects.
CRIS-Team WoS Importer:2019-10-11

Surprising prenatal toxicity of epidermal lipoxygenase-3 - Vierling, F.; Dick, Angela; Wahlbuhl, Mandy; Krieg, P.; Henke, Christine; Ruebner, M.; Schneider, Holm (Placenta, 2014)
Metabolites of the epidermal lipoxygenase-3 (eLOX-3) are involved in various metabolic pathways. Most unexpectedly, intra-amniotic delivery of eLOX-3 to mice at gestational day 14.5, both via an adenoviral vector and as recombinant protein, resulted in fetal growth restriction and intrauterine death. Periodic acid-Schiff staining and RT-PCR analysis of placentae from fetuses exposed to eLOX-3 indicated a lack of glycogen trophoblasts in the junctional zone. Placenta-specific gene expression was altered. Thus, the observed prenatal toxicity of eLOX-3 could be due to a strong effect on placental development.
EVALuna2:17431

Surveillance of Acute SARS-CoV-2 Infections in Elementary Schools and Daycare Facilities in Bavaria, Germany (09/2020-03/2021) - Kern, Anna; Kuhlmann, Pia H.; Matl, Stefan; Ege, Markus; Maison, Nicole; Eckert, Jana; Von Both, Ulrich; Behrends, Uta; Anger, Melanie; Fruehwald, Michael C.; Gerstlauer, Michael; Wölfle, Joachim; et al. (Frontiers in Pediatrics, 2022)
IntroductionHere we report our results of a multi-center, open cohort study ("COVID-Kids-Bavaria") investigating the distribution of acute SARS-CoV-2 infections among children and staff in 99 daycare facilities and 48 elementary schools in Bavaria, Germany. Materials and MethodsOverall, 2,568 children (1,337 school children, 1,231 preschool children) and 1,288 adults (466 teachers, 822 daycare staff) consented to participate in the study and were randomly tested in three consecutive phases (September/October 2020, November/December 2020, March 2021). In total, 7,062 throat swabs were analyzed for SARS-CoV-2 by commercial RT-PCR kits. ResultsIn phase I, only one daycare worker tested positive. In phase II, SARS-CoV-2 was detected in three daycare workers, two preschool children, and seven school children. In phase III, no sample tested positive. This corresponds to a positive test rate of 0.05% in phase I, 0.4% in phase II and 0% in phase III. Correlation of a positive PCR test result with the local-7-day incidence values showed a strong association of a 7-day-incidence of more than 100/100,000 as compared to <100/100,000 (OR = 10.3 [1.5-438], p < 0.005). After phase III, antibody testing was offered to 713 study participants in elementary schools. A seroprevalence rate of 7.7% (students) and 4.5% (teachers) was determined. DiscussionDuring the initial waves of the SARS-CoV-2 pandemic, the risk of a positive SARS-CoV-2 result correlated positively with the local 7-day incidence. Hence, the occurrence of SARS-CoV-2 infections were reflected in schools and daycare facilities. An increased risk of SARS-CoV-2 transmission in the setting of daycare and elementary schooling was unlikely.
CRIS-Team WoS Importer:2022-08-05

Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation - Böhm, Svea; Wustrau, Katharina; Pachlopnik Schmid, Jana; Prader, Seraina; Ahlmann, Martina; Yacobovich, Joanne; Beier, Rita; Speckmann, Carsten; Behnisch, Wolfgang; Ifversen, Marianne; Jordan, Michael; Marsh, Rebecca; et al. (Blood, 2024)
Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
CRIS-Team Scopus Importer:2024-02-16

Sustained complete molecular remission after imatinib discontinuation in children with chronic myeloid leukemia - Moser, Olga; Krumbholz, Manuela; Thiede, Christian; Tauer, Josephine T.; Janz, Indra; Lauten, Melchior; Dilloo, Dagmar; Metzler, Markus; Suttorp, Meinolf (Pediatric Blood & Cancer, 2014)
Approximately 40% of adults with chronic myeloid leukemia (CML) in prolonged complete molecular response (CMR) remain in CMR after imatinib discontinuation. Corresponding information in children is lacking. Two children with CML in CMR for 48 and 19 months after imatinib discontinuation showed low-level fluctuating disease at RNA transcript and genomic DNA levels. Both patients were low risk according to adult criteria. Since adults with molecular relapse responded to re-introduction of imatinib, we postulated that treatment discontinuation in low risk children might be justified within clinical trials with close monitoring. This may help to minimize exposure to imatinib and its potential side effects.
EVALuna2:18892

Sustained Need for High-Dose Zinc Supplementation in Children With Acrodermatitis Enteropathica - Hammersen, Johanna; Has, Cristina; Galiano, Matthias; Lindner, Martin; Rossi, Rainer; Kohlhase, Juergen; Schneider, Holm (Clinical Pediatrics, 2018)
EVALuna2:34298

Sweating ability and genotype in individuals with X-linked hypohidrotic ectodermal dysplasia - Schneider, Holm; Hammersen, Johanna; Preisler-Adams, Sabine; Huttner, Kenneth; Rascher, Wolfgang; Bohring, Axel (Journal of Medical Genetics, 2011)
Background: X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common type of ectodermal dysplasia, is caused by EDA gene mutations. Reduced sweating contributes substantially to XLHED associated morbidity and mortality. To characterise the genotypeephenotype relationship, sweat gland function was assessed non-invasively in XLHED patients and healthy controls. Subjects and methods: In 36 genotyped XLHED patients and 29 control subjects aged 0e57 years, pilocarpine-induced sweat volume, palmar sweat pore density, and palmar skin conductance before and after stimulation were determined. Results: Among 31 XLHED males, 14 had neither detectable sweat pores nor inducible sweating, 10 showed a few sweat pores but absent sweating, and 7 produced reduced sweat volumes (1e11 ml) as compared with controls (38e93 ml). Two of the low sweating XLHED subjects had normal sweat pore counts. In all 5 heterozygous females, some sweat was detected, but generally less than in female controls. Basal and stimulated skin conductance readings were reduced in 23 of 24 non-sweating, but only in 3 of 12 low-sweating XLHED subjects. There was no correlation between sweat production and number of missing teeth. Conclusions: In contrast to prior reports on nongenotyped hypohidrotic ectodermal dysplasia populations, this study confirmed a consistent, quantifiable defect of sweat gland function in male XLHED subjects as a disease biomarker. Among 26 different EDA genotypes, specific mutations were shown to be consistently associated with anhidrosis, implying that systematic mapping of EDA mutations together with the analysis of objective clinical data may help to distinguish functionally crucial mutations from those allowing residual activity of the gene product.
CRIS-Team Scopus Importer:2020-07-01

Sweating ability of patients with p63-associated syndromes - Ferstl, Paul; Wohlfart, Sigrun; Schneider, Holm (European Journal of Pediatrics, 2018)
Sweating deficiency has been reported to represent a cardinal symptom of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, two rare p63-associated disorders. According to online resources, hypohidrosis may lead to most life-threatening complications in affected patients. Thus, counseling on the prevention of hyperthermia would be indispensable in case of such syndromes, although detailed information on this issue is missing in the literature. We investigated 14 individuals with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (age range 2-48 years) and 9 individuals with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome (0.5-60 years of age) by confocal laser scanning microscopy to determine their palmar sweat duct density and by quantification of pilocarpine-induced sweating. Genotype-phenotype correlations were assessed. In 12 of 23 patients (52%), a normal amount of sweat ducts was detected. These individuals (9 with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, 3 with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome) produced sufficient sweat volumes (≥ 20 μl) in response to pilocarpine. All other patients had clearly reduced sweating ability and fewer sweat glands, but no anhidrosis. Alteration of a specific proline residue (Pro590) of p63 was consistently linked to impaired perspiration.Conclusion: Hypohidrosis in p63-associated syndromes is less common and potentially less severe than previously thought and may be attributable to certain genotypes. What is Known: • Hypohidrosis which has been listed as a cardinal symptom of AEC and EEC syndromes may lead to life-threatening hyperthermia. What is New: • Patients with EEC and AEC syndromes often can sweat normally. • Hypohidrosis seems to be attributed to certain TP63 genotypes.
EVALuna2:35484

Synergistic lethality in chronic myeloid leukemia – targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment - Häselbarth, Lukas; Gamali, Sara; Saul, Domenica; Krumbholz, Manuela; Böttcher-Loschinski, Romy; Böttcher, Martin; Zou, Deyu; Metzler, Markus; Karow, Axel; Mougiakakos, Dimitrios (BMC Cancer, 2023)
Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic agent. Stress-related apoptosis was triggered via a caspase cascade including the cleavage of caspase 3 and the inactivation of poly ADP ribose polymerase 1 (PARP1). The inhibition of PARP by olaparib also increased CML death in combination with TKIs. Our findings suggest a rationale for combining TKIs with 8-Cl-Ado or olaparib for future clinical studies in CML.
CRIS-Team Scopus Importer:2023-12-15
Keywords: 8-chloroadenosine; ATF4; Caspase 3; CML; Olaparib; Oligomycin; Oxidative phosphorylation; PARP; Thapsigargin; TKI; UPR

Synergy of simultaneous activation of cell death pathways of unfolded protein response and of protein synthesis inhibition converges at IRE1a-immunotoxins generate a therapeutic window - Gsottberger, Franziska; Meier, Christina; Ammon, Anna-Maria; Petkovic, S.; Mellenthin, Lisa; Krumbholz, Manuela; Metzler, Markus; Mackensen, Andreas; Müller, Fabian (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Systematic comparison of donor chimerism in peripheral blood and bone marrow after hematopoietic stem cell transplantation - Bach, Christian; Steffen, M.; Rösler, Wolf; Winkler, Jürgen; Mackensen, Andreas; Stachel, Daniel; Metzler, Markus; Spriewald, B. M. (Blood Cancer Journal, 2017)
EVALuna2:13436

Systematic evaluation of exertional hyperthermia in children and adolescents with hypohidrotic ectodermal dysplasia: An observational study - Hammersen, Johanna E.; Neukam, Valentin; Nüsken, Kai-Dietrich; Schneider, Holm (Pediatric Research, 2011)
To evaluate exertional overheating and the impact of physical exercise on individuals with hypohidrotic ectodermal dysplasia (HED) and to assess protective effects of cooling devices, 13 boys and male adolescents with X-linked HED (XLHED) and age-matched healthy male controls were studied during standardized exercise on a bicycle ergometer at ambient temperatures of 25 and 30°C, without cooling and with evaporative skin cooling devices at 30°C. Body core temperature during and after exercise, heart rate, performance, endurance, and serum lactate were investigated. XLHED subjects experienced a significantly greater rise in body temperature after cycling than healthy controls, and their body temperature remained elevated longer. Maximum heart rates and lactate values did not differ significantly between XLHED and control groups. Application of skin cooling devices led to a clinically relevant attenuation of exertional hyperthermia in XLHED patients, and a previous tendency toward lower performance disappeared. This first systematic study of the effects of physical exercise on HED patients demonstrates a rapid and lasting body temperature increase in XLHED subjects after cycling, posing them at risk of exercise-induced hyperthermia. External evaporative skin cooling attenuates exertional overheating in HED patients and may facilitate their participation in athletic activities and professional life. Copyright © 2011 International Pediatric Research Foundation, Inc.
CRIS-Team Scopus Importer:2020-07-01

Systemic-to-pulmonary artery shunting using heparin-bonded grafts - Ambarsari, Yuletta Adny; Purbojo, Ariawan; Blumauer, Robert; Glöckler, Martin; Toka, Okan; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2018)
OBJECTIVES: Systemic-to-pulmonary artery shunting remains an important palliative procedure in the staged management of complex congenital heart defects. The use of heparin-bonded polytetrafluoroethylene shunts (HBPSs) should enhance graft patency. This study aimed to review the single-centre experience using HBPS in the context of congenital cardiac surgery. METHODS: The records of 51 patients treated using HBPS between 2010 and 2016 were retrospectively reviewed. The median age and weight of the patients were 8 (range 3-83) days and 3.2 (range 1.8-5.7) kg, respectively. Selected shunt size was 3.5 mm in all patients. Fourteen (27.5%) patients were planned for future biventricular repair and 37 (72.5%) patients underwent univentricular pathway. Shunt modifications included central aortopulmonary shunts (n = 35; 68.6%) and modified Blalock-Taussig shunts (n = 16; 31.4%). Shunt patency and survival until estimated 2nd procedure were calculated using the Kaplan-Meier method. RESULTS: Shunt patency was 90 ± 4% after a median duration of 133 (range 0-315) days. Early mortality (30 days) was 3.9% (n = 2). Another 3 patients died during their hospital stay. All the deceased patients had univentricular morphology, and the cause of death was not shunt related in all patients. Five patients developed subtotal HBPS thrombosis intraoperatively (n = 3), early postoperatively after 3 days (n = 1, 1.9%) or late after 41 days (n = 1, 1.9%). Treatment of those patients comprised right ventricular outflow tract opening (n = 2, 3.9%) or new shunting (n = 3, 5.9%). Elective shunt takedown was performed during corrective surgery (n = 10, 19.6%), bidirectional Glenn (n = 25, 49%) or shunt replacement (n = 5, 9.8%). At the end of follow-up, 1 (1.9%) patient had still an HBPS in situ. The survival rate until planned 2nd procedure was 87 ± 6% in univentricular patients and 100% in biventricular patients (P = 0.17). CONCLUSIONS: The use of HBPS in the context of palliative heart surgery is safe and seems to warrant a long-term patency of systemic-to-pulmonary shunts. However, by acting on only 1 site of Virchow's triad, shunt thrombosis, occurring predominantly early, cannot be totally excluded.
EVALuna2:35480

Targeted deletion of Interleukin-3 results in asthma exacerbations - Kölle, Julia; Zimmermann, Theodor; Kiefer, Alexander; Rieker, Ralf; Xepapadaki, Paraskevi; Zundler, Sebastian; Papadopoulos, Nikolaos G.; Finotto, Susetta (iScience, 2022)
The cytokine interleukin-3 (IL-3) acts on early hematopoietic precursor cells. In humans, Treg cells secrete IL-3 and repress inflammatory cells except for basophils. The present study aims to elucidate the contribution of IL-3 in the development and the course of allergic asthma. We therefore analyzed the secretion of IL-3 in PBMCs and total blood cells in two cohorts of pre-school children with and without asthma. In a murine model of allergic asthma, we analyzed the phenotype of IL-3−/− mice compared to wild-type mice. PBMCs from asthmatic children showed increased IL-3 secretion, which directly correlated with improved lung function. IL-3−/− asthmatic mice showed increased asthmatic traits. Moreover, IL-3-deficient mice had a defect in T regulatory cells in the lung. In conclusion, IL-3 downregulation was found associated with more severe allergic asthma in pre-school children. Consistently, targeting IL-3 resulted in an induced pathophysiological response in a murine model of allergic asthma.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Biological sciences; immune response; Immunology

Targeted deletion of NFAT-Interacting-Protein-(NIP) 45 resolves experimental asthma by inhibiting Innate Lymphoid Cells group 2 (ILC2) - Koch, Sonja; Knipfer, Lisa; Kölle, Julia; Mirzakhani, Hooman; Graser, Anna; Zimmermann, Theodor; Kiefer, Alexander; Melichar, Volker O.; Rascher, Wolfgang; Papadopoulos, Nikolaos G.; Rieker, Ralf; Raby, Benjamin A.; et al. (Scientific Reports, 2019)
Here we investigated the role of NFAT-interacting protein (NIP)-45, an Interleukin (IL)-4 inducing Transcription Factor, and its impact on the differentiation of Group 2 Innate -Lymphoid -Cells (ILC2s) in the pathogenesis of asthma. NIP45, a transcription factor regulating NFATc1 activity, mRNA was found to be induced in the Peripheral Blood mononuclear cells (PMBCs) of asthmatic pre-school children with allergies and in the peripheral blood CD4+ T cells from adult asthmatic patients. In PBMCs of asthmatic and control children, NIP45 mRNA directly correlated with NFATc1 but not with T-bet. Targeted deletion of NIP45 in mice resulted in a protective phenotype in experimental asthma with reduced airway mucus production, airway hyperresponsiveness and eosinophils. This phenotype was reversed by intranasal delivery of recombinant r-IL-33. Consistently, ILC2s and not GATA3+ CD4+ T-cells were decreased in the lungs of asthmatic NIP45−/− mice. Reduced cell number spleen ILC2s could be differentiated from NIP45−/− as compared to wild-type mice after in vivo injection of a microcircle-DNA vector expressing IL-25 and decreased cytokines and ILC2 markers in ILC2 differentiated from the bone marrow of NIP45−/− mice. NIP45 thus emerges as a new therapeutic target for the resolution of the airway pathology, down-regulation of ILC2s and mucus production in asthma.
CRIS-Team Scopus Importer:2019-11-08

Targeted Inhibition of Protein Biosynthesis sensitizes Cancer Cells to IRE1a-mediated Apoptosis as a Consequence of the unfolded protein response - Gsottberger, Franziska; Meier, Christina; Ammon, Anna-Maria; Parker, S.; Wendland, Kerstin; George, Rebekka; Petkovic, S.; Mellenthin, Lisa; Emmerich, C.; Lutzny-Geier, Gloria; Mackensen, Andreas; Metzler, Markus; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response - Gsottberger, Franziska; Meier, Christina; Ammon, Anna-Maria; Parker, Scott; Wendland, Kerstin; George, Rebekka; Petkovic, Srdjan; Mellenthin, Lisa; Emmerich, Charlotte; Lutzny-Geier, Gloria; Metzler, Markus; Mackensen, Andreas; et al. (Cell Death & Disease, 2023)
Cellular stress responses including the unfolded protein response (UPR) decide over the fate of an individual cell to ensure survival of the entire organism. During physiologic UPR counter-regulation, protective proteins are upregulated to prevent cell death. A similar strategy induces resistance to UPR in cancer. Therefore, we hypothesized that blocking protein synthesis following induction of UPR substantially enhances drug-induced apoptosis of malignant cells. In line, upregulation of the chaperone BiP was prevented by simultaneous arrest of protein synthesis in B cell malignancies. Cytotoxicity by immunotoxins—approved inhibitors of protein synthesis—was synergistically enhanced in combination with UPR-inducers in seven distinct hematologic and three solid tumor entities in vitro. Synergistic cell death depended on mitochondrial outer membrane permeabilization via BAK/BAX, which correlated with synergistic, IRE1α-dependent reduction of BID, accompanied by an additive fall of MCL-1. The strong synergy was reproduced in vivo against xenograft mouse models of mantle cell lymphoma, Burkitt’s lymphoma, and patient-derived acute lymphoblastic leukemia. In contrast, synergy was absent in blood cells of healthy donors suggesting a tumor-specific vulnerability. Together, these data support clinical evaluation of blocking stress response counter-regulation using inhibitors of protein synthesis as a novel therapeutic strategy.
CRIS-Team Scopus Importer:2023-09-08

Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding - Lee, Olivia W.; Rodrigues, Calvin; Lin, Shu Hong; Luo, Wen; Jones, Kristine; Brown, Derek W.; Zhou, Weiyin; Karlins, Eric; Khan, Sairah M.; Baulande, Sylvain; Raynal, Virginie; Surdez, Didier; et al. (American Journal of Human Genetics, 2023)
Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.
CRIS-Team Scopus Importer:2023-03-17
Keywords: 6p25.1; Ewing sarcoma; EWSR1-FLI1; germline somatic interaction; GGAA microsatellite; GWAS; long-read sequencing; RREB1

Targeting metabolism effectively complements tyrosine kinase inhibitor treatment of chronic myeloid leukemia - Häselbarth, Lukas; Saul, Domenica; Krumbholz, Manuela; Mougiakaos, D.; Metzler, Markus; Karow, A. (KLINISCHE PADIATRIE, 2022)
CRIS-Team WoS Importer:2022-07-08

Targeting Muscular Hemoglobin Content for Classification of Peripheral Arterial Disease by Noninvasive Multispectral Optoacoustic Tomography - Günther, Josefine; Knieling, Ferdinand; Träger, Anna P.; Lang, Werner; Meyer, Alexander; Regensburger, Adrian; Wagner, Alexandra; Trollmann, Regina; Wölfle, Joachim; Klett, Daniel; Uter, Wolfgang; Uder, Michael; et al. (Journal of the American College of Cardiology : Cardiovascular imaging, 2023)
Created from Fastlane, Scopus look-up

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway - Bozec, Aline; Zaiss, Mario; Kagwiria, Rosebeth; Voll, Reinhard; Rauh, Manfred; Chen, Zhu; Müller-Schmucker, Sandra; Kroczek, Richard A.; Heinzerling, Lucie; Moser, Muriel; Mellor, Andrew L.; David, Jean-Pierre; et al. (Science Translational Medicine, 2014)
Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
EVALuna2:12912

T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency - Heller, Stephanie; Kölsch, Uwe; Magg, Thomas; Krüger, Renate; Scheuern, Andrea; Schneider, Holm; Eichinger, Anna; Wahn, Volker; Unterwalder, Nadine; Lorenz, Myriam; Schwarz, Klaus; Meisel, Christian; et al. (Journal of Clinical Immunology, 2020)
Purpose: NEMO-deficient patients present with variable degrees of immunodeficiency. Accordingly, treatment ranges from antibiotic prophylaxis and/or IgG-substitution to allogenic hematopoietic stem cell transplantation (HSCT). The correct estimation of the immunodeficiency is essential to avoid over- as well as under-treatment. We compare the immunological phenotype of a NEMO-deficient patient with a newly-described splice site mutation that causes truncation of the NEMO zinc-finger (ZF) domain and a severe clinical course with the immunological phenotype of three NEMO-deficient patients with missense mutations and milder clinical courses and all previously published patients. Methods: Lymphocyte subsets, proliferation, and intracellular NEMO-expression were assessed by FACS. NF-κB signal transduction was determined by measuring IκBα-degradation and the production of cytokines upon stimulation with TNF-α, IL-1β, and TLR-agonists in immortalized fibroblasts and whole blood, respectively. Results: The patient with truncated ZF-domain of NEMO showed low levels of IgM and IgG, reduced class-switched memory B cells, almost complete skewing towards naïve CD45RA+ T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-α, IL-1β, and TLR-agonists. He suffered from severe infections (sepsis, pneumonia, osteomyelitis) during infancy. In contrast, three patients with missense mutations in IKBKG presented neither skewing of T cells towards naïvety nor impaired T cell proliferation. They are stable on prophylactic IgG-substitution or even off any prophylactic treatment. Conclusion: The loss of the ZF-domain and the impaired T cell proliferation accompanied by almost complete persistence of naïve T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.
CRIS-Team Scopus Importer:2020-02-04
Keywords: CD45RA; immunological phenotype; NEMO deficiency; Primary immunodeficiency; T cell deficiency

Teachability of multispectral optoacoustic tomography - Li, Yi; Gröhl, Janek; Haney, Briain; Caranovic, Milenko; Lorenz-Meyer, Eva; Papatheodorou, Nikolaos; Kempf, Julius; Regensburger, Adrian; Nedoschill, Emmanuel; Bühler, Adrian; Siebenlist, Gregor; Lang, Werner; et al. (Journal of Biophotonics, 2024)
To date, the appropriate training required for the reproducible operation of multispectral optoacoustic tomography (MSOT) is poorly discussed. Therefore, the aim of this study was to assess the teachability of MSOT imaging. Five operators (two experienced and three inexperienced) performed repositioning imaging experiments. The inexperienced received the following introductions: personal supervision, video meeting, or printed introduction. The task was to image the exact same position on the calf muscle for seven times on five volunteers in two rounds of investigations. In the first session, operators used ultrasound guidance during measurements while using only photoacoustic data in the second session. The performance comparison was carried out with full-reference image quality measures to quantitatively assess the difference between repeated scans. The study demonstrates that given a personal supervision and hybrid ultrasound real-time imaging in MSOT measurements, inexperienced operators are able to achieve the same level as experienced operators in terms of repositioning accuracy.
CRIS-Team Scopus Importer:2024-05-17
Keywords: MSOT; multispectral optoacoustic imaging; teachability; ultrasound

Telemonitoring with Electronic Devices in Patients with a Single Ventricle Anatomy - Zartner, Peter A.; Mini, Nathalie; Momcilovic, Diana; Schneider, Martin B.; Dittrich, Sven (Thoracic and Cardiovascular Surgeon, 2021)
Background A growing number of patients with a single ventricle anatomy, who had a Fontan palliation as a child, are now reaching adulthood. Many need an epimyocardial pacemaker system with an optional telemonitoring (TM) unit, which evaluates the collected data and sends it via Internet to the patient's physician. There are no data on the reliability and clinical relevance of these systems in this patient group. Methods We analyzed data in 48 consecutive patients (mean age 18 years, standard deviation 9 years) with a Fontan or Fontan-like palliation who received a cardiac implantable electronic device with a TM unit from Biotronik (Home Monitoring) or Medtronic (CareLink) between 2005 and 2020 with regard to the reliability and clinical relevance of the downloaded data. Results The observation period was from 4 months to 14 years (mean 7 years, standard deviation 3.9 years). A total of 2.9 event messages (EMs)/patient/month and 1.3 intracardiac electrogram recordings/patient/month were received. Two patients died during follow-up. The combination of regularly arriving statistical data and 313 clinically relevant EMs led to the modification of antiarrhythmic or diuretic medication, hospitalization with cardioversion or ablation, and cortisone therapy to avoid exit block in 21 (44%) patients. Conclusion TM is an instrument to receive functional and physiologic parameters of our Fontan patients. It provides the ability to respond early for signs of system failure, or arrhythmia, even if the patient is not experiencing any problems. It is a useful tool to manage this difficult patient population without frequent hospital visits.
CRIS-Team WoS Importer:2021-12-17

Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis - Sehm, Tina; Rauh, Manfred; Wiendieck, Kurt; Buchfelder, Michael; Eyüpoglu, Ilker Yasin; Savaskan, Nicolai E. (Oncotarget, 2016)
The glutamate exchanger xCT (SLC7a11) is causally linked with the malignancy grade of brain tumors and represents a key player in glutamate, cystine and glutathione metabolism. Although blocking xCT is not cytotoxic for brain tumors, xCT inhibition disrupts the neurodegenerative and microenvironment-toxifying activity of gliomas. Here, we report on the use of various xCT inhibitors as single modal drugs and in combination with the autophagy-inducing standard chemotherapeutic agent temozolomide (Temodal/Temcad®, TMZ). xCT overexpressing cells (xCTOE) are more resistant to the FDA and EMA approved drug sulfasalazine (Azulfidine/Salazopyrin/Sulazine®, SAS) and RNAi-mediated xCT knock down (xCTKD) in gliomas increases the susceptibility towards SAS in rodent gliomas. In human gliomas, challenged xCT expression had no impact on SAS-induced cytotoxicity. Noteworthy, other xCT inhibitors such as erastin and sorafenib showed enhanced efficacy on xCTKD gliomas. In contrast, cytotoxic action of TMZ operates independently from xCT expression levels on rodent gliomas. Human glioma cells with silenced xCT expression display higher vulnerability towards TMZ alone as well as towards combined TMZ and SAS. Hence, we tested the partial xCT blockers and ferroptosis inducing agents erastin and sorafenib (Nexavar®, FDA and EMA-approved drug for lung cancer). Noteworthy, xCTOE gliomas withstand erastin and sorafenib-induced cell death in a concentration-dependent manner, whereas siRNA-mediated xCT knock down increased susceptibility towards erastin and sorafenib. TMZ efficacy can be potentiated when combined with erastin, however not by sorafenib. Moreover, gliomas with high xCT expression are more vulnerable towards combinatorial treatment with erastin-temozolomide. These results disclose that ferroptosis inducers are valid compounds for potentiating the frontline therapeutic agent temozolomide in a multitoxic approach.
EVALuna2:33853

Temporal evolution and differential patterns of cellular reconstitution after therapy for childhood cancers - Hofmann, Gina; Zierk, Jakob; Sobik, Bettina; Wotschofsky, Zofia; Sembill, Stephanie; Krumbholz, Manuela; Metzler, Markus; Karow, Axel (Scientific Reports, 2023)
The cellular reconstitution after childhood cancer therapy is associated with the risk of infection and efficacy of revaccination. Many studies have described the reconstitution after stem cell transplantation (SCT). The recovery after cancer treatment in children who have not undergone SCT has mainly been investigated in acute lymphoblastic leukemia (ALL), less for solid tumors. Here, we have examined the temporal evolution of total leukocyte, neutrophil and lymphocyte counts as surrogate parameters for the post-therapeutic immune recovery in a cohort of n = 52 patients with ALL in comparison to n = 58 patients with Hodgkin’s disease (HD) and n = 22 patients with Ewing sarcoma (ES). Patients with ALL showed an efficient increase in blood counts reaching the age-adjusted lower limits of normal between 4 and 5 months after the end of maintenance therapy. The two groups of patients with HD and ES exhibited a comparably delayed recovery of total leukocytes due to a protracted post-therapeutic lymphopenia which was most pronounced in patients with HD after irradiation. Overall, we observed a clearly more efficient resurgence of total lymphocyte counts in patients aged below 12 years compared to patients aged 12 to 18 years. Our results underline that the kinetics of cellular reconstitution after therapy for HD and ES differ significantly from ALL and depend on treatment regimens and modalities as well as on patient age. This suggests a need for disease, treatment, and age specific recommendations concerning the duration of infection prophylaxis and the timing of revaccination.
CRIS-Team Scopus Importer:2023-03-24

Tetrasomy of SCN2A associated with refractory neonatal epileptic encephalopathy - Krumbiegel, Mandy; Trollmann, Regina; Mammadova, Dilbar; Schnell, Alexander; Kraus, Cornelia; Ekici, Arif Bülent; Reis, André; Zweier, Christiane (EUROPEAN JOURNAL OF HUMAN GENETICS, 2020)
CRIS-Team WoS Importer:2021-01-22

Tgf-beta regulation and regulated anti-rhinovirus (RV) immune responses in asthma - Finotto, Susetta; Bielor, Carina; Sopel, Nina; Vuorinen, T.; Melichar, V. O.; Kiefer, Alexander; Zimmermann, Theodor; Papadopoulos, N. G.; Weiss, S. T. (2017)
EVALuna2:33023

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma - Ubel, Caroline; Sopel, Nina; Graser, Anna; Hildner, Kai; Reinhardt, Cornelia; Zimmermann, Theodor; Rieker, Ralf Joachim; Maier, Anja; Neurath, Markus; Murphy, Kenneth M.; Finotto, Susetta (Journal of Allergy and Clinical Immunology, 2014)
Mice without the basic leucine zipper transcription factor, ATF-like (BATF) gene (Batf(-/-)) lack TH17 and follicular helper T cells, which demonstrates that Batf is a transcription factor important for T- and B-cell differentiation.In this study we examined whether BATF expression would influence allergic asthma.In a cohort of preschool control children and children with asthma, we analyzed BATF mRNA expression using real-time PCR in PBMCs. In a murine model of allergic asthma, we analyzed differences in this allergic disease between wild-type, Batf transgenic, and Batf(-/-) mice.In the absence of corticosteroid treatment, children with recurrent asthma have a significant increase in BATF mRNA expression in their PBMCs. Batf(-/-) mice display a significant reduction in the pathophysiologic responses seen in asthmatic wild-type littermates. Moreover, we discovered a decrease in IL-3 production and IL-3-dependent mast cell development in Batf(-/-) mice. By contrast, IFN-? was induced in lung CD4(+) and CD8(+) T cells. Intranasal delivery of anti-IFN-? antibodies induced airway hyperresponsiveness and inflammation in wild-type but not in Batf(-/-) mice. Transgenic overexpression of Batf under the control of the CD2 promoter/enhancer augmented lung inflammation and IgE levels in the setting of experimental asthma.BATF is increased in non-steroid-treated asthmatic children. Targeting BATF expression resulted in amelioration of the pathophysiologic responses seen in children with allergic asthma, and BATF has emerged as a novel target for antiasthma interventions.
EVALuna2:1742

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13 - Zanetti, Costanza; Kumar, Rahul; Ender, Joscha; Godavarthy, Parimala S.; Hartmann, Mark; Hey, Joschka; Breuer, Kersten; Weissenberger, Eva S.; Minciacchi, Valentina R.; Karantanou, Christina; Gu, Zhaohui; Roberts, Kathryn G.; et al. (Blood, 2021)
B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL–initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL–initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
CRIS-Team Scopus Importer:2021-11-19

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13. - Zanetti, Costanza; Kumar, Rahul; Ender, Joscha; Godavarthy, Parimala S.; Hartmann, Mark; Hey, Joschka; Breuer, Kersten; Weissenberger, Eva S.; Minciacchi, Valentina R.; Karantanou, Christina; Gu, Zhaohui; Roberts, Kathryn G.; et al. (Blood, 2021)
B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
EVALuna2:490620

The anti-viral properties of IL-17A in allergic asthma - Graser, Anna; Ekici, Arif Bülent; Melichar, Volker O.; Zimmermann, Theodor; Papadopoulos, Nikolaos G.; Taka, Stella; Ferrazzi, Fulvia; Vuorinen, Tytti; Finotto, Susetta (2015)
EVALuna2:25975

The association of leptin secretion with cognitive performance in patients with eating disorders - Wollenhaupt, Carina; Wilke, Leonhard; Erim, Yesim; Rauh, Manfred; Steins-Loeber, Sabine; Paslakis, Georgios (Psychiatry Research, 2019)
This study is an investigation of neuropsychological performance in patients with anorexia nervosa, bulimia nervosa, and binge eating disorder and hormonal secretion patterns for ghrelin, leptin, insulin, and glucose. An oral glucose tolerance test (OGTT)was performed in a cohort of n = 30 female patients suffering from eating disorders as well as n = 20 control females. All participants underwent the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), and a go/no-go task using food vs. neutral stimuli. Patients with anorexia nervosa differed from controls in their leptin response to the OGTT. While the four groups under investigation did not differ in neuropsychological performance, we found leptin responses to the OGTT to be associated with performance in the food-specific go/no-go task. These preliminary results may indicate a putative association between leptin concentrations and neuropsychological performance, particularly in measures of inhibitory control. Further studies investigating the role of leptin in impulsive behaviors in eating disorders would be useful.
CRIS-Team Scopus Importer:2019-05-28
Keywords: Eating disorder; Ghrelin; Go/no-go test; Leptin; Neuropsychological performance; Oral glucose tolerance test

The components of arginine and methylarginine metabolism are indicative of altered kidney function in intrauterine growth-restricted neonates - Kleinebenne, Lina; Röhrig, Waldemar; Ebach, Fabian; Reutter, Heiko Martin; Pankraz, Alexander; Heuchel, Katharina Monika; Müller, Andreas; Hilger, Alina (Journal of Hypertension, 2024)
Background: Intrauterine fetal growth restriction (IUGR) affects up to 10% of all pregnancies. Severe IUGR is associated with impaired kidney development, reduced nephron endowment, and chronic kidney disease later in life. Currently, no early predictive biomarker exists for detecting altered kidney function in neonates with IUGR. Because nephrons produce key enzymes for the metabolism of arginine and methylarginine components, we quantified and compared the concentrations of arginine and methylarginine metabolites between IUGR and non-IUGR neonates to identify potential biomarkers for the early detection of altered kidney function in IUGR neonates. Methods: Seventy-one IUGR and 123 non IUGR neonates were examined. Serum and Urine samples were obtained between 30 h and 5 days of life and between 5 and 70 days of life. Serum concentrations of creatinine, urea, symmetric and asymmetric-dimethylarginine metabolites (SDGV, SDMA, ADGV, and ADMA), guanidino-2-oxo-caproic acid (GOCA), citrulline, homocitrulline, arginine, and homoarginine were quantified using LC-MS/MS and standard clinical laboratory methods. Datasets were compared by Mann - Whitney - Wilcoxon or Chi-square tests for continuous and discrete parameters. P values were corrected for multiple comparisons using the Bonferroni method. Results: After Bonferroni correction, we found that serum creatinine, urea, SDGV, ADGV, and GOCA levels were significantly lower in neonates with IUGR. Consequently, the ratios of SDGV/SDMA, ADGV/ADMA, and GOCA/homoarginine were significantly lower in IUGR neonates. Conclusion: Our study suggests that arginine and methylarginine are possible early biomarkers for detecting altered kidney function in IUGR neonates.
CRIS-Team Scopus Importer:2024-09-06
Keywords: ADMA; AGXT2; arginine metabolites; glomerular filtration rate; homoarginine; IUGR; kidney function; SDMA

The Congenital Cardiology Cloud - Optimizing long-term care by connecting ambulatory and hospital medical attendance via telemedicine - Rottermann, Kathrin; Doll, Ulrike; Pfenning, Simon; Reichenbach, Marc; Fey, Dietmar; Dobler, Alexander; Siauw, Céline; Reif, Fabian; Gnibl, Julia; Cesnjevar, Robert; Dittrich, Sven (Klinische Pädiatrie, 2023)
Background Patients with complex congenital heart disease frequently undergo a life-long ambulatory therapy with the need for repeated hospital interventions. To optimize this manifold interplay, we designed and implemented a tele-medical service, the Congenital Cardiology Cloud (CCC). This study aims to analyse the requirements for its implementation through the comprehensive assessment of design, installation and impact on patient's care. Methods CCC's development comprised the analysis of historically raised admission and discharge management and the definition of technical and organizational requirements. Elaboration of procedural flow charts, description of data formats and technical processes as well as distribution of patient structure formed part of this process. Results Analysis of existing workflows uncovered a need for the rebuilding of admission and discharge process and decision making for further treatment. The CCC reduces conference-meetings in general and repetitive meetings up to less than a third. Real-time dispatch of discharge documents guarantees an instantaneous access to patient-related data. Comparative analyses show a more complex patient group to be involved in tele-medical services. Conclusions The CCC enables the sharing of complex clinical information by overcoming sectoral barriers and improves mutual patient advice. Implementation of a tele-medical network requires willingness, perseverance and professional engagement. Future application analysis and possible introduction of refinancing concepts will show its long-term feasibility.
CRIS-Team Scopus Importer:2023-10-06
Keywords: cloud; congenital heart disease; data security; pediatric cardiology; telecardiology; telemedicine

The Congenital Cardiology Cloud: Proof of feasibility of Germany's first tele-medical network for pediatric cardiology - Klais, Marko; Doll, Ulrike; Purbojo, Ariawan; Dittrich, Sven; Rottermann, Kathrin (Journal of Telemedicine and Telecare, 2023)
Background: For an optimal interplay based on the data-secure exchange of diagnostic data between patients, ambulatory care, and hospital care, we implemented the first tele-medical network for pediatric cardiology in Germany, the Congenital Cardiology Cloud. This study focuses on its feasibility, technical characteristics, and implementation in routine clinical work. Methods: Tele-medical traffic comprised numbers of incoming/outgoing data, related file types, treatment options for tele-medically processed patients, and patient classification with respect to the severity of disease. Proof of feasibility was related to the number of successful tele-medical transmissions of discharge documents at the end of the observation period (02/2020–10/2020). Results: Analysis of Congenital Cardiology Cloud's data communication showed a number of 1178 files for a total of 349 patients, favoring transmissions towards the clinic. Incoming traffic was predominantly characterized by diagnostic data regarding tele-consultations (76.6%), consisting of a multitude of file types, whereas 93.4% of the dispatched data corresponded to discharge letters. The number of tele-consultations counted up to 61, with a necessary subsequent treatment or diagnostic procedure in 90.2% of the presented cases. Tele-medically processed patients generally showed to be more complex (severe chronic heart disease 42.4% vs. 23.7%). At the end of the observation period, 97.6% of the discharge documents were transmitted via telemedicine. Discussion: The implementation of the first tele-medical network for pediatric cardiology in Germany proves recent technological developments to successfully enable innovative patient care, connecting the ambulatory and hospital sector for a joint patient advice, predominantly in more complex cases. Possible governmentally guided refinancing concepts will show its long-term feasibility.
CRIS-Team Scopus Importer:2023-04-07
Keywords: cloud-based healthcare; congenital heart disease; pediatric cardiology; teleconsulting; Telemedicine

The Cytogenetic Landscape of Pediatric Chronic Myeloid Leukemia Diagnosed in Chronic Phase - Karow, Axel; Göhring, Gudrun; Sembill, Stephanie; Lutterloh, Friederike; Neuhaus, Fina; Callies, Sara; Schirmer, Elke; Wotschofsky, Zofia; Roche-Lancaster, Oisin; Suttorp, Meinolf; Krumbholz, Manuela; Metzler, Markus (Cancers, 2022)
Philadelphia chromosome-positive chronic myeloid leukemia (CML) is cytogenetically characterized by the classic translocation t(9;22)(q34;q11), whereas additional non-Philadelphia aberrations (nPhAs) have been studied extensively in adult patients with CML, knowledge on nPhAs in pediatric patients with CML is still sparse. Here, we have determined nPhAs in a cohort of 161 patients younger than 18 years diagnosed with chronic phase CML and consecutively enrolled in the German national CML-PAED-II registry. In 150 cases (93%), an informative cytogenetic analysis had been performed at diagnosis. In total, 21 individuals (13%) showed nPhAs. Of these, 12 (8%) had a variant translocation, 4 (3%) additional chromosomal aberrations (ACAs) and 5 (3%) harbored a complex karyotype. Chromosome 15 was recurrently involved in variant translocations. No significant impact of the cytogenetic subgroup on the time point of cytogenetic response was observed. Patients with a complex karyotype showed an inferior molecular response compared to patients carrying the classic translocation t(9;22)(q34;q11), variant translocations or ACAs. No significant differences in the probability of progression-free survival and overall survival was found between patients with nPhAs and patients with the classic Philadelphia translocation only. Our results highlight the distinct biology of pediatric CML and underline the need for joint international efforts to acquire more data on the disease pathogenesis in this age group.
CRIS-Team Scopus Importer:2022-04-08
Keywords: additional chromosomal aberrations; chronic myeloid leukemia; complex karyotype; cytogenetic response; molecular response; pediatric chronic myeloid leukemia; Philadelphia chromo-some; tyrosine kinase inhibitor treatment; variant translocations

The EDELIFE clinical trial, the first investigation of a signalling molecule to treat in utero a human developmental genetic disorder - Schneider, Holm; Hadj-Rabia, Smail; Faschingbauer, Florian; Bodemer, Christine; Grange, Dorothy K.; Guillén-Navarro, Encarna; Tadini, Gianluca; Clarke, Angus (European Journal of Human Genetics, 2024)

The effect of dietary lipid quality in early life on serum LysoPC(18:2) levels and their association with adult blood glucose levels in intrauterine growth restricted rats - Kodde, Andrea; Mischke, Mona; Rakhshandehroo, Maryam; Voggel, Jenny; Fink, Gregor; Nuesken, Eva; Rauh, Manfred; Van Der Beek, Eline M.; Doetsch, Joerg; Nuesken, Kai-Dietrich (Nutrition & Metabolism, 2021)
Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p < 0.01) and restored in CLM fed animals (p < 0.05). LysoPC(18:2) levels at PN42 correlated inversely with adult blood glucose levels. These data indicate that early-life LysoPC(18:2) blood levels may predict adult blood glucose levels and are affected by a postnatal diet with an adapted lipid droplet structure in IUGR offspring.
CRIS-Team WoS Importer:2021-12-03

The effect of spironolactone on diastolic function in haemodialysis patients - Hauser, T.; Dornberger, V.; Malzahn, U.; Grebe, S. J.; Liu, D.; Stoerk, S.; Nauck, M.; Friedrich, N.; Doerr, M.; Wanner, C.; Krane, V.; Hammer, F. (International Journal of Cardiovascular Imaging, 2021)
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e’. Changes in the frequency of HFpEF were analysed using the comprehensive ‘HFA-PEFF score’. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e’ was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e’ between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m2 vs. 1.7 ± 14.1 ml/m2, p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m2 vs. + 2.7 ± 15.9 g/m2; p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients. The trial has been registered at clinicaltrials.gov (NCT01691053; first posted Sep. 24, 2012).
CRIS-Team Scopus Importer:2021-03-05
Keywords: Diastolic function; E/e’; Echocardiography; Haemodialysis; HFpEF; Spironolactone

The ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24-25, 2015. Workshop Report - Kager, Leo; Whelan, Jeremy; Dirksen, Uta; Hassan, Bass; Anninga, Jakob; Bennister, Lindsey; Bovee, Judith V. M. G.; Brennan, Bernadette; Broto, Javier M.; Brugieres, Laurence; Cleton-Jansen, Anne-Marie; Copland, Christopher; et al. (Clinical Sarcoma Research, 2016)
This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.
EVALuna2:34002

The epidemiology of drug-related hospital admissions in paediatrics – a systematic review - Eberl, Sonja; Heus, Pauline; Toni, Irmgard; Bachmat, Igor; Neubert, Antje (Archives of Public Health, 2024)
Background: Despite previous efforts, medication safety in paediatrics remains a major concern. To inform improvement strategies and further research especially in outpatient care, we systematically reviewed the literature on the frequency and nature of drug-related hospital admissions in children. Methods: Searches covered Embase, Medline, Web of Science, grey literature sources and relevant article citations. Studies reporting epidemiological data on paediatric drug-related hospital admissions published between 01/2000 and 01/2024 were eligible. Study identification, data extraction, and critical appraisal were conducted independently in duplicate using templates based on the ’Joanna Briggs Institute’ recommendations. Results: The review included data from 45 studies reporting > 24,000 hospitalisations for adverse drug events (ADEs) or adverse drug reactions (ADRs). Due to different reference groups, a total of 52 relative frequency values were provided. We stratified these results by study characteristics. As a percentage of inpatients, the highest frequency of drug-related hospitalisation was found with ‘intensive ADE monitoring’, ranging from 3.1% to 5.8% (5 values), whereas with ‘routine ADE monitoring’, it ranged from 0.2% to 1.0% (3 values). The relative frequencies of ‘ADR-related hospitalisations’ ranged from 0.2% to 6.9% for ‘intensive monitoring’ (23 values) and from 0.04% to 3.8% for ‘routine monitoring’ (8 values). Per emergency department visits, five relative frequency values ranged from 0.1% to 3.8% in studies with ‘intensive ADE monitoring’, while all other eight values were ≤ 0.1%. Heterogeneity prevented pooled estimates. Studies rarely reported on the nature of the problems, or studies with broader objectives lacked disaggregated data. Limited data indicated that one in three (median) drug-related admissions could have been prevented, especially by more attentive prescribing. Besides polypharmacy and oncological therapy, no other risk factors could be clearly identified. Insufficient information and a high risk of bias, especially in retrospective and routine observational studies, hampered the assessment. Conclusion: Given the high frequency of drug-related hospitalisations, medication safety in paediatrics needs to be further improved. As routine identification appears unreliable, clinical awareness needs to be raised. To gain more profound insights especially for generating improvement strategies, we have to address under-reporting and methodological issues in future research. Trial registration: PROSPERO (CRD42021296986)
CRIS-Team Scopus Importer:2024-09-06
Keywords: Adverse drug events; Adverse drug reactions; Children; Drug-related hospitalisations; Drug-related problems; Hospital admissions; Hospitalisation; Medication safety; Paediatric

The EU paediatric regulation: still a large discrepancy between therapeutic needs and approved paediatric investigation plans - Wimmer, Stefan; Rascher, Wolfgang; Mccarthy, Suzanne; Neubert, Antje (Paediatric Drugs, 2014)
Prior to the implementation of the EU Paediatric Regulation, the European Medicines Agency (EMA) defined unmet paediatric needs for active substances already available on the market. Seven years after the Paediatric Regulation came into force, we investigated the extent to which previously identified needs have led to programmes for generating evidence necessary for the regulatory approval of medicines for managing childhood conditions.The websites of the EMA and the European Commission Community Research and Development Information Service (CORDIS) were systematically screened to identify active substances from the assessment of paediatric needs, off-patent priority list, agreed Paediatric Investigation Plans (PIP) and 7th Framework Programme (FP7) projects related to paediatric medicines.A total of 357 active substances with paediatric needs were identified by June 2013. 511 PIPs were agreed by the Paediatric Committee at the EMA (PDCO), including 51 (14.3 %) PIPs for a previously identified need. Amongst those, 21 were off-patent at the time of the PIP approval, 15 of which received funding from the European Commission's FP7. According to the assessment of paediatric needs, evidence is particularly needed for active substances treating cardiovascular diseases (n = 61), cancer (n = 40) and in the field of anaesthesiology (n = 38). Whereas oncology drugs (n = 66) were frequently represented in PIPs, drugs for cardiovascular diseases (n = 39) and anaesthesiology (n = 3) rarely were.Most PIPs are attributable to marketing authorisations of new active substances, whereas off-patent drugs which are commonly used off-label remain unstudied to a large extent. More effort including ongoing research funding is essential to further regularise and standardise paediatric pharmacotherapy.
EVALuna2:18901

THE FMF&AID SURVEY - A PATIENT ORGANIZATION DRIVEN SURVEY FOR AUTOINFLAMMATORY DISEASES - Rech, Jürgen; Tascilar, Koray; Tufan, A.; Gattorno, M.; Kuemmerle-Deschner, J. B.; Ozen, S.; Krickau, Tobias; Cohen, E.; Mendonca, L. Oliveira; Kontzias, A.; Vetterli, M. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

The Fontan and the Sea: First-in-Man Data on Swimming and Diving Physiology in Fontan Patients - Paech, C.; Gebauer, R. A.; Weidenbach, M.; Mensch, S.; Kalden, P.; Markel, F.; Michaelis, A.; Schöffl, Isabelle; Daehnert, I.; Riede, F. T.; Rudrich, P.; Wolfarth, B.; et al. (Pediatric Cardiology, 2021)
While swimming represents a popular recreational activity, the immersion of the human body into the water requires a complex physiologic adaption of the whole cardiopulmonary and circulatory system. While this sport is regarded as beneficial, especially in cardiovascular patients, current guidelines hypothesized a possible hazardous effect of swimming and especially diving in patients with univentricular hearts after Fontan palliation. Yet, actual data to underline or contradict these assumptions are lacking. Therefore, this study aimed to conduct a first feasibility study for the evaluation of these effects on Fontan physiology and elucidate the gap of evidence currently preventing patients after Fontan palliation from being restricted from swimming or diving on doctoral advice. Patients recruited from the Heart Center Leipzig, Department of pediatric cardiology, underwent spiroergometry treadmill testing followed by a spiroergometry swimming stress test in a counter current pool. Physiologic data were recorded. A short apnea diving test was performed. The current study found similar physiologic reactions comparing treadmill and swimming exercise stress testing. Heart rate response and oxygen uptake were comparable on land and in the water. This study presents the first-in-man data on swimming and diving in Fontan patients. In this small study cohort of three Fontan patients, there were no adverse events triggered by swimming and breath-hold diving seen. Basically, the physiologic response to exercise was comparable on land and in the water.
CRIS-Team WoS Importer:2021-06-11

The genomic architecture of bladder exstrophy epispadias complex - Beaman, Glenda M.; Cervellione, Raimondo M.; Keene, David; Reutter, Heiko Martin; Newman, William G. (Genes, 2021)
The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current knowledge on this multifactorial disorder, including phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components.
CRIS-Team Scopus Importer:2021-08-13
Keywords: BEEC; Bladder exstrophy; Cloacal exstrophy; Epispadias

The German National Registry of Primary Immunodeficiencies (2012-2017) - El-Helou, Sabine M.; Biegner, Anika-Kerstin; Bode, Sebastian; Ehl, Stephan R.; Heeg, Maximilian; Maccari, Maria E.; Ritterbusch, Henrike; Speckmann, Carsten; Rusch, Stephan; Scheible, Raphael; Warnatz, Klaus; Atschekzei, Faranaz; et al. (Frontiers in Immunology, 2019)
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
CRIS-Team WoS Importer:2019-08-06

The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents: Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project - Carucci, Sara; Zuddas, Alessandro; Lampis, Angelico; Man, Kenneth K.C.; Balia, Carla; Buitelaar, Jan; Danckaerts, Marina; Dittmann, Ralf W.; Donno, Federica; Falissard, Bruno; Gagliano, Antonella; Garas, Peter; et al. (Journal of Attention Disorders, 2024)
Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.
CRIS-Team Scopus Importer:2024-03-01
Keywords: ADHD; bone age; growth; methylphenidate; pubertal maturation

THE INFLUENCE OF ANNOYANCE DUE TO AIRCRAFT NOISE ON RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, Dennis; Ott, Christian; Harazny, J. M.; Striepe, Kristina; Karg, M. V.; Jung, Susan; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

THE INFLUENCE OF ANNOYANCE DUE TO NOISE ON RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, Dennis; Ott, C.; Harazny, J. M.; Striepe, Kristina; Karg, M.; Dienemann, T.; Jung, Susan; Schmieder, Roland (2018)
EVALuna2:202962

The Influence of the Age of the Bone Marrow Microenvironment on Leukaemia Progression - Zanetti, Costanza; Ender, Joscha; Hartmann, Mark; Hey, Joschka; Godavarthy, Parimala Sonika; Weissenberger, Eva; Kumar, Rahul; Metzler, Markus; Gu, Zhaohui; Roberts, Kathryn G.; Filmann, Natalie; Bloomfield, Clara D.; et al. (BLOOD, 2019)
CRIS-Team WoS Importer:2021-10-18

The influence of the optical properties on the determination of capillary diameters - Späth, Moritz; Rohde, Maximilian; Ni, Dongqin; Knieling, Ferdinand; Stelzle, Florian; Schmidt, Michael; Klämpfl, Florian; Hohmann, Martin (Scientific Reports, 2022)
Various clinically applicable scores and indices are available to help identify the state of a microcirculatory disorder in a patient. Several of these methods, however, leave room for interpretation and only provide clues for diagnosis. Thus, a measurement method that allows a reliable detection of impending or manifest circulatory malfunctions would be of great value. In this context, the optical and non-invasive method of shifted position-diffuse reflectance imaging (SP-DRI) was developed. It allows to determine the capillary diameter and thus to assess the state of the microcirculation. The aim of the present study is to investigate how the quantification of capillary diameters by SP-DRI behaves in different individuals, i.e. for a wide range of optical properties. For this, within Monte-Carlo simulations all optical properties (seven skin layers, hemoglobin) were randomly varied following a Gaussian distribution. An important finding from the present investigation is that SP-DRI works when the optical properties are chosen randomly. Furthermore, it is shown that appropriate data analysis allows calibration-free absolute quantification of the capillary diameter across individuals using SP-DRI. This underpins the potential of SP-DRI to serve as an early alert system for the onset of microcirculatory associated diseases.

The influence of the orthotropic tissue in an electromechanical heart model - Holz, David; Martonová, Denisa; Schaller, Emely; Duong, Minh Tuan; Alkassar, Muhannad; Leyendecker, Sigrid (conference, 27th Congress of the European Society of Biomechanics, 2022)

The Multiple Sclerosis Inventory of Cognition for Adolescents (MUSICADO): A brief screening instrument to assess cognitive dysfunction, fatigue and loss of health-related quality of life in pediatric-onset multiple sclerosis - Storm van's Gravesande, K.; Calabrese, P.; Blaschek, A.; Rostásy, K.; Huppke, P.; Rothe, L.; Mall, V.; Kessler, J.; Kalbe, E.; Kraus, V.; Dornfeld, E.; Elpers, C.; et al. (European Journal of Paediatric Neurology, 2019)
Objective: Screening for cognitive impairment (CI), fatigue and also Health-related quality of life (HRQoL) in patients with pediatric-onset multiple sclerosis (POMS) is of utmost importance in clinical practice. The aim of this study was to establish a new and validated pediatric screening tool “MUSICADO” that is easy to use and time economical. Methods: 106 patients with POMS aged 12–18 years and 210 healthy controls (HCs) stratified for age and education underwent neuropsychological testing including a screening test “Multiple Sclerosis Inventory of Cognition” for adults and 8 standardized cognitive tests and established scales to assess fatigue and HRQoL. Results: The phonemic verbal fluency task (RWT “s-words”), the Trail Making Test A (TMT-A), and the Digit Span Forward discriminated significantly between patients and HCs (p = 0.000, respectively) and showed the highest proportion of test failure in patients (24.5%, 17.9%; 15.1%, respectively). Therefore, they were put together to form the cognitive part of the “MUSICADO”. After applying a scoring algorithm with balanced weighting of the subtests and age and education correction and a cut-off score for impairment, 35.8% of patients were categorized to be cognitively impaired (specificity: 88.6%). Fatigue was detected in 37.1% of the patients (specificity: 94.0%) and loss of HRQoL in 41.8% (specificity 95.7%) with the screening version, respectively. Conclusion: The MUSICADO is a newly designed brief and easy to use screening test to help to early identify CI, fatigue, and loss of HRQoL in patients with POMS as cut scores are provided for all three items. Further studies will have to show its usability in independent samples of patients with POMS.
CRIS-Team Scopus Importer:2019-10-01
Keywords: Cognition; Fatigue; Health-related quality of life; Pediatric-onset multiple sclerosis; Screening instrument

The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy - Hebebrand, Moritz; Hüffmeier, Ulrike; Trollmann, Regina; Hehr, Ute; Uebe, Steffen; Ekici, Arif Bülent; Kraus, Cornelia; Krumbiegel, Mandy; Reis, André; Thiel, Christian; Popp, Bernt (Orphanet Journal of Rare Diseases, 2019)
BackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.ResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.ConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.
CRIS-Team WoS Importer:2019-02-27

The natural history of pediatric Sturge-Weber Syndrome: A multinational cross-sectional study - Disse, Sigrid Claudia; Küpper, Hanna; Bock, Annette; Korenke, Georg Christoph; Ramantani, Georgia; Weidner, Birgit; Preisel, Martin; Trollmann, Regina; Wiemer-Kruel, Adelheid; Brockmann, Knut; Schroeder, Simone; Meyer, Sascha (European Journal of Paediatric Neurology, 2025)
Background: Sturge-Weber Syndrome (SWS) is a capillary-venous malformation which includes the brain (leptomeningeal venous capillary malformation), the eye (choroidal angioma) and the skin (facial portwine birthmark, FPB). Structural epilepsy, glaucoma and FPBs pose therapeutic challenges. Considerable advances include improved neuroimaging, new antiseizure medication (ASM) and progress in epilepsy surgery. Yet, comprehensive data on epidemiology, clinical features, diagnostics, and treatment in contemporary pediatric SWS cohorts is scarce. Methods: We conducted a multinational cross-sectional observational study in Germany, Switzerland and Austria to identify potential patients and build up a comprehensive database containing anonymized patient data. The patients’ guardians and child neurologists filled in detailed questionnaires on histories, clinical features, diagnostic and therapeutic measures. Results: Forty-seven SWS patients from Germany, Switzerland or Austria participated in our survey (111 notifications, i.e. the participation rate was 43 %). Prevalence was 7.37/million in Germany, 4.60/million in Switzerland, 2.61/million in Austria. Severity of skin, eye and brain involvement varied highly. Forty-three patients (91 %) were diagnosed with epilepsy. Median age at first seizure was 6.5 months. Thirty-two percent of the cohort received ASM in monotherapy, fifty-three percent received combination therapy and thirteen percent received no ASM. Eight percent underwent epilepsy surgery. Conclusions: In this European pediatric SWS cohort from a well-established tertiary child neurologist network, the condition was commonly diagnosed within the first year of life. 40 % of the cohort were seizure-free at inclusion; only 8.5 % of the cohort underwent epilepsy surgery. Our findings are concordant with published data from U.S. registries and case series. While our results indicate diagnostic improvement as compared to published studies, epilepsy management in SWS remains a challenge.
CRIS-Team Scopus Importer:2025-02-28
Keywords: ESNEK; Observational study; Pediatric study; Phacomatosis; Sturge-Weber Syndrome

The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor β and contributes to the development of experimental dermal fibrosis - Avouac, Jerome; Palumbo-Zerr, Katrin; Ruzehaji, Nadira; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Distler, Alfiya; Beyer, Christian; Schneider, Holm; Distler, Oliver; Schett, Georg; Allanore, Yannick; et al. (Arthritis and Rheumatology, 2014)
Objective Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis. Methods CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor type I (TβRI-CA). Results Up-regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of CAR messenger RNA and protein in a Smad-dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGFβ on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGFβ on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGFβ signaling in murine models of SSc and exacerbated bleomycin-induced and TβRI-CA-induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation. Conclusion Our findings indicate that CAR is up-regulated in SSc and regulates TGFβ signaling. Activation of CAR increases the profibrotic effects of TGFβ in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGFβ signaling in SSc and in other fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

The ovine cerebral venous system: comparative anatomy, visualization, and implications for translational research - Hoffmann, Anke; Stoffel, Michael H.; Nitzsche, Bjoern; Lobsien, Donald; Seeger, Johannes; Schneider, Holm; Boltze, Johannes (PLoS ONE, 2014)
Cerebrovascular diseases are significant causes of death and disability in humans. Improvements in diagnostic and therapeutic approaches strongly rely on adequate gyrencephalic, large animal models being demanded for translational research. Ovine stroke models may represent a promising approach but are currently limited by insufficient knowledge regarding the venous system of the cerebral angioarchitecture. The present study was intended to provide a comprehensive anatomical analysis of the intracranial venous system in sheep as a reliable basis for the interpretation of experimental results in such ovine models. We used corrosion casts as well as contrast-enhanced magnetic resonance venography to scrutinize blood drainage from the brain. This combined approach yielded detailed and, to some extent, novel findings. In particular, we provide evidence for chordae Willisii and lateral venous lacunae, and report on connections between the dorsal and ventral sinuses in this species. For the first time, we also describe venous confluences in the deep cerebral venous system and an 'anterior condylar confluent' as seen in humans. This report provides a detailed reference for the interpretation of venous diagnostic imaging findings in sheep, including an assessment of structure detectability by in vivo (imaging) versus ex vivo (corrosion cast) visualization methods. Moreover, it features a comprehensive interspecies-comparison of the venous cerebral angioarchitecture in man, rodents, canines and sheep as a relevant large animal model species, and describes possible implications for translational cerebrovascular research.
EVALuna2:18907

The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas - Chen, Daishi; Rauh, Manfred; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai (Oncotarget, 2017)
Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat®, Temodal® or Temodar®) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4OE) and ATF4 knock down (ATF4KD). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4OE) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4KD) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4OE gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4KD gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4OE glioma cells is almost not affected by TMZ treatment. In contrast, ATF4KD gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas.
EVALuna2:34245

The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase? - Azukaitis, Karolis; Simkova, Eva; Majid, Mohammad Abdul; Galiano, Matthias; Benz, Kerstin; Amann, Kerstin Ute; Bockmeyer, Clemens; Gajjar, Radha; Meyers, Kevin E.; Cheong, Hae Ii; Lange-Sperandio, Baerbel; Jungraithnnayr, Therese; et al. (Journal of the American Society of Nephrology, 2017)
The recent discovery of mutations in the gene encoding diacylglycerol kinase ? (DGKE) identified a novel pathophysiologic mechanism leading to HUS and/or MPGN. We report ten new patients from eight unrelated kindreds with DGKE nephropathy. We combined these cases with all previously published cases to characterize the phenotypic spectrum and outcomes of this new disease entity. Most patients presented with HUS accompanied by proteinuria, whereas a subset of patients exhibited clinical and histologic patterns of MPGN without TMA. We also report the first two patients with clinical and histologic HUS/MPGN overlap. DGKE-HUS typically manifested in the first year of life but was not exclusively limited to infancy, and viral triggers frequently preceded HUS episodes. We observed signs of complement activation in some patients with DGKE-HUS, but the role of complement activation remains unclear. Most patients developed a slowly progressive proteinuric nephropathy: 80% of patients did not have ESRD within 10 years of diagnosis. Many patients experienced HUS remission without specific treatment, and a few patients experienced HUS recurrence despite complete suppression of the complement pathway. Five patients received renal allografts, with no post-transplant recurrence reported. In conclusion, we did not observe a clear genotype-phenotype correlation in patients with DGKE nephropathy, suggesting additional factors mediating phenotypic heterogeneity. Furthermore, the benefits of anti-complement therapy are questionable but renal transplant may be a feasible option in the treatment of patients with this condition.
EVALuna2:25541

The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction? - Fahlbusch, F. B.; Menendez-Castro, C.; Nögel, Stephanie; Marek, I.; Beckmann, Matthias; Schleussner, E.; Ruebner, M.; Huebner, H.; Dörr, Helmuth-Günther; Schild, R. L.; Doetsch, J.; Rascher, Wolfgang; et al. (Journal of Developmental Origins of Health and Disease, 2015)
Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase ?, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.
EVALuna2:17439

The preleukemic TCF3-PBX1 gene fusion can be generated in utero and is present in ≈0.6% of healthy newborns - Hein, Daniel; Dreisig, Karin; Metzler, Markus; Izraeli, Shai; Schmiegelow, Kjeld; Borkhardt, Arndt; Fischer, Ute (Blood, 2019)
CRIS-Team Scopus Importer:2019-11-12

The Prevalence of and Predisposing Factors for Late Atrial Arrhythmias after Transcatheter Closure of Secundum Atrial Septal Defects in Children - Abu-Tair, Tariq; Martin, Claudia; Wiethoff, Christiane M.; Kampmann, Christoph (Journal of Clinical Medicine, 2023)
Background: A 24 h Holter study in children after transcatheter secundum ASD (ASD II) closure was conducted to detect the prevalence of defects and/or device-related late atrial arrhythmias (LAAs). ASD II closure with an Amplatzer septal occluder (ASO) is an established procedure. Little is known about LAAs after device implantation. Methods: The eligible participants were children who had undergone ASO implantation, with a follow-up of ≥5 years, as well as one pre- and at least one post-procedural Holter ECG. Results: In total, 161 patients (mean age: 6.2 ± 4.3 years), with a mean follow-up of 12.9 ± 3.1 years (range 5–19), were included. A median of four Holter ECGs per patient were available. LAAs occurred before intervention in four patients (2.5%), and it was peri-interventional in four patients (2.5%), sustained in three patients (1.9%), and developed in three patients (1.9%). In patients with pre- and peri-interventional LAAs, the Qp/Qs ratio was higher (6.4 ± 3.9 vs. non-AA: 2.0 ± 1.1 (p = 0.002)) and the IAS/ASO ratio was lower (1.18 ± 0.27 vs. non-AA: 1.7 ± 0.4 (p < 0.001)). The patients with LAAs differed from those without LAAs in their Qp/Qs (6.8 ± 3.5 vs. 2.0 ± 1.3; p < 0.0001) and IAS/ASO ratios (1.14 ± 0.19 vs. 1.73 ± 0.45; p < 0.001). The patients with LAAs had a Qp/Qs ratio ≥2.94:1, and those who developed LAAs had an IAS/ASO ratio <1.15. Conclusions: LAAs occurred in 1.9% of patients and were sustained in another 1.9% of patients but persisted in those with large shunt defects and large occluders in relation to the atrial septal length. The predisposing factors for LAAs after ASD closure were a high Qp/Qs ratio, pre-existing atrial arrhythmias, and a low IAS/ASO ratio.
CRIS-Team Scopus Importer:2023-06-30
Keywords: arrhythmia; ASD closure; interventional cardiology; pediatric

Therapy with low-dose azacitidine for MDS in children and young adults: a retrospective analysis of the EWOG-MDS study group - Cseh, Annamaria M.; Niemeyer, Charlotte M.; Yoshimi, Ayami; Catala, Albert; Fruehwald, Michael C.; Hasle, Henrik; Van Den Heuvel-Eibrink, Mary M.; Lauten, Melchior; De Moerloose, Barbara; Smith, Owen P.; Bernig, Toralf; Gruhn, Bernd; et al. (British Journal of Haematology, 2016)
Low-dose azacitidine is efficient and safe in the therapy of malignant myeloid disorders in adults but data in children are lacking. We present a retrospective analysis of 24 children and young adults with myelodysplastic syndrome (MDS) who received azacitidine at the time of first diagnosis or relapse after allotransplant (2 children were treated with azacitidine both initially and for relapse). Diagnoses were refractory cytopenia of childhood (N = 4), advanced primary MDS (N = 9) and secondary MDS (N = 11). The median duration of treatment was four cycles. Azacitidine was well tolerated, but cytopenias led to dose reduction in five cases. Treatment was discontinued in one child because of impaired renal function. Sixteen MDS patients were treated with azacitidine at first diagnosis. One complete clinical remission was observed and one child showed complete marrow remission; six children experienced stable disease with haematological improvement. Ten children received azacitidine for relapsed MDS after transplant: of these, seven experienced stable disease for 2-30 cycles (median 3), including one patient with haematological improvement for seven cycles. In summary, azacitidine is effective in some children with MDS and appears to be a non-toxic option in palliative situations to prolong survival.
EVALuna2:33875

The role of de novo variants in formation of human anorectal malformations - Dworschak, Gabriel C.; van Rooij, Iris A.L.M.; Reutter, Heiko Martin (Genes, 2021)
Anorectal malformations (ARM) represent a rare birth defect of the hindgut that occur in approximately 1 in 3000 live births. Around 60% of ARM occur with associated anomalies including defined genetic syndromes and associations with chromosomal aberrations. The etiology of ARM is heterogeneous, with the individual environmental or genetic risk factors remaining unknown for the majority of cases. The occurrence of familial ARM and previous epidemiologic analysis suggest autosomal dominant inheritance in a substantial subset of ARM patients. The implicated mortality and reduced fecundity in patients with ARM would lead to allele loss. However, mutational de novo events among the affected individuals could compensate for the evolutionary pressure. With the implementation of exome sequencing, array-based molecular karyotyping and family-based rare variant analyses, the technologies are available to identify the respective factors. This review discusses the identification of disease-causing variants among individuals with ARM. It highlights the role of mutational de novo events.
CRIS-Team Scopus Importer:2021-09-10
Keywords: Anorectal malformation (ARM); Birth defect; Copy number variation (CNV); De novo; Fecundity; Heritability

The role of de novo variants in patients with congenital diaphragmatic hernia - Bendixen, Charlotte; Reutter, Heiko Martin (Genes, 2021)
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both de novo and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of de novo variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of de novo variants in CDH. This review gives an overview of the known de novo disease-causing variants in CDH patients.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Congenital diaphragmatic hernia; De novo variants; Impaired reproductive fitness; Mortality

The role of interferon type I and type III receptors in rhinovirus induced allergic asthma - Krug, J.; Kölle, Julia; Kiefer, Alexander; Vuorinen, T.; Xepapadaki, P.; Stanic, B.; Akdis, M.; Zimmermann, Theodor; Papadopoulos, N. G.; Finotto, Susetta; Chiriac, Mircea-Teodor (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

The role of interleukin 3 (IL3) in allergic asthma - Kölle, Julia; Vuorinen, T.; Kiefer, Alexander; Zimmermann, Theodor; Xepapadaki, P.; Rieker, Ralf; Papadopoulos, N. G.; Finotto, Susetta (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

The role of regulated on activation, normal T cell expressed and secreted (RANTES) in allergic asthma - Li, N.; Kölle, Julia; Kiefer, Alexander; Xepapadaki, P.; Kowalski, M. L.; Bachert, C.; Jartti, T.; Vuorinen, T.; Lewandowska-Polak, A.; Zhang, N.; Lukkarinen, H.; Zimmermann, Theodor; et al. (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

The Safety of Drug Therapy in Children - Wimmer, Stefan; Neubert, Antje; Rascher, Wolfgang (Deutsches Ärzteblatt international, 2015)
1.7% of children taking medication on an outpatient basis in Germany have at least one adverse drug reaction (ADR). The corresponding figure for hospitalized children is estimated at 10% .This review is based on pertinent literature retrieved by a selective search in PubMed.According to reports submitted to the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft, AkdÄ), serious ADRs can arise, for example, after the administration of dimenhydrinate, ?-adrenergic nose drops, enemas containing phosphate, ACE inhibitors, angiotensin-2-receptor antagonists (sartans), and methylphenidate. The causes of ADRs include overdoses, drug administration despite contraindications, and inadequate monitoring of long-term treatment. Errors can also be made in communication, labeling, and drug administration. The risk of ADRs is especially high in off-label use. Computerized physician order entry systems, individual packaging and labeling of single doses, and the use of bar codes for patient and drug identification can help prevent such errors.The process of drug administration should be optimized through suitable interventions and electronic support, with due consideration of local circumstances. Clinical trials on children should be encouraged as a means of improving drug safety, and additional financial incentives should be created for trials concerning drugs that are off-patent. Physicians and pharmacists should take care to report adverse reactions as they are required to do by professional code, particularly in the case of new drugs, off-label use, or medication errors. A recognized national standard for dosing that can be implemented in computerized physician order entry systems is needed so that evidence-based pediatric dosages can be calculated.
EVALuna2:18938

The second European interdisciplinary Ewing sarcoma research summit–A joint effort to deconstructing the multiple layers of a complex disease - Kovar, Heinrich; Amatruda, James; Brunet, Erika; Burdach, Stefan; Cidre-Aranaz, Florencia; De Alava, Enrique; Dirksen, Uta; Van Der Ent, Wietske; Grohar, Patrick; Grunewald, Thomas G. P.; Helman, Lee; Houghton, Peter; et al. (Oncotarget, 2016)
Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second "European interdisciplinary Ewing sarcoma research summit" assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.
EVALuna2:33876

The thoracic and cardiovascular surgeon and the pediatric cardiologist - Dittrich, Sven (Thoracic and Cardiovascular Surgeon, 2019)
CRIS-Team Scopus Importer:2019-08-23

The Treatment of Growth Disorders in Childhood and Adolescence. - Wölfle, Joachim; Schnabel, Dirk; Binder, Gerhard (Deutsches Ärzteblatt international, 2024)
BACKGROUND: 3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. METHODS: This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience. RESULTS: Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management. CONCLUSION: There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.
EVALuna2:549518

The Use of Cannabinoids in Pediatric Palliative Care—A Retrospective Single-Center Analysis - Tagsold, David; Toni, Irmgard; Trollmann, Regina; Wölfle, Joachim; Gravou-Apostolatou, Chara (Children, 2024)
This data analysis aimed to systematically analyze a pediatric patient population with a life-limiting disease who were administered cannabinoids. It was a retrospective single-center analysis of patients under supervision of the specialized outpatient pediatric palliative care (SOPPC) team at the Department of Pediatrics and Adolescent Medicine of the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU). Thirty-one patients with a primary diagnosis of neuropediatric, oncologic, metabolic, and cardiologic categories were included. The indications we identified were spasticity, pain, restlessness, anxiety, loss of appetite, epilepsy, and paresis. Certain aspects of quality of life were improved for 20 of 31 patients (64.5%). For nine patients (29%), no improvement was detected. No conclusions could be drawn for two patients (6.5%). Adverse events were reported for six of the thirty-one patients (19.4%). These were graded as mild, including symptoms such as restlessness, nausea, and behavioral issues. We detected no clinically relevant interactions with other medications. We collected fundamental data on the use of cannabinoids by pediatric palliative patients. Cannabinoids are now frequently administered in pediatric palliative care. They seem to be safe to use and should be considered an add-on therapy for other drug regimens.
CRIS-Team Scopus Importer:2024-04-26
Keywords: cannabinoids; palliative care; pediatric

Third-generation dual-source 70-kVp chest CT angiography with advanced iterative reconstruction in young children: image quality and radiation dose reduction - Rompel, Oliver; Glöckler, Martin; Janka, Rolf Matthias; Dittrich, Sven; Cesnjevar, Robert; Lell, Michael; Uder, Michael; Hammon, Matthias (Pediatric Radiology, 2016)
Many technical updates have been made in multi-detector CT.To evaluate image quality and radiation dose of high-pitch second- and third-generation dual-source chest CT angiography and to assess the effects of different levels of advanced modeled iterative reconstruction (ADMIRE) in newborns and children.Chest CT angiography (70 kVp) was performed in 42 children (age 158 ± 267 days, range 1-1,194 days). We evaluated subjective and objective image quality, and radiation dose with filtered back projection (FBP) and different strength levels of ADMIRE. For comparison were 42 matched controls examined with a second-generation 128-slice dual-source CT-scanner (80 kVp).ADMIRE demonstrated improved objective and subjective image quality (P < .01). Mean signal/noise, contrast/noise and subjective image quality were 11.9, 10.0 and 1.9, respectively, for the 80 kVp mode and 11.2, 10.0 and 1.9 for the 70 kVp mode. With ADMIRE, the corresponding values for the 70 kVp mode were 13.7, 12.1 and 1.4 at strength level 2 and 17.6, 15.6 and 1.2 at strength level 4. Mean CTDIvol, DLP and effective dose were significantly lower with the 70-kVp mode (0.31 mGy, 5.33 mGy*cm, 0.36 mSv) compared to the 80-kVp mode (0.46 mGy, 9.17 mGy*cm, 0.62 mSv; P < .01).The third-generation dual-source CT at 70 kVp provided good objective and subjective image quality at lower radiation exposure. ADMIRE improved objective and subjective image quality.
EVALuna2:14476

Three-Dimensional Rotational Angiography during Catheterization of Congenital Heart Disease – A ten Years’ experience at a single center - Söder, Stephan; Wällisch, Wolfgang; Dittrich, Sven; Cesnjevar, Robert; Pfammatter, Jean Pierre; Glöckler, Martin (Scientific Reports, 2020)
This paper aims to assess the usability and advantages of three-dimensional rotational angiography (3DRA) in patients with congenital heart disease (CHD) and its application in the cath lab. Up to now, its use in CHD is not widespread or standardized. We analyzed all patients with CHD who underwent a 3DRA at our facility between January 2010 and May 2019. The 3DRAs were evaluated for radiation exposure, contrast dye consumption, diagnostic utility and image quality. We performed 872 3DRAs. 3DRA was used in 67.1% of the cases for interventional procedures and in 32.9% for diagnostic purposes. Two different acquisition programs were applied. The median dose-area product (DAP) for all 872 rotations was 54.1 µGym2 (21.7–147.5 µGym2) and 1.6 ml/kg (0.9–2.07 ml/kg) of contrast dye was used. Diagnostic utility of the generated 3D-model was rated superior to the native 3D angiography in 94% (819/872). 3DRA is an excellent and save diagnostic and interventional tool. However, 3DRA has not become a standard imaging procedure in pediatric cardiology up to now. Effort and advantage seems to be unbalanced, but new less invasive techniques may upgrade this method in future.
CRIS-Team Scopus Importer:2020-05-05

Three-Dimensional Rotational Angiography in the Pediatric Cath Lab: Optimizing Aortic Interventions - Stenger, Anna; Dittrich, Sven; Glöckler, Martin (Pediatric Cardiology, 2016)
The aim of this study was to evaluate usability and accuracy of three-dimensional rotational angiography (3DRA) during interventions of the aorta in congenital heart disease (CHD). 3DRA is an accurate, encompassing and fast imaging technique in the cath lab. However, there is only few published data about its use during interventions in CHD. Between January 2010 and January 2014, 3DRA was performed in 77 patients with aortic issues: in 65 % cases, an intervention was performed, of which 72 % had aortic isthmus stenosis. Data were obtained retrospectively. The accuracy of 3DRA was evaluated on the basis of comparative measurements (n = 60) of the aortic diameter between 3DRA and conventional biplane angiography. Measurements presented a high accuracy with an average deviation of 3.89 % [±3 %] and a significant correlation of r = 0.99 after Pearson (p < 0.0001). Clinical benefit was assessed using a five-point Likert scale and could be shown in 98 %. Comparison with a control group showed a reduced fluoroscopy time from 10.2 to 8.30 min (median, p < 0.01) and decreased radiation dose of 0.18 compared to 0.56 Gy cm(2)/kg (median, p < 0.02). The use of 3DRA in patients with aortic anomalies has advantages in comparison with conventional angiography. It improves diagnostic accuracy, and 3D guidance enables a faster and simplified intervention with enhanced patients' safety and the potential to reduce radiation dose.
EVALuna2:25120

Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer - El Baba, Chirine; Mahadevan, Vijayalakshmi; Fahlbusch, Fabian B.; Mohan, Suma S.; Rau, Tilman; Gali-Muhtasib, Hala; Schneider-Stock, Regine (Molecular Cancer, 2014)
Thymoquinone (TQ) was shown to reduce tumor growth in several cancer models both in vitro and in vivo. So far only a few targets of TQ, including protein kinases have been identified. Considering that kinases are promising candidates for targeted anticancer therapy, we studied the complex kinase network regulated by TQ.Novel kinase targets influenced by TQ were revealed by in silico analysis of peptide array data obtained from TQ-treated HCT116wt cells. Western blotting and kinase activity assays were used to determine changes in kinase expression patterns in colorectal cancer cells (HCT116wt, DLD-1, HT29). To study the viability/apoptotic effects of combining the PAK1 inhibitor IPA-3 and TQ, crystal violet assay and AnnexinV/PI staining were employed. Interactions between PAK1 and ERK1/2 were investigated by co-immunoprecipitation and modeled by docking studies. Transfection with different PAK1 mutants unraveled the role of TQ-induced changes in PAK1 phosphorylation and TQ's effects on PAK1 scaffold function.Of the 104 proteins identified, 50 were upregulated >= 2 fold by TQ and included molecules in the AKT-MEK-ERK1/2 pathway. Oncogenic PAK1 emerged as an interesting TQ target. Time-dependent changes in two PAK1 phosphorylation sites generated a specific kinase profile with early increase in pPAK(Thr212) followed by late increase in pPAK(Thr423). TQ induced an increase of pERK1/2 and triggered the early formation of an ERK1/2-PAK1 complex. Modeling confirmed that TQ binds in the vicinity of Thr212 accompanied by conformational changes in ERK2-PAK1 binding. Transfecting the cells with the non-phosphorylatable mutant T212A revealed an increase of pPAK(Thr423) and enhanced apoptosis. Likewise, an increase in apoptosis was observed in cells transfected with both the kinase-dead K299R mutant and PAK1 siRNA. Using structural modeling we suggest that TQ interferes also with the kinase domain consequently disturbing its interaction with pPAK(Thr423), finally inhibiting MEK-ERK1/2 signaling and disrupting its prosurvival function. pERK1/2 loss was also validated in vivo.Our study shows for the first time that the small molecule TQ directly binds to PAK1 changing its conformation and scaffold function. Because TQ affects the central RAF/MEK/ERK1/2 pathway, the combination of TQ with targeted therapies is worth considering for future anticancer treatments.
EVALuna2:6620

Time Tracking of Standard Ultrasound Examinations in Pediatric Hospitals and Pediatric Medical Practices - A Multicenter Study by the Pediatric Section of the German Society of Ultrasound in Medicine (DEGUM) - Regensburger, Adrian; Knieling, Ferdinand; Feldkamp, Axel; Rascher, Wolfgang; Diesch, Katharina; Wölfle, Joachim; Prokosch, Hans-Ulrich; Jüngert, Jörg M. (Ultraschall in der Medizin, 2019)
PURPOSE: Ultrasonography is the primary imaging modality in pediatrics but still lacks sufficient reimbursement in Germany. In this multicenter study, national data for the duration of standard ultrasound in pediatrics were systematically documented in order to specify the actual time required. MATERIALS AND METHODS: N = 10 hospitals (N = 5 university hospitals, N = 5 non-university hospitals) and N = 3 medical practices in Germany recorded the entire process of an ultrasound examination in a special protocol developed by the Pediatric Section of the DEGUM. The duration of each of seven single steps during ultrasonography (from data input to final discussion of the results) of different organ systems was logged. RESULTS: In total, N = 2118 examinations from different organ systems were recorded. N = 10 organ systems were examined frequently (> 30 times). The total duration of an ultrasound examination was statistically significantly longer in hospitals compared to medical practices (median (IQR) 27 min. (18-38) vs. 12 min. (9-17), p < 0.001). The "hands-on" patient time was approximately one half of the total required time in both settings (49.9 % vs. 48.9 %). Ultrasonography of the abdomen and brain lasted longer in university hospitals than in non-university hospitals (p < 0.001, and p = 0.04, respectively). Cooperation and age did not uniformly correlate with the total duration. CONCLUSION: This study provides novel comprehensive national data for the duration of standardized ultrasound examinations of children and adolescents in Germany. These data are essential for a further evaluation of the economic costs and should support better remuneration in the future.
EVALuna2:209480

Time trends towards earlier puberty in boys and girls with type 1 diabetes: Insights from the German Diabetes Prospective Follow-up (DPV) registry, 2000 to 2021 - Gohlke, Bettina; Reschke, Felix; Lanzinger, Stefanie; Boettcher, Claudia; Gemulla, Gitta; Thiele-Schmitz, Susanne; Dunstheimer, Désirée; van den Boom, Louise; Wölfle, Joachim; Holl, R. W. (Diabetes Obesity & Metabolism, 2023)
Aim: To examine the time trends and factors associated with the onset of puberty in children with type 1 diabetes (T1D) using data from the German Diabetes Prospective Follow-up (Diabetes-Patienten-Verlaufsdokumentation [DPV]) registry. Methods: A total of 13 127 children with T1D, aged 6 to 18 years, were included in the analysis. Regression analysis was performed to investigate the relationship between diabetes duration, body mass index (BMI) standard deviation score (SDS), glycated haemoglobin (HbA1c) level, migration background, and the onset of puberty, stratified by sex. Results: Our findings revealed a significant trend towards earlier puberty in both girls and boys with T1D over the observed period (2000 to 2021). Puberty onset in girls (thelarche Tanner stage B2) decreased from 11.48 (11.35-11.65) years in 2000 to 10.93 (10.79-11.08) years in 2021 and gonadarche (Tanner stage G2/testicular volume >3 mL) decreased from 12.62 (12.42-12.82) years in 2000 to 11.98 (11.79-12.16) years in 2021 in boys (both P < 0.001). Longer diabetes duration, higher BMI SDS, and lower HbA1c level were associated with earlier puberty in both sexes (P < 0.001). Conclusions: Our study highlights earlier puberty in children with T1D, influenced by BMI SDS, HbA1c level, and migration background. This has important implications for diabetes management and supporting healthy development. Further research is needed to understand the underlying mechanisms and develop potential interventions for this vulnerable population.
CRIS-Team Scopus Importer:2023-10-20
Keywords: body composition; clinical physiology; cohort study; type 1 diabetes

Timing of first arteriovenous fistula cannulation in children on hemodialysis - Almási-Sperling, Veronika; Galiano, Matthias; Lang, Werner; Rother, Ulrich; Rascher, Wolfgang; Regus, Susanne (Pediatric Nephrology, 2016)
Due to lower complication rates in comparison to central venous catheter (CVC) arteriovenous fistulas (AVFs) are now the preferred hemodialysis access. Recommendations for the first access cannulation range from 6 to 12 weeks, which could lead to temporary or even permanent preference for CVC while awaiting the maturation of the newly created AVF. The aim of this study was to evaluate the influence of first cannulation of AVFs on primary (PP) and secondary (SP) patency rates in children on hemodialysis (HD).This was a retrospective cohort study of 42 pediatric patients with a median age of 14 (range 7-17) years. At the time of surgical AVF creation 21 patients (end-stage renal disease) were still on HD via CVC or peritoneal catheter, while 21 were pre-emptive with initiation of HD expected within a few weeks. All patients received an AVF by the same experienced surgeon between February 1993 and May 2014. Primary failure (PF) was defined as the inability to use the AVF even once due to absent maturation or occlusion within 4 weeks after creation. PP was defined as the interval from time of access placement to any intervention designed to maintain or reestablish patency, to access thrombosis or the time of measurement of patency, while SP was defined as the total lifespan from creation to access abandonment, end of follow-up or loss.Primary failure was observed in six (14.3 %) of 42 AVFs (all radiocephalic fistulas) within the first 10 days after cannulation. Excluding PF, the PP/SP rates at 1, 3, 6, 12, 18 and 24 months were 100/100, 91/99, 86/98, 76/95, 55/85 and 44/77 %, respectively. There was a significant decrease in PP when first cannulation was performed within the first 30 days after creation compared to first cannulation performed after 30 days (p = 0.004). In terms of PP/SP outcome and timing of the first cannulation, there was no significant difference in thee outcome of PP/SP between first cannulation within the first 45 days after creation and that after 45 days (p = 0.091/0.883).The findings suggest that cannulation of AVF within 30 days after surgical creation reduces PP, while SP may be influenced less by time until cannulation. We also found no significant differences in PP after maturing periods of >45 days.
EVALuna2:15275

Tissue sodium concentration correlates with hypertrophic vascular remodelling in type 2 diabetes - Kannenkeril, Dennis; Jung, Susan; Harazny, Jeremy; Striepe, Kristina; Ott, Christian; Linz, Peter; Nagel, Armin Michael; Uder, Michael; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma - Krug, Jasmin; Kiefer, Alexander; Kölle, Julia; Vuorinen, Tytti; Xepapadaki, Paraskevi; Stanic, Barbara; Chiriac, Mircea-Teodor; Akdis, Muebeccel; Zimmermann, Theodor; Papadopoulos, Nikolaos G.; Finotto, Susetta (European Respiratory Journal, 2021)
Introduction: Interferon (IFN) responses have been reported to be defective in rhinovirus (RV)-induced asthma. The heterodimeric receptor of type I IFN (IFN-α/β) is composed of IFN-αR1 and IFN-αR2. Ligand binding to the IFN-α/β receptor complex activates signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2 intracellularly. Although type III IFN (IFN-λ) binds to a different receptor containing IFN-λR1 and interleukin-10R2, its triggering leads to activation of the same downstream transcription factors. Here, we analysed the effects of RV on IFN type I and III receptors, and asked about possible Toll-like receptor 7/8 (TLR7/8) agonist R848-mediated IFN-αR1 and IFN-λR1 regulation. Methods: We measured IFN-α, IFN-β and IFN-λ and their receptor levels in peripheral blood mononuclear cell (PBMC) supernatants and cell pellets stimulated with RV1b and R848 in two cohorts of children with and without asthma recruited at pre-school age (PreDicta) and at primary school age (AGENDAS) as well as in cell supernatants from total lung cells isolated from mice. Results: We observed that R848 induced IFN-λR mRNA expression in PBMCs of healthy and asthmatic children, but suppressed IFN-αR mRNA levels. In murine lung cells, RV1b alone and together with R848 suppressed IFN-αR protein in T-cells compared with controls and in total lung IFN-λR mRNA compared with RV1b infection alone. Conclusions: In PBMCs from pre-school age children, IFN-αR mRNA was reduced and IFN-λR1 mRNA was induced upon treatment with the TLR7/8 agonist R848, thus suggesting new avenues for induction of antiviral immune responses in paediatric asthma.
CRIS-Team Scopus Importer:2021-06-04

TNF promotes DECTIN2 family C-type lectin receptor expression in human macrophages. - Haberkamp, Carl; Allabauer, Ida; Blaha, Niklas; Bodendorfer, Barbara; Cunningham, Sarah; Hörning, André; Lang, Roland (Journal of Leukocyte Biology, 2023)
TNF blockade constitutes an effective therapy for inflammatory bowel disease, yet increases the risk for infection, including active tuberculosis. The DECTIN2 family C-type lectin receptors MINCLE, MCL, and DECTIN2 sense mycobacterial ligands and activate myeloid cells. In mice, upregulation of DECTIN2 family C-type lectin receptor after stimulation with Mycobacterium bovis Bacille Calmette-Guérin requires TNF. Here, we investigated whether TNF controls inducible C-type lectin receptor expression in human myeloid cells. Monocyte-derived macrophages were stimulated with Bacille Calmette-Guérin and the TLR4 ligand lipopolysaccharide, and expression of C-type lectin receptor was analyzed. Bacille Calmette-Guérin and lipopolysaccharide strongly upregulated messenger RNA expression of DECTIN2 family C-type lectin receptor but not of DECTIN1. Bacille Calmette-Guérin and lipopolysaccharide also induced robust production of TNF. Recombinant TNF was sufficient to upregulate expression of DECTIN2 family C-type lectin receptor. Blocking TNF with the TNFR2-Fc fusion protein etanercept abrogated, as expected, the effect of recombinant TNF and impaired induction of DECTIN2 family C-type lectin receptor by Bacille Calmette-Guérin and lipopolysaccharide. Flow cytometry confirmed upregulation of MCL at the protein level by recombinant TNF and showed inhibition of Bacille Calmette-Guérin-induced MCL by etanercept. To investigate the impact of TNF on C-type lectin receptor expression in vivo, we analyzed peripheral blood mononuclear cells of patients with inflammatory bowel disease and observed downregulation of MINCLE and MCL expression after therapeutic TNF blockade. Together, TNF is sufficient to upregulate DECTIN2 family C-type lectin receptor in human myeloid cells and contributes to this process after encounter with Bacille Calmette-Guérin or lipopolysaccharide. Impaired C-type lectin receptor expression in patients receiving TNF blockade may dampen the sensing of microbes and defense against infection.
EVALuna2:531674
Keywords: MINCLE; MCL; DECTIN2; TNF blockade; mycobacteria; inflammatory bowel disease

Tolerability of Tumor Treating Fields in pediatric high-grade glioma patients illustrated by post-market surveillance data - Suchorska, B.; Lucaciu, R.; Jung, S.; Leyh, Jörg; Woelfl, M.; Hirt, C.; Scholz, M. (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Tolvaptan treatment in an adult Fontan patient with protein-losing enteropathy: a serial 23Na-MRI investigation - Moosmann, Julia; Toka, Okan; Linz, Peter; Dahlmann, Anke; Nagel, Armin M.; Schiffer, Mario; Uder, Michael; Cesnjevar, Robert; Dittrich, Sven; Kopp, Christoph (Therapeutic Advances in Chronic Disease, 2021)
Background: Protein-losing enteropathy (PLE) is a severe complication of the univentricular Fontan circulation and associated with disturbances in salt and water homeostasis. Fontan patients with PLE have a poor prognosis, with increased morbidity and mortality. Due to limited therapeutic strategies, patients are often treated only symptomatically. Methods: We report our first experience of Tolvaptan (TLV) treatment in a Fontan patient with PLE, severe volume retention and hyponatraemia, refractory to conventional diuretic therapy. In addition to clinical parameters, we monitored drug effects including tissue sodium and volume status via serial 23Na-magnetic resonance imaging (23Na-MRI) and bioimpedance spectroscopy compared with age-matched controls. Results: 23Na-MRI identified elevated tissue sodium, which decreased under TLV treatment, as well as volume status, while serum sodium increased and the patient’s symptoms improved. During long-term treatment, we were able to differentiate between sodium and volume status in our patient, suggesting that TLV uncoupled body sodium from water. Conclusion: TLV in addition to loop diuretics improved clinical symptoms of PLE and lowered tissue sodium overload. Long-term effects should be further evaluated in Fontan patients.
CRIS-Team Scopus Importer:2021-04-30
Keywords: Congenital heart disease; Fontan; RAAS; Tolvaptan

Toward evidence-based diagnosis of myocarditis in children and adolescents: Rationale, design, and first baseline data of MYKKE, a multicenter registry and study platform - Messroghli, Daniel R.; Pickardt, Thomas; Fischer, Marcus; Opgen-Rhein, Bernd; Papakostas, Konstantin; Bocker, Dorothee; Jakob, Andre; Khalil, Markus; Mueller, Goetz C.; Sclunidt, Florian; Kaestner, Michael; Ten Cate, Floris E. A. Udink; et al. (American Heart Journal, 2017)
The aim of this registry is to provide data on age-related clinical features of suspected myocarditis and to create a study platform allowing for deriving diagnostic criteria and, at a later stage, testing therapeutic interventions in patients with myocarditis. STUDY DESIGN AND RESULTS: After an initial 6-month pilot phase, MYKKE was opened in June 2014 as a prospective multicenter registry for patients from pediatric heart centers, university hospitals, and community hospitals with pediatric cardiology wards in Germany. Inclusion criteria consisted of age<18 years and hospitalization for suspected myocarditis as leading diagnosis at the discretion of the treating physician. By December 31, 2015, fifteen centers across Germany were actively participating and had enrolled 149 patients. Baseline data reveal 2 age peaks (<2 years, >12 years), show higher proportions of males, and document a high prevalence of severe disease courses in pediatric patients with suspected myocarditis. Severe clinical courses and early adverse events were more prevalent in younger patients and were related to severely impaired leftventricular ejection fraction at initial presentation. SUMMARY: MYKKE represents a multicenter registry and research platform for children and adolescents with suspected myocarditis that achieve steady recruitment and generate a wide range of real-world data on clinical course, diagnostic workup, and treatment of this group of patients. The baseline data reveal the presence of 2 age peaks and provide important insights into the severity of disease in children with suspected myocarditis. In the future, MYKKE might facilitate interventional substudies by providing an established collaborating network using common diagnostic approaches.
EVALuna2:33733

Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes - Newe, Axel; Wimmer, Stefan; Neubert, Antje; Becker, Linda; Prokosch, Hans-Ulrich; Beckmann, Matthias; Fietkau, Rainer; Forster, Christian; Neurath, Markus; Schett, Georg; Ganslandt, Thomas (PLoS ONE, 2015)
Background The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though. Methods In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration. Result The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations. Discussion The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combination

Transcatheter Intervention of Bilateral Renal Artery Stenosis in an Infant after arterial Switch to Control Arterial Hypertension - Wiewrodt, B.; Dittrich, Sven; Uder, Michael; Wirbelauer, J. (Klinische Pädiatrie, 2016)
EVALuna2:14584

Transfontanellar Contrast-Enhanced Ultrasound for Monitoring Brain Perfusion During Neonatal Heart Surgery - Knieling, Ferdinand; Rüffer, André; Cesnjevar, Robert; Regensburger, Adrian; Purbojo, Ariawan; Dittrich, Sven; Münch, Frank; Neubert, Antje; Meyer, Sebastian; Strobel, Deike; Rascher, Wolfgang; Wölfle, Joachim; et al. (Circulation: Cardiovascular Imaging, 2020)
CRIS-Team Scopus Importer:2020-03-13

Transfontanellar Contrast-enhanced US for Intraoperative Imaging of Cerebral Perfusion during Neonatal Arterial Switch Operation - Knieling, Ferdinand; Cesnjevar, Robert; Regensburger, Adrian; Wagner, Alexandra; Purbojo, Ariawan; Dittrich, Sven; Münch, Frank; Neubert, Antje; Wölfle, Joachim; Jüngert, Jörg M.; Rüffer, André (Radiology, 2022)
Background Brain injury and subsequent neurodevelopmental disorders are major determinants for later-life outcomes in neonates with transposition of the great arteries (TGA). Purpose To quantitatively assess cerebral perfusion in neonates with TGA undergoing arterial switch operation (ASO) using transfontanellar contrast-enhanced US (T-CEUS). Materials and Methods In a prospective single-center cross-sectional diagnostic study, neonates with TGA scheduled for ASO were recruited from February 2018 to February 2020. Measurements were performed at five time points before, during, and after surgery (T1-T5), and 11 perfusion parameters were derived per cerebral hemisphere. Neonate clinical characteristics, heart rate, mean arterial pressure, central venous pressure, near-infrared spectroscopy, blood gas analyses, ventilation time, time spent in the pediatric intensive care unit, and time in hospital were correlated with imaging parameters. Analysis of variance or a mixed-effects model were used for groupwise comparisons. Results A total of 12 neonates (mean gestational age, 39 6/7 weeks ± 1/7 [SD]) were included and underwent ASO a mean of 6.9 days ± 3.4 after birth. When compared with baseline values, T-CEUS revealed a longer mean time-to-peak (right hemisphere, 4.3 seconds ± 2.1 vs 17 seconds ± 6.4 [P < .001]; left hemisphere, 4.0 seconds ± 2.3 vs 21 seconds ± 8.7 [P < .001]) and rise time (right hemisphere, 3.5 seconds ± 1.7 vs 11 seconds ± 5.1 [P = .002]; left hemisphere, 3.4 seconds ± 2.0 vs 22 seconds ± 7.8 [P = .004]) in both cerebral hemispheres during low-flow cardiopulmonary bypass and hypothermia (T4) for all neonates. Neonate age at surgery negatively correlated with T-CEUS parameters during ASO, as calculated with the area under the flow curve (AUC) during wash-in (R = -0.60, P = .020), washout (R = -0.82, P = .002), and both wash-in and washout (R = -0.79, P = .004). Mean AUC values were lower in neonates older than 7 days compared with younger neonates during wash-in ([87 arbitrary units au ± 77] × 102 vs [270 au ± 164] × 102, P = .049]), washout ([15 au ± 11] × 103 vs [65 au ± 38] × 103, P = .020]) and both wash-in and washout ([24 au ± 18] × 103 vs [92 au ± 53] × 103, P = .023). Conclusion Low-flow hypothermic conditions resulted in reduced cerebral perfusion, as measured with transfontanellar contrast-enhanced US, which inversely correlated with age at surgery. Clinical trial registration no. NCT03215628 © RSNA, 2022 Online supplemental material is available for this article.
CRIS-Team Scopus Importer:2022-07-01

Transforming Growth Factor ß1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis - Laubach, Joern Pascal; Ludwig, Michael; Horn, Tabea; Eickmeier, Olaf; Smaczny, Christina; Schubert, Ralf; Zielen, Stefan; Majoor, Christof; Aydin, Malik; Schnell, Alexander; Schmitt-Grohé, Sabina (Frontiers in Bioscience - Landmark, 2023)
Background: High TGFβ1-producing variants cause severe clinical disease in F508del homozygous patients. Lately, we showed that a single nucleotide polymorphism (SNP), rs41266431, in the GJA4 gene modifies the disease severity of cystic fibrosis (CF). Our aim was to investigate whether the clinical phenotype associated with GJA4 variants was independent of TGFβ1 variants. Methods: Homozygous F508del patients (n = 115, mean age 27.2 years, m/f (65/50)) were included in this study. A deep sequence analysis was performed for GJA4 and TGBβ1, and disease severity was assessed over 3 years using lung function tests (LFTs), body mass index, diabetes mellitus, colonization with Pseudomonas aeruginosa, survival to end-stage lung disease (ESLD), as well as distinct inflammatory biomarkers. Results: The analyses revealed that one SNP (rs41266431) in GJA4 may be clinically relevant. Carriers homozygous for the G variant (n = 84; 73%) presented with worse LFTs (forced vital capacity (FVC) % predicted: mean 80/86.6, p < 0.035) and a lower survival to ESLD (p < 0.029). For the TGBβ1 variant: 509 carriers of the C variant (CT + CC genotype, n = 105, 91.3%) had better LFTs (Forced expiratory flow at 75% of the FVC (FEF75% predicted: median 40/29.5, p < 0.015), although a similar outcome to ESLD. A gene–gene interaction was not observed between TGBβ1 and GJA4 variants for any clinical measure. Conclusions: GJA4 variants are independent of TGBβ1 variants. Both variants had an impact on the LFTs, although only GJA4 variants were associated with an improved outcome for ESLD. Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.
CRIS-Team Scopus Importer:2023-09-29
Keywords: bronchial inflammation; cystic fibrosis; F508del homozygous; gap junction protein alpha 4; gene–gene interaction; geno-/phenotype relation; precision medicine; transforming growth factor beta1

Transfusion-related alloimmune neutropenia with no pulmonary complications: one donor-five cases - Hauck-Dlimi, Barbara; Ruppel, Renate; Zimmermann, Robert; Strobel, Joachim; Reil, Angelika; Eckstein, Reinhold; Zingsem, Jürgen (Transfusion, 2016)
Neutrophil alloantibodies are well-known triggers of transfusion-related acute lung injury (TRALI) and also cause immune neutropenia. Alloimmune neutropenia due to transfusion is an isolated phenomenon that is only rarely identified. Its incidence is specified in the literature as being less than one in 10,000 transfused plasma-containing units. We expect that this phenomenon is underreported.We observed five cases of alloimmune neutropenia with no respiratory complications with only one case initially reported as a suspected transfusion reaction. The other four cases were detected in the course of the subsequent lookback investigation.The first case was reported as a potential transfusion reaction when a female patient showed a decrease in the white blood cell count after a platelet (PLT) transfusion. Examinations of the donor blood revealed an antibody against the human neutrophil antigen HNA-1b; the recipient was typed HNA-1b positive and HNA-1a negative. After examining the blood counts of other patients who previously received PLT concentrates from the same donor, we identified four other patients with an unreported decrease in the leukocyte and/or granulocyte count of more than approximately 50% after transfusion.HNA antibodies are generally regarded as potential triggers of TRALI. Here we describe an HNA antibody that reproducibly caused transfusion-related neutropenia only without pulmonary complications. Factors predisposing patients to TRALI development are widely discussed. Our case suggests that antibody characteristics are also relevant in the development of TRALI. Current measures to prevent TRALI should also prevent transfusion-related alloimmune neutropenia.
EVALuna2:15990

Transition of juvenile patients with neuromuscular disease and respiratory insufficiency Transition bei neuromuskulären Erkrankungen mit chronisch respiratorischer Insuffizienz - Winterholler, M.; Trollmann, Regina (Pneumologe, 2021)
Diseases of the organs responsible for movement, i.e. the motor neurons, the neuromuscular transfer and the muscles themselves, are designated as neuromuscular diseases. Neuromuscular diseases occurring in childhood are either genetically linked or triggered by disorders of the immune system. In total, approximately 0.2–0.5% of all children are affected by neuromuscular diseases, whereby the frequency of individual entities of these always rare diseases greatly varies. The more complex the disease symptoms, the rarer the disease and the more severe the disability is in an adolescent, the more helpful is a meticulous transition from pediatrics to the medical world of adults. Muscle centers and medical centers for adults with intellectual and multiple disabilities are capable of maintaining a multiprofessional treatment concept, when necessary also into adulthood.
CRIS-Team Scopus Importer:2021-02-19
Keywords: Autoimmune disease; Muscular dystrophy; Respiratory muscle weakness; Spinal muscular atrophy; Treatment concept

Transmural fibre orientations based on Laplace-Dirichlet-Rule-Based-Methods and their influence on human heart simulations - Holz, David; Martonová, Denisa; Schaller, Emely; Duong, Minh Tuan; Alkassar, Muhannad; Weyand, Michael; Leyendecker, Sigrid (Journal of Biomechanics, 2023)

Transmural Placement of Endocardial Pacing Leads in Patients With Congenital Heart Disease - Sandrio, Stany; Purbojo, Ariawan; Toka, Okan; Dittrich, Sven; Cesnjevar, Robert; Rueffer, Andre (Annals of Thoracic Surgery, 2016)
This study evaluates the feasibility and outcomes of transmural placement of endocardial leads (TML) in patients with congenital heart disease.Between October 2009 and May 2015, 29 TML procedures were performed in 27 patients. Leads are grouped according to their pacing site: atrial (TML-A, n = 24) or ventricular (TML-V, n = 12). The TML-V includes transatrial and transventricular approaches. Clinical outcome, functional properties of TML, and Kaplan-Meier freedom from lead dysfunction were evaluated.Median age was 4 years (range, 29 days to 43 years). Median follow-up duration was 2 years (range, 1 day to 5.7 years). There was no early mortality. Three late deaths were observed (2 unrelated, 1 related to pacing). In group TML-A, no lead dysfunction was noted. In group TML-V, there were 3 lead dislodgements and 1 lead fracture. Kaplan-Meier freedom from lead dysfunction after 0.5, 1, and 5 years, respectively, was 100% in group TML-A and 82% ± 11%, 73% ± 13%, and 59% ± 17% in group TML-V (log rank p < 0.01). Mean acute (at implantation) and chronic (at last follow-up) sensing thresholds were 3.1 ± 2.3 mV and 3.5 ± 2.5 mV in group TML-A and 11.6 ± 4.9 mV and 7.5 ± 4.6 mV in group TML-V, respectively. Mean acute and chronic pacing thresholds at 0.5 ms were 1.1 ± 0.6 V and 0.6 ± 0.3 V in group TML-A and 1.0 ± 0.6 V and 0.9 ± 0.5 V in group TML-V, respectively.The transmural approach provides an alternative method in patients with congenital cardiac defects who cannot receive transvenous leads and who have extensive epicardial scarring. Subanalysis shows superior midterm performance for TML-A compared with TML-V.
EVALuna2:25118

Transrectal Absorber Guide Raster-Scanning Optoacoustic Mesoscopy for Label-Free In Vivo Assessment of Colitis - Bühler, Adrian; Brown, Emma; Paulus, Lars-Philip; Eckstein, Markus; Thoma, Oana-Maria; Oraiopoulou, Mariam-Eleni; Rother, Ulrich; Hörning, André; Hartmann, Arndt; Neurath, Markus; Wölfle, Joachim; Friedrich, Oliver; et al. (Advanced Science, 2023)
Optoacoustic imaging (OAI) enables microscale imaging of endogenous chromophores such as hemoglobin at significantly higher penetration depths compared to other optical imaging technologies. Raster-scanning optoacoustic mesoscopy (RSOM) has recently been shown to identify superficial microvascular changes associated with human skin pathologies. In animal models, the imaging depth afforded by RSOM can enable entirely new capabilities for noninvasive imaging of vascular structures in the gastrointestinal tract, but exact localization of intra-abdominal organs is still elusive. Herein the development and application of a novel transrectal absorber guide for RSOM (TAG-RSOM) is presented to enable accurate transabdominal localization and assessment of colonic vascular networks in vivo. The potential of TAG-RSOM is demonstrated through application during mild and severe acute colitis in mice. TAG-RSOM enables visualization of transmural vascular networks, with changes in colon wall thickness, blood volume, and OAI signal intensities corresponding to colitis-associated inflammatory changes. These findings suggest TAG-RSOM can provide a novel monitoring tool in preclinical IBD models, refining animal procedures and underlines the capabilities of such technologies to address inflammatory bowel diseases in humans.
CRIS-Team WoS Importer:2023-05-12

Transvascular kidney biopsy in adolescent patients-safe alternative to open procedures - Utsch, Boris; Hoppe, Hanno; Dittrich, Katalin; Amann, Kerstin Ute; Gugger, Mathias; Tschumi, Sibylle; Galiano, Matthias; Plank, Christian Georg; Rascher, Wolfgang; Schmid, Axel; Uder, Michael; Dötsch, Jörg (Clinical Kidney Journal, 2021)
CRIS-Team WoS Importer:2021-05-21

Treatment of Esophageal Atresia in Germany: Analysis of National Hospital Discharge Data From 2016 to 2022 - Ungruh, Max; Hubertus, Jochen; Widenmann, Anke; Kaufmann, Jost; Reutter, Heiko Martin; Busse, Reinhard; Wilms, Miriam; Nimptsch, Ulrike (Journal of Pediatric Surgery, 2024)
Background: Esophageal atresia (EA) is a complex malformation. Multidisciplinary management is necessary, with the operative repair being the most challenging step in the treatment algorithm. The complete care structure for children with EA in Germany has not been analyzed yet. Methods: In the observed period 2016–2022, inpatient EA cases were analyzed 1) during the hospital stay of birth, and 2) during the hospital stay of corrective surgery in patients aged up to 365 days, both based on national hospital discharge data. Patients’ comorbidities, hospital caseload, treatment characteristics (e.g. surgical approach) and outcome parameters were analyzed. Results: 1) 1190 newborn EA cases were treated in 260 hospitals during the perinatal period. 54% had at least one additional malformation, and 16% had a birthweight below 1500 g. In-hospital mortality was 8.4%. 2) 1475 corrective operations for EA were performed in 111 hospitals with a consistent median annual caseload of 2 (P25–P95 1–8) per hospital. At least one indicator for a complicated perioperative course was documented in 63.7% of cases. The use of bronchoscopy was coded in 50% of cases. Median ventilation time during the entire hospital stay was 176 h (P25–P95: 95–1759 h). Conclusions: Newborns with EA are complex and early postoperative complications are common. The care structure is decentralized, and there was no trend towards centralization in the observed period. The low documented use of bronchoscopy is noteworthy. Centralization of the highly complex and schedulable corrective surgery for EA is necessary to evaluate outcomes and might improve the quality of care and resource utilization. Category of the manuscript and type of study: original article, observational cross-sectional study, secondary data analysis.
CRIS-Team Scopus Importer:2024-10-11
Keywords: Caseload; Centralization; Esophageal atresia; Quality of care; Volume-outcome relationship

Treatment of severe traumatic brain injury in German pediatric intensive care units—a survey of current practice - Regensburger, Adrian; Konrad, V.; Trollmann, Regina; Eyüpoglu, Ilker Yasin; Huebner, H.; Zierk, Jakob; Voelkl, T. M. K.; Fahlbusch, F. B. (Childs Nervous System, 2019)
Purpose: German pediatric guidelines for severe traumatic brain injury (TBI) management expired in 2011. Thus, divergent evidence-based institutional protocols are predominantly being followed. We performed a survey of current Pediatric Intensive Care Unit (PICU) management of isolated severe TBI in Germany to reveal potential varying practices. Methods: Seventy German PICUs were invited to join an anonymous online survey from February to May 2017. Twenty-nine participants (41.4%) successfully completed the survey (17 university hospitals and 12 district hospitals). The majority of items were polar (yes/no) or scaled (e.g., never - always). Main topics were imaging, neurosurgery, neuromonitoring, adjuvant therapy, and medication. Severity of TBI was defined via Glasgow Coma Scale. Results: The majority of respondents (93.1%) had internal TBI standards, and patients were mainly administered to interdisciplinary trauma units. The use of advanced neuromonitoring techniques, intracranial hypertension management, and drug treatment differed between PICUs. Routine administration of hypertonic saline in TBI-associated cerebral edema was performed by 3.4%, while it was never an option for 31.0% of the participants. Prophylactic anticonvulsive therapy was restrictively performed. If indicated, the main anticonvulsive drugs used were phenobarbital and levetiracetam. Neuroendocrine follow-up was recommended/performed by 58.6% of the PICUs. Conclusions: This survey provides an overview of the current PICU practices of isolated severe TBI management in Germany and demonstrates a wide instrumental and therapeutical range, revealing an unmet need for the revised national guideline and further (international) clinical trials for the treatment of severe TBI in pediatrics.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Adjuvant therapy; ICP; Neuroimaging; Neuromonitoring

Treatment of Unspecific Back Pain in Children and Adolescents: Results of an Evidence-Based Interdisciplinary Guideline - Frosch, Michael; Leinwather, Stina; Bielack, Stefan; Bloedt, Susanne; Dirksen, Uta; Dobe, Michael; Geiger, Florian; Haefner, Renate; Hoefel, Lea; Huebner-Moehler, Bettina; Von Kalle, Thekla; Lawrenz, Burkhard; et al. (Children, 2022)
Using a structured approach and expert consensus, we developed an evidence-based guideline on the treatment and prevention of non-specific back pain in children and adolescents. A comprehensive and systematic literature search identified relevant guidelines and studies. Based on the findings of this literature search, recommendations on treatment and prevention were formulated and voted on by experts in a structured consensus-building process. Physical therapy (particularly physical activity) and psychotherapy (particularly cognitive behavioral therapy) are recommended for treating pediatric non-specific back pain. Intensive interdisciplinary treatment programs should be provided for chronic and severe pain. Drug therapy should not be applied in children and adolescents. Further research on non-specific back pain in childhood and adolescence is strongly needed to reduce the imbalance between the high burden of non-specific back pain in childhood and adolescence and the low research activity in this field.
CRIS-Team Scopus Importer:2022-04-08
Keywords: adolescents; back pain; children; evidence-based; guideline; prevention; treatment

Trial in Progress: eine multizentrische Open-label Phase IB/ II Studie zur Bestimmung der Dosierung und Sicherheit von Asciminib bei padiatrischen Patienten mit chronischer myeloischer Leukamie in der chronischen Phase (ASC4kids) - Metzler, Markus; Escherich, G.; Reinhardt, D.; Kapoor, S.; Hoch, M.; Descamps, L.; Bayar, M. A.; Ramscar, N.; Hijiya, N. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

TRIM28 haploinsufficiency predisposes to Wilms tumor - Diets, Illja J.; Hoyer, Juliane; Ekici, Arif Bülent; Popp, Bernt; Hoogerbrugge, Nicoline; van Reijmersdal, Simon V.; Bhaskaran, Rajith; Hadjihannas, Michel; Vasileiou, Georgia; Thiel, Christian; Seven, Didem; Uebe, Steffen; et al. (International Journal of Cancer, 2019)
Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.
CRIS-Team Scopus Importer:2019-05-02
Keywords: genetic predisposition; haploinsufficiency; TRIM28; Wilms tumor

Trio Exome Sequencing in VACTERL Association - Ćomić, Jasmina; Tilch, Erik; Riedhammer, Korbinian M.; Brugger, Melanie; Brunet, Theresa; Eyring, Katharina; Vill, Katharina; Redler, Silke; Tasic, Velibor; Schmiedeke, Eberhard; Schäfer, Frank Mattias; Abazi-Emini, Nora; et al. (Kidney International Reports, 2025)
Introduction: Currently, there is only limited data on monogenic causes of vertebral defects, anorectal malformations, cardiac defects, esophageal atresia or tracheoesophageal fistula, renal malformations, and limb defects (VACTERL) association. The aim of this study was to extend the spectrum of disease-causing variants in known genes, to determine the diagnostic yield of monogenic causes, and to identify candidate genes and rare variants by applying comprehensive genetic testing or rare variant burden. Methods: The total cohort comprised 101 affected individuals and their parents. Trio exome sequencing was only performed in 96 individuals and their parents because of DNA quality reasons and case-control gene and pathway burden tests were calculated and evaluated by quantile-quantile plots, principal component analysis plots and family-based association test (FBAT). Results: In 5 of 96 individuals, disease-causing variants in known genes or loci were identified to be associated with the following 4 disorders: Kabuki syndrome, Sotos syndrome, MELAS syndrome, and deletion syndrome encompassing TWIST1. In 91 individuals, no disease-causing variants were found. FBAT showed 14 significant variants, 2 significant genes (LOC645752 and ZNF417), and 8 significant pathways. Conclusion: This study shows that most individuals with VACTERL association do not have known discrete genetic syndromes, implying that pathomechanisms or variants not identifiable by exome sequencing may exist requiring further investigation.
CRIS-Team Scopus Importer:2025-01-31
Keywords: burden test; exome sequencing; mitochondriopathy; VACTERL association; VACTERL-like phenotype; ZNF417

Trophoblast expression dynamics of the tumor suppressor gene gastrokine 2 - Fahlbusch, Fabian B.; Ruebner, Matthias; Hübner, Hanna; Volkert, Gudrun; Bartunik, Hannah; Winterfeld, Ilona; Hartner, Andrea; Menendez-Castro, Carlos; Nögel, Stephanie; Marek, Ines; Wachter, David; Schneider-Stock, Regine; et al. (Histochemistry and Cell Biology, 2015)
Gastrokines (GKNs) were originally described as stomach-specific tumor suppressor genes. Recently, we identified GKN1 in extravillous trophoblasts (EVT) of human placenta. GKN1 treatment reduced the migration of the trophoblast cell line JEG-3. GKN2 is known to inhibit the proliferation, migration and invasion of gastric cancer cells and may interact with GKN1. Recently, GKN2 was detected in the placental yolk sac of mice. We therefore aimed to further characterize placental GKN2 expression. By immunohistochemistry, healthy first-trimester placenta showed ubiquitous staining for GKN2 at its early gestational stage. At later gestational stages, a more differentiated expression pattern in EVT and villous cytotrophoblasts became evident. In healthy third-trimester placenta, only EVT retained strong GKN2 immunoreactivity. In contrast, HELLP placentas showed a tendency of increased levels of GKN2 expression with a more prominent GKN2 staining in their syncytiotrophoblast. Choriocarcinoma cell lines did not express GKN2. Besides its trophoblastic expression, we found human GKN2 in fibrotic villi, in amniotic membrane and umbilical cord. GKN2 co-localized with smooth muscle actin in villous myofibroblasts and with HLA-G and GKN1 in EVT. In the rodent placenta, GKN2 was specifically located in the spongiotrophoblast layer. Thus, the gestational age-dependent and compartment-specific expression pattern of GKN2 points to a role for placental development. The syncytial expression of GKN2 in HELLP placentas might represent a reduced state of functional differentiation of the syncytiotrophoblast. Moreover, the specific GKN2 expression in the rodent spongiotrophoblast layer (equivalent to human EVT) might suggest an important role in EVT physiology.
EVALuna2:6725

Troponin I levels in extracorporeal membrane oxygenation following congenital heart surgery - Rüffer, André; Münch, Frank; Potapov, Sergej; Purbojo, Ariawan; Toka, Okan; Dodge-Khatami, Ali; Dittrich, Sven; Cesnjevar, Robert (World Journal for Pediatric and Congenital Heart Surgery, 2014)
Correlating postcardiotomy extracorporeal membrane oxygenation (ECMO) troponin I (TnI) levels and outcomes.Between January 2006 and August 2010, 34 patients needed postcardiotomy ECMO for low cardiac output. Bailout ECMO was required either after unsuccessful weaning from bypass (n = 17, 50%), postoperatively from prolonged hemodynamic failure (n = 8, 23.5%), or following resuscitation (n = 9, 26.5%). The TnI levels were measured following surgery or resuscitation during 10 days and compared between survivors (group I) and non-survivors (group II).Median support duration was seven days (range: 0-31). Surgery involving hypoplastic aortic arch repair (Norwood palliation; n = 7, 20.6%, or biventricular repair; n = 11, 32.4%) led to most ECMO runs. Successful weaning from ECMO and hospital survival were 76.5% and 50%, respectively. In group I, peak TnI levels were reached by 24 hours postoperatively, comparable to levels in group II (36 ± 34 vs 49 ± 38 ng/mL; P = .98). However, in group II, TnI levels formed a plateau by the second postoperative day, whereas group I showed a steep decline in TnI levels, suggesting myocardial recovery (P = .028). All patients (n = 4) who reached or maintained peak TnI levels at 48 hours died. On days 8, 9 and 10, TnI levels were significantly higher in group II (P = .024, .019, and .013, respectively).Postcardiotomy ECMO was most commonly required after aortic arch repair. In the absence of ongoing myocardial insult due to ECMO hardware issues, coronary insufficiency or residual lesions, plateau TnI levels at 48 hours may seem to indicate an unfavorable outcome due to irreversible myocardial damage.
EVALuna2:25107

Tryptophan Catabolism to Serotonin and Kynurenine in Women Undergoing in-vitro Fertilization - Bodis, Jozsef; Sulyok, Endre; Koppan, Miklos; Varnagy, Akos; Premusz, Viktoria; Godony, Krisztina; Rascher, Wolfgang; Rauh, Manfred (Physiological Research, 2020)
This cross-sectional clinical study was designed to explore the impact of tryptophan-kynurenine and tryptophan-serotonin (5-HT) pathways on reproductive performance during in vitro fertilization (IVF). Paired serum and follicular fluid (FF) samples were obtained from 64 consecutive IVF patients. The analysis was done by using LC-MS/MS. Ovarian hyperstimulation resulted in decreased serum tryptophan (p<0.004), 5-HT (p<0.049) and kynurenine (p<0.001). FF levels of tryptophan (R=0.245, p<0.051), kynurenine (R=0.556, p<0.001) and 5-HT (R=0.523, p<0.001) were positively related to their respective serum levels. Clinical pregnancy was associated with higher serum 5-HT (p<0.045) and FF 5-HT (p<0.020) and lower kynurenine to 5-HT ratio (p<0.024). Chemical pregnancy was also positively related to FF 5-HT (R=0.362, p<0.024). Moreover, there was a direct relationship of the number of mature oocytes to the FF 5-HT (R=0.363, p<0.020) but it was inversely related to FF tryptophan to 5-HT and FF kynurenine to 5-HT ratios (R=-0.389, p<0.016 and R=-0.337, p<0.036, respectively). Multivariate logistic regression revealed that the number of mature oocytes was significantly influenced by FF 5-HT (β=0.473, p<0.001). In IVF patients ovarian hyperstimulation results in a reduction of the availability of tryptophan to catabolic pathways to kynurenine and 5-HT. Outcome measures improved significantly when 5-HT predominated over kynurenine.
CRIS-Team Scopus Importer:2021-04-19
Keywords: in vitro Fertilization; Kynurenine; Oocyte maturation; Serotonin; Tryptophan

Twelve-month outcome in juvenile proliferative lupus nephritis: results of the German registry study - Suhlrie, Adriana; Hennies, Imke; Gellermann, Jutta; Buescher, Anja; Hoyer, Peter; Waldegger, Siegfried; Wygoda, Simone; Beetz, Rolf; Lange-Sperandio, Baerbel; Klaus, Guenter; Konrad, Martin; Holder, Martin; et al. (Pediatric Nephrology, 2020)
Background Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare. Methods Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015. Results At the time of diagnosis, median age was 13.7 (interquartile range 11.8-15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75 ml/min/1.73 m(2). At 12 months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26-22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients. Conclusions In this cohort of juvenile proliferative LN, renal outcome at 12 months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols.
CRIS-Team WoS Importer:2020-04-07

Twenty years of newborn screening for congenital adrenal hyperplasia and congenital primary hypothyroidism - experiences from the DGKED/AQUAPE study group for quality improvement in Germany - Hammersen, Johanna; Bettendorf, Markus; Bonfig, Walter; Schoenau, Eckhard; Warncke, Katharina; Eckert, Alexander J.; Fricke-Otto, Susanne; Palm, Katja; Holl, Reinhard W.; Wölfle, Joachim (Medizinische Genetik, 2022)
Congenital primary hypothyroidism (CH) and congenital adrenal hyperplasia (CAH) are targeted by the German and Austrian newborn screening. For both diseases, there are registries for quality improvement, based on standardized observational data from long-term patient follow-up, under the auspices of the DGKED study group. By September 2021, the CH registry HypoDOK includes datasets from 23,348 visits of 1,840 patients, and the CAH registry contains datasets from 36,237 visits of 1,976 patients. Here, we report on the recruitment process, patient characteristics, and research contributions from the registries, and underline that the registries are an important tool to improve patient care and outcomes. Registries for rare conditions should thus be considered as an important public health measure and they should be adequately institutionalized and funded.
CRIS-Team WoS Importer:2022-05-20
Keywords: congenital adrenal hyperplasia; congenital primary hypothyroidism; patient registry; newborn screening; quality management; benchmarking

Type 1 interferon alpha (IFN-a) regulation by respiratory viruses in pediatric asthma - Finotto, Susetta; Bergauer, Annika; Sopel, Nina; Kross, B.; Vuorinen, T.; Weiss, S. T.; Rauh, Manfred; Melichar, V. O.; Kiefer, Alexander; Zimmermann, Theodor; Ml, Kowalski; Jartti, T.; et al. (2017)
EVALuna2:33022

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 in Pediatric Inflammatory Bowel Disease—A Review of the State of the Art and Future Perspectives - Hörning, André; Jüngert, Jörg; Siebenlist, Gregor; Knieling, Ferdinand; Regensburger, Adrian (Children, 2024)
Inflammatory bowel disease (IBD) comprises a group of relapsing, chronic diseases of the gastrointestinal tract that, in addition to adults, can affect children and adolescents. To detect relapses of inflammation, these patients require close observation, frequent follow-up, and therapeutic adjustments. While reference standard diagnostics include anamnestic factors, laboratory and stool sample assessment, performing specific imaging in children and adolescents is much more challenging than in adults. Endoscopic and classic cross-sectional imaging modalities may be invasive and often require sedation for younger patients. For this reason, intestinal ultrasound (IUS) is becoming increasingly important for the non-invasive assessment of the intestine and its inflammatory affection. In this review, we would like to shed light on the current state of the art and provide an outlook on developments in this field that could potentially spare these patients more invasive follow-up procedures.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Crohn’s disease; optoacoustics; pediatric inflammatory bowel disease; ulcerative colitis; ultrasound

Ultrasound Localization Microscopy for the Assessment of Microvascular Circulation in Ischemic Perinatal Stroke - Regensburger, Adrian; Wachter, Felix; Denis, Louise; Mandelbaum, Henriette; Schey, Frauke; Bühler, Adrian; Siebenlist, Gregor; Schwarz, Simone; Schulz-Heise, Susanne; Rompel, Oliver; Trollmann, Regina; Wölfle, Joachim; et al. (Stroke, 2024)
CRIS-Team Scopus Importer:2024-11-15
Keywords: diagnostic imaging; microcirculation; neonate; stroke; ultrasound

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

Ultrasound Super-Resolution Imaging of Neonatal Cerebral Vascular Reorganization - Schwarz, Simone; Denis, Louise; Nedoschill, Emmanuel; Bühler, Adrian; Danko, Vera; Hilger, Alina; Brevis Nuñez, Francisco; Dürr, Nikola R.; Schlunz-Hendann, Martin; Brassel, Friedhelm; Felderhoff-Müser, Ursula; Reutter, Heiko Martin; et al. (Advanced Science, 2025)
During the first days of neonatal growth, the central nervous system (CNS) develops self-regulatory mechanisms to ensure constant cerebral perfusion. However, this vascular neogenesis takes place at a microscopic scale that cannot be observed with current clinical imaging techniques. Ultrasound localization microscopy (ULM) allows us to observe micro-vessels of the order of a few microns at depths of several centimeters. This can be done using conventional clinical ultrasound scanners and contrast sequences (CEUS). In this study, ULM is used to observe the human microvasculature in neonatal patients undergoing treatment for life-threatening malformations forming direct connections between the cerebral arterial and venous systems. It is observed that neuroendovascular treatment of neonatal arteriovenous malformations causes remodeling and reorganization of the cerebral vasculature by also activating corticomedullary vascular connections. ULM enables us to follow microvascular changes in human neonates with high spatio-temporal resolution. ULM may provide a novel clinical translatable tool, particularly including cerebral imaging in very young patients.
CRIS-Team Scopus Importer:2025-02-14
Keywords: CEUS; microbubbles; super-resolution imaging; ultrasound; ultrasound localization microscopy; Vein of Galen malformation

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

Unveiling Metabolic Similarities of Entheses in Patients with Psoriasis and Psoriatic Arthritis Using Noninvasive In Vivo Molecular Imaging: Results From a Cross-sectional Exploratory Study - Fagni, Filippo; Tascilar, Koray; Noversa de Sousa, Rita; Bayat, Sara; Sollfrank, Lukas; Kleyer, Arnd; Sticherling, Michael; Regensburger, Adrian; Knieling, Ferdinand; Neurath, Markus; Schett, Georg; Waldner, Maximilian; et al. (Arthritis and Rheumatology, 2024)
Objective: We assessed and compared molecular tissue changes at the entheses in patients with psoriasis (PsO) and psoriatic arthritis (PsA) and in healthy controls (HCs) in vivo using multispectral optoacoustic tomography (MSOT) and described their relationship with clinical and ultrasound findings of enthesitis. Methods: A cross-sectional study (MSOT and Arthrosonography in PsA) in biologic disease-modifying antirheumatic drug–naïve patients with PsA and PsO and HCs was performed. Participants underwent clinical, ultrasonographic, and MSOT examination of six entheses (lateral humeral epicondyle, distal patellar tendon attachment, and Achilles tendon attachment). MSOT-measured hemoglobin (Hb), oxygen saturation (SO2), collagen, and lipid levels were quantified, and mean differences between groups were calculated using linear mixed effects models. MSOT-measured analytes were compared between entheses with and without clinical and ultrasound anomalies. Results: Ninety participants were included (30 PsO, 30 PsA, and 30 HCs), 540 entheses were clinically assessed, and 540 ultrasound and 830 MSOT scans were obtained. Patients with PsA and PsO showed increased oxygenated Hb (PsA: P = 0.003; PsO: P = 0.054) and SO2 (PsA: P < 0.001; PsO: P = 0.001) levels and decreased collagen signals (PsA: P < 0.001; PsO: P < 0.001) compared with HCs, with more pronounced changes in PsA. Significantly lower collagen levels (P = 0.01) and increased lipids (P = 0.03) were recorded in tender entheses compared with nontender ones. Erosions and enthesophytes on ultrasound were associated with significant differences in SO2 (P = 0.014) and lipid signals (P = 0.020), respectively. Conclusion: Patients with PsA and PsO exhibit an analogous metabolic pattern at the entheses that is exacerbated in the presence of inflammation. These findings support the notion of a psoriatic disease spectrum characterized by common immunometabolic tissue changes.
CRIS-Team Scopus Importer:2024-07-19

Urinary Dickkopf-related protein 3 as a novel biomarker for kidney function decline in children with Alport syndrome - Boeckhaus, Jan; Tönshoff, Burkhard; Weber, Lutz T.; Pape, Lars; Latta, Kay; Fehrenbach, Henry; Lange-Sperandio, Baerbel; Kettwig, Matthias; König, Sabine; John-Kroegel, Ulrike; Gellermann, Jutta; Galiano, Matthias; et al. (Pediatric Nephrology, 2025)
Background: Chronic kidney disease (CKD) seriously affects the well-being and shortens the life expectancy of children and adolescents, but its progression is challenging to predict. Therefore, there is an urgent need for biomarkers that can identify children at risk of faster CKD progression. Alport syndrome (AS) is the most common monogenetic glomerular kidney disease. Urinary Dickkopf-related protein 3 (DKK3) is associated with a decline in estimated glomerular filtration rate (eGFR) in adults and children with advanced CKD. However, its potential for early detection of CKD and its prognostic value in children with AS remain unknown. Methods: Urine samples from 49 children enrolled in the EARLY PRO-TECT Alport trial were analyzed to evaluate whether DKK3 could identify children with AS to be at risk for faster CKD progression. Results: DKK3 levels in patients with AS were higher than those of healthy individuals reported in the literature. DKK3 levels were more elevated in patients with later stages of AS. Furthermore, children who were not treated with renin angiotensin system inhibitors (RASi) had higher DKK3 levels than treated children. Children with above-average DKK3 levels were more likely to have increased albuminuria after 2 years of follow-up than children with below-average DKK3 levels. Conclusion: Urinary DKK3 is significantly elevated in children at early stages of AS. There was a potential association between higher DKK3 levels, worsening albuminuria, and a decline in kidney function. These findings suggest that DKK3 may be a prognostic marker for predicting the risk of kidney damage in children with AS.
CRIS-Team Scopus Importer:2025-02-21
Keywords: Albuminuria; Alport syndrome; Dickkopf-related protein 3; DKK3; Hereditary kidney disease; Kidney failure

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 Machine Learning and Feature Importance to Identify Risk Factors for Mortality in Pediatric Heart Surgery - Kapsner, Lorenz; Feißt, Manuel; Purbojo, Ariawan; Prokosch, Hans-Ulrich; Ganslandt, Thomas; Dittrich, Sven; Mang, Jonathan M.; Wällisch, Wolfgang (Diagnostics, 2024)
Background: The objective of this IRB-approved retrospective monocentric study was to identify risk factors for mortality after surgery for congenital heart defects (CHDs) in pediatric patients using machine learning (ML). CHD belongs to the most common congenital malformations, and remains the leading mortality cause from birth defects. Methods: The most recent available hospital encounter for each patient with an age <18 years hospitalized for CHD-related cardiac surgery between the years 2011 and 2020 was included in this study. The cohort consisted of 1302 eligible patients (mean age [SD]: 402.92 [±562.31] days), who were categorized into four disease groups. A random survival forest (RSF) and the ‘eXtreme Gradient Boosting’ algorithm (XGB) were applied to model mortality (incidence: 5.6% [n = 73 events]). All models were then applied to predict the outcome in an independent holdout test dataset (40% of the cohort). Results: RSF and XGB achieved average C-indices of 0.85 (±0.01) and 0.79 (±0.03), respectively. Feature importance was assessed with ‘SHapley Additive exPlanations’ (SHAP) and ‘Time-dependent explanations of machine learning survival models’ (SurvSHAP(t)), both of which revealed high importance of the maximum values of serum creatinine observed within 72 h post-surgery for both ML methods. Conclusions: ML methods, along with model explainability tools, can reveal interesting insights into mortality risk after surgery for CHD. The proposed analytical workflow can serve as a blueprint for translating the analysis into a federated setting that builds upon the infrastructure of the German Medical Informatics Initiative.
CRIS-Team Scopus Importer:2024-12-06
Keywords: congenital heart defects (CHDs); eXtreme Gradient Boosting (XGB); feature importance; machine learning (ML); mortality; random survival forest (RSF); risk factors

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, Dennis; 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)
<br
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

Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure - Marton, Adriana; Saffari, Seyed Ehsan; Rauh, Manfred; Sun, Ruo Ning; Nagel, Armin Michael; Linz, Peter; Lim, Tzy Tiing; Takase-Minegishi, Kaoru; Pajarillaga, Anastacia; Saw, Sharon; Morisawa, Norihiko; Yam, Wan Keat; et al. (Journal of the American College of Cardiology, 2024)
Background: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. Objectives: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. Methods: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. Results: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor–naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51–4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98–3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77–12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: −9.1 mL/kg/d [95% CI: −14 to −4.12; P < 0.001]; late: −11.0 mL/kg/d [95% CI: −15.94 to −6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28–229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: −1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: −3.83 to 5.62]; P = 0.70). Conclusions: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).
CRIS-Team Scopus Importer:2024-04-12
Keywords: aestivation; decongestion; longevity; water conservation

What Is and Isn’t an Ectodermal Dysplasia? - Peschel, Nicolai; Schneider, Holm (Springer Nature, 2025)
This chapter discusses the classification of ectodermal dysplasias, which has evolved over decades from one based purely on clinical symptoms to one based on molecular changes and signaling pathways. As there are many different disease entities and a broad spectrum of clinical manifestations, a distinctive classification according to the molecular pathways or the cell structures involved is not only useful but has become the gold standard for classifying any group of rare genetic diseases. The general transition from a descriptive clinical to a molecular approach occurred because user-friendly and accessible molecular diagnostic tests are now available in almost every diagnostic laboratory and because the identification of pathogenic gene variants can often quickly objectify a clinical suspicion, allowing better comparability of the different patients seen by healthcare professionals.
CRIS-Team Scopus Importer:2025-05-02
Keywords: Classification; Criteria; Syndromes

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

Which congenital heart defects can be detected in newborns with pulse oximetry screening? Welche angeborenen Herzfehler lassen sich bei Neugeborenen mit dem Pulsoximetrie-Screening erkennen? - Dittrich, Sven (gynäkologische praxis, 2022)
In January 2017, the Joint Federal Committee added pulse oximetry screening for critical congenital heart defects to the scope of U1/U2 screening as a new screening for newborns. With a positive pulse oximetry screening, every fourth to fifth child is expected to have a ductus-dependent heart defect. This article describes the cardiac defects that may be conspicuous in pulse oximetry screening and their pathophysiological effects.
CRIS-Team Scopus Importer:2024-12-16
Keywords: aortic isthmus stenosis; left heart obstruction vitias; pulse oximetry screening; right heart obstruction vitias

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

Radical Prostatectomy in Kidney Transplant Recipients—A Multicenter Experience - Schmidt, Jacob; Yakac, Abdulbaki; Peters, Robert; Friedersdorff, Frank; Kernig, Karoline; Kienel, Anna; Winterhagen, Franziska I.; Köpp, Friedrich; Foller, Susan; DiQuilio, Francesca; Weigand, Karl; Flegar, Luka; et al. (European Urology Open Science, 2024)
Background and objective: Kidney transplant recipients (KTRs) have an increased risk of developing genitourinary cancers, including prostate cancer (PCa), which is expected to become more prevalent due to an aging KTR population. Thus, knowledge of surgical outcomes, including treatment of PCa, within this unique cohort is required. Methods: Data of 62 KTRs undergoing radical prostatectomy (RP) between 2006 and 2023 at nine urologic transplant centers were analyzed. Complications were assessed using the Clavien-Dindo classification. Perioperative outcomes were evaluated, and a follow-up was conducted. Overall survival (OS), biochemical recurrence–free survival (BRFS), and death-censored graft survival were determined via the Kaplan-Meier method and log-rank testing. Key findings and limitations: Overall, 50 open radical retropubic RPs and 12 robot-assisted RPs (RARPs) were included. The intraoperative blood loss was lower after RARP, but operative time was longer. Of the patients, 50% experienced no postoperative complication, and grade ≥3 complications were observed in 14.5%. There was no graft loss related to RP. A histopathologic analysis revealed pN1 in 8.1% and positive surgical margins in 25.8% of the cases. At a median follow-up of 48.5 mo, the median OS was 128 (95% confidence interval [CI] 71.2–184.8) mo, BRFS was 106 (95% CI 55.8; 156.2) mo, and graft survival was 127 (95% CI 66.7–187.3) mo. Limitations include the retrospective design, and variations between groups and centers. Conclusions and clinical implications: Our findings support RP as a feasible and safe treatment option for localized PCa in KTRs with acceptable oncologic outcome. Special care is required in screening and awareness for the risk of understaging. Patient summary: This study analyzed the safety and effectiveness of two prostate cancer surgery methods—open and robot-assisted surgery—in the special group of kidney transplant recipients. Both surgical methods were performed safely with acceptable oncologic outcomes; however, sample size was too small to draw definite conclusions between the two operative methods.
CRIS-Team Scopus Importer:2024-08-09
Keywords: Kidney transplantation; Open surgery; Prostate cancer; Prostatectomy; Robot-assisted surgery

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