RELATION BETWEEN NOISE ANNOYANCE, STRESS HORMONES AND THE RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, Dennis; Rauh, Manfred; Ott, Christian; Striepe, Kristina; Jung, Susanne; Kolwelter, Julie; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis - Nießl, Christina; Boulesteix, Anne Laure; Oh, Jun; Palm, Katja; Schlingmann, Peter; Wygoda, Simone; Haffner, Dieter; Wühl, Elke; Tönshoff, Burkhard; Buescher, Anja; Billing, Heiko; Hoppe, Bernd; et al. (Molecular Genetics and Metabolism, 2022)
Infantile nephropathic cystinosis, due to impaired transport of cystine out of lysosomes, occurs with an incidence of 1 in 100–200,000 live births. It is characterized by renal Fanconi syndrome in the first year of life and glomerular dysfunction progression to end-stage kidney disease by approximately 10 years of age. Treatment with oral cysteamine therapy helps preserve glomerular function, but affected individuals eventually require kidney replacement therapy. This is because glomerular damage had already occurred by the time a child is diagnosed with cystinosis, typically in the second year of life. We performed a retrospective multicenter study to investigate the impact of initiating cysteamine treatment within the first 2 months of life in some infants and comparing two different levels of adherence in patients diagnosed at the typical age. We collected 3983 data points from 55 patients born between 1997 and 2020; 52 patients with 1592 data points could be further evaluated. These data were first analyzed by dividing the patient cohort into three groups: (i) standard treatment start with good adherence, (ii) standard treatment start with less good adherence, and (iii) early treatment start. At every age, mean estimated glomerular filtration rate (eGFR) was higher in early-treated patients than in later-treated patients. Second, a generalized additive mixed model (GAMM) was applied showing that patients with initiation of treatment before 2 months of age are expected to have a 34 ml/min/1.73 m2 higher eGFR than patients with later treatment start while controlling for adherence and patients' age. These data strongly suggest that oral cysteamine treatment initiated within 2 months of birth preserves kidney function in infantile nephropathic cystinosis and provide evidence of the utility of newborn screening for this disease.
CRIS-Team Scopus Importer:2022-07-22
Keywords: Cysteamine; Cystinosis; Glomerular function

Relevance of glomerular c4d deposition in pediatric patients with henoch-schönlein purpura compared to IgA nephritis - Benz, Kerstin; Ferrazzi, Fulvia; Galiano, Matthias; Sauerstein, Katja; Vonbrunn, Eva; Daniel, Christoph; Büttner-Herold, Maike; Amann, Kerstin Ute (Journal of Nephropathology, 2021)
Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) in western countries and Henoch-Schönlein purpura nephritis (HSPN) is the most common form of vasculitis in childhood. Renal biopsy findings in both nephropathies are often similar and are characterized by mesangioproliferative GN with mesangial or mesangiocapillary IgA and C3c deposits. Objectives: The aim of this study was to investigate the significance of glomerular C4d-deposition as a discriminating factor between pediatric HSPN and IgAN. Patients and Methods: We retrospectively analyzed patient records and renal biopsies from 53 pediatric patients from one single center with a median age of 10.5 years (range 2.3-18 years). Twenty-two patients suffered from IgAN and 31 from HSPN. Work-up of all renal biopsies was performed using standard protocols including immunohistochemistry for C4d. Results: Pediatric IgAN patients presented significantly more often with gross hematuria, higher serum creatinine, lower glomerular filtration rate, lower serum C3 and proteinuria and on histology less endocapillary hypercellularity compared to HSPN patients. However, the rate of glomerular C4d-positivity was not different between IgAN (36%) and HSPN (42%). Comparing all cases with positive versus negative glomerular C4d-staining, pediatric patients with glomerular C4d-positivity showed significantly lesser gross hematuria and received significantly more often cyclophosphamide. This was in line with a tendency towards more proteinuria, hypertension and renal insufficiency at last follow-up in C4d-positive compared to C4d-negative patients. Conclusion: In conclusion, in our monocentric study glomerular C4d does not differ between pediatric HSPN and IgAN, but was associated with a tendency to a more severe course of the disease that needs to be confirmed in larger multicentric studies.
CRIS-Team Scopus Importer:2021-01-22
Keywords: C4d staining; Glomerulonephritis; Henoch-Schönlein purpura; IgA nephritis; IgA vasculitis; Pediatric nephrology

Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography - Hammersen, Johanna; Wohlfart, Sigrun; Goecke, Tamme W.; Köninger, Angela; Stepan, Holger; Gallinat, Ralph; Morris, Susan; Bücher, Katharina; Clarke, Angus; Wünsche, Stephanie; Beckmann, Matthias; Schneider, Holm; et al. (Prenatal Diagnosis, 2019)
Objective: In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. Methods: Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. Results: In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. Conclusion: Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.
CRIS-Team Scopus Importer:2019-08-27

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis - Mocker, Alexander; Hilgers, Karl Friedrich; Cordasic, Nada; Wachtveitl, Rainer; Menendez-Castro, Carlos; Wölfle, Joachim; Hartner, Andrea; Fahlbusch, Fabian (International Journal of Molecular Sciences, 2019)
Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models.
CRIS-Team Scopus Importer:2019-12-24
Keywords: 2-kidney-1-clip; 2k1c; chemerin; CmklR1; renal fibrosis; renal inflammation; renal injury; renovascular hypertension; Thy1.1 nephritis

Renal transplantation: Opportunities and risks for medical refugees - Mammadova, Dilbar; Hirsch, K.; Schwaiger, Brigitte; Wullich, Bernd; Rascher, Wolfgang (Urologe, 2018)
BACKGROUND: Families with children and adolescents with end-stage renal disease came to Germany from the former Eastern Bloc countries before the wave of refugees in 2015, in order to enable their children to survive with adequate kidney replacement therapy and in the best case a kidney transplant. METHODS: In a case study, medical records of 4 childen and adolescents were retrospectively analyzed. These patients who fled to Germany for the treatment of terminal renal failure applied for asylum and were successfully transplanted after the usual waiting period. RESULTS: Four of the eight children and adolescents who came to Erlangen for treatment of terminal renal failure between 2003 and 2013 received a functioning kidney transplant (deceased donor kidney) after dialysis therapy was difficult due to lack of compliance to drug and dietary recommendations such as fluid restriction. Since children and adolescents are treated with chronic dialysis only with the aim of kidney transplantation, a living donation was discussed but was not possible for medical reasons. 3 recipients are symptom-free with a functional graft. DISCUSSION: The case study demonstrates that children and adolescents fleeing to Germany due to their end stage renal disease are better integrated after kidney transplantation, have better chances of obtaining a good education and can be expected to live independently with their own income in the future.
EVALuna2:35726

Repair of common arterial trunk: palliation and delayed correction as a viable alternative strategy in selected patients - Cuomo, Michela; Purbojo, Ariawan; Blumauer, Robert; Schober, Martin; Wällisch, Wolfgang; Dittrich, Sven; Cesnjevar, Robert (European Journal of Cardio-Thoracic Surgery, 2021)
OBJECTIVES Primary repair of common arterial trunk (CAT) is burdened by high mortality rates, especially in the presence of multiple risk factors. Timing, possible palliative methods, optimal management of associated cardiac lesions and handling of a poor preoperative state are still under discussion. METHODS We retrospectively analysed all patients who underwent surgery for CAT in our institution between 2008 and November 2020. We included 22 patients, 11 of whom received primary correction (PC) and 11 of whom underwent initial palliation by partial repair, leaving the ventricular septal defect open and connecting the right ventricle to the pulmonary arteries with a small valveless right ventricle-to-pulmonary artery conduit. A delayed correction (DC) was performed after 11.5 ± 3.6 months. RESULTS The overall operative mortality was 4.5%; 1 patient (affected by severe truncal valve stenosis and presenting in a poor state preoperatively) in the DC group died after palliation. The incidence of postoperative pulmonary hypertensive crisis was significantly higher in the PC group (P = 0.027). No patient from either group required postoperative extracorporeal support. Survival rates after 6 years differed slightly (PC group, 90%; DC group, 70%; log-rank = 0.270). CONCLUSIONS PC of CAT remains an optimal surgical approach for patients with an expected low mortality. However, our data support palliation and DC as a suitable alternative strategy, especially in the presence of significant risk factors like interrupted aortic arch, poor preoperative condition or complex surgical anatomy.
CRIS-Team WoS Importer:2022-05-13
Keywords: Common arterial trunk; Palliation; Sano-Shunt; Outcomes; Patient-tailored therapy; Congenital cardiac surgery

Repeated Use of Prescription Drugs in Pediatrics: Comprehensive Overview Based on German Claims Data - Scholle, Oliver; Neubert, Antje; Riedel, Oliver; Toni, Irmgard; Haug, Ulrike (Frontiers in Pharmacology, 2021)
Background: Investigating drug utilization in large and unselected samples of children and adolescents is an important component of public health monitoring. Most existing studies in this field focused on any drug use (i.e., >= 1 prescription of a certain drug) although chronic drug use may be more relevant. This study aimed to provide a comprehensive overview of prevalence and types of prescription drugs used repeatedly in children and adolescents in Germany in 2016. Methods: We used the German Pharmacoepidemiological Research Database (GePaRD)-a claims database covering similar to 20% of the German population. We included children and adolescents aged 0-17 years and assessed repeated use of prescription drugs (>= 3 prescriptions in 2016) on two levels: therapeutic subgroups (ATC 2nd level) and chemical substances (ATC 5th level). Analyses were stratified by sex and age groups (<2, 2-5, 6-12, and 13-17 years). Results: Overall, 2.5 million children and adolescents were included. In the age groups below 13 years, the prevalence rates of repeated use of prescription drugs (ATC 2nd level) were higher in boys than in girls (113-152 vs. 83-130 per 1,000 person-years), whereas in the age group 13-17 years, they were twice as high in girls than in boys (236 vs. 118 per 1,000 person-years). In boys and girls aged below six years, systemic antibiotics, topical ocular antibiotics, and drugs for constipation were among the most common drugs used repeatedly. For higher ages, methylphenidate, levothyroxine, and combined hormonal contraceptives, were among the most common drugs used repeatedly. Conclusions: Overall, about one in ten children in Germany repeatedly used prescription drugs. This proportion as well as the type of drugs used repeatedly markedly varied by sex and age. For certain drugs, our findings raise concerns regarding appropriateness of prescribing that should be addressed in future studies.
CRIS-Team WoS Importer:2021-08-13

Report from the HarmoSter study: Different LC-MS/MS androstenedione, DHEAS and testosterone methods compare well; however, unifying calibration is a double-edged sword - Fanelli, Flaminia; Peitzsch, Mirko; Bruce, Stephen; Cantù, Marco; Temchenko, Anastasia; Mezzullo, Marco; Lindner, Johanna M.; Hawley, James M.; Ackermans, Mariette T.; Van Den Ouweland, Jody; Köppl, Daniel; Nardi, Elena; et al. (Clinical Chemistry and Laboratory Medicine, 2024)
Current LC-MS/MS applications for circulating androgen measurements are technically diverse. Previously, variable results have been reported for testosterone. Data are scarce for androstenedione and absent for DHEAS. We assessed the agreement of androstenedione, DHEAS and testosterone LC-MS/MS measurements among nine European centers and explored benefits of calibration system unification. Androgens were measured twice by laboratory-specific procedures in 78 patient samples and in EQA materials. Results were obtained by in-house and external calibration. Intra- and inter-laboratory performances were valued. Intra-laboratory CVs ranged between 4.2-13.2 » % for androstenedione, 1.6-10.8 » % for DHEAS, and 4.3-8.7 » % and 2.6-7.1 » % for female and male testosterone, respectively. Bias and trueness in EQA materials were within ±20 » %. Median inter-laboratory CV with in-house vs. external calibration were 12.0 vs. 9.6 » % for androstenedione (p<0.001), 7.2 vs. 4.9 » % for DHEAS (p<0.001), 6.4 vs. 7.6 » % for female testosterone (p<0.001) and 6.8 and 7.4 » % for male testosterone (p=0.111). Median bias vs. all laboratory median with in-house and external calibration were -13.3 to 20.5 » % and -4.9 to 18.7 » % for androstenedione, -10.9 to 4.8 » % and -3.4 to 3.5 » % for DHEAS, -2.7 to 6.5 % and -11.3 to 6.6 » % for testosterone in females, and -7.0 to 8.5 » % and -7.5 to 11.8 » % for testosterone in males, respectively. Methods showed high intra-laboratory precision but variable bias and trueness. Inter-laboratory agreement was remarkably good. Calibration system unification improved agreement in androstenedione and DHEAS, but not in testosterone measurements. Multiple components, such as commutability of calibrators and EQA materials and internal standard choices, likely contribute to inter-laboratory variability.
CRIS-Team Scopus Importer:2024-01-26
Keywords: androstenedione; dehydroepiandrosterone-sulfate; harmonization; inter-laboratory performance; liquid chromatography-tandem mass spectrometry; testosterone

Report from the HarmoSter study: impact of calibration on comparability of LC-MS/MS measurement of circulating cortisol, 17OH-progesterone and aldosterone - Fanelli, Flaminia; Cantu, Marco; Temchenko, Anastasia; Mezzullo, Marco; Lindner, Johanna M.; Peitzsch, Mirko; Hawley, James M.; Bruce, Stephen; Binz, Pierre-Alain; Ackermans, Mariette T.; Heijboer, Annemieke C.; Van Den Ouweland, Jody; et al. (Clinical Chemistry and Laboratory Medicine, 2022)
Objectives Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is recommended for measuring circulating steroids. However, assays display technical heterogeneity. So far, reproducibility of corticosteroid LC-MS/MS measurements has received scant attention. The aim of the study was to compare LC-MS/MS measurements of cortisol, 17OH-progesterone and aldosterone from nine European centers and assess performance according to external quality assessment (EQA) materials and calibration. Methods Seventy-eight patient samples, EQA materials and two commercial calibration sets were measured twice by laboratory-specific procedures. Results were obtained by in-house (CAL1) and external calibrations (CAL2 and CAL3). We evaluated intra and inter-laboratory imprecision, correlation and agreement in patient samples, and trueness, bias and commutability in EQA materials. Results Using CAL1, intra-laboratory CVs ranged between 2.8-7.4%, 4.4-18.0% and 5.2-22.2%, for cortisol, 17OH-progesterone and aldosterone, respectively. Trueness and bias in EQA materials were mostly acceptable, however, inappropriate commutability and target value assignment were highlighted in some cases. CAL2 showed suboptimal accuracy. Median inter-laboratory CVs for cortisol, 17OH-progesterone and aldosterone were 4.9, 11.8 and 13.8% with CAL1 and 3.6, 10.3 and 8.6% with CAL3 (all p<0.001), respectively. Using CAL1, median bias vs. all laboratory-medians ranged from -6.6 to 6.9%, -17.2 to 7.8% and -12.0 to 16.8% for cortisol, 17OH-progesterone and aldosterone, respectively. Regression lines significantly deviated from the best fit for most laboratories. Using CAL3 improved cortisol and 17OH-progesterone between-method bias and correlation. Conclusions Intra-laboratory imprecision and performance with EQA materials were variable. Inter-laboratory performance was mostly within specifications. Although residual variability persists, adopting common traceable calibrators and RMP-determined EQA materials is beneficial for standardization of LC-MS/MS steroid measurements.
CRIS-Team WoS Importer:2022-03-04

Report from the HarmoSter study: inter-laboratory comparison of LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone - Fanelli, Flaminia; Bruce, Stephen; Cantu, Marco; Temchenko, Anastasia; Mezzullo, Marco; Lindner, Johanna M.; Peitzsch, Mirko; Binz, Pierre-Alain; Ackermans, Mariette T.; Heijboer, Annemieke C.; Van Den Ouweland, Jody; Koeppl, Daniel; et al. (Clinical Chemistry and Laboratory Medicine, 2022)
Objectives Liquid chromatography-tandem mass spectrometry (LC-MS/MS) panels that include glucocorticoid-related steroids are increasingly used to characterize and diagnose adrenal cortical diseases. Limited information is currently available about reproducibility of these measurements among laboratories. The aim of the study was to compare LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone at eight European centers and assess the performance after unification of calibration. Methods Seventy-eight patient samples and commercial calibrators were measured twice by laboratory-specific procedures. Results were obtained according to in-house and external calibration. We evaluated intra-laboratory and inter-laboratory imprecision, regression and agreement against performance specifications derived from 11-deoxycortisol biological variation. Results Intra-laboratory CVs ranged between 3.3 and 7.7%, 3.3 and 11.8% and 2.7 and 12.8% for corticosterone, 11-deoxycortisol and cortisone, with 1, 4 and 3 laboratories often exceeding the maximum allowable imprecision (MAI), respectively. Median inter-laboratory CVs were 10.0, 10.7 and 6.2%, with 38.5, 50.7 and 2.6% cases exceeding the MAI for corticosterone, 11-deoxycortisol and cortisone, respectively. Median laboratory bias vs. all laboratory-medians ranged from -5.6 to 12.3% for corticosterone, -14.6 to 12.4% for 11-deoxycortisol and -4.0 to 6.5% for cortisone, with few cases exceeding the total allowable error. Modest deviations were found in regression equations among most laboratories. External calibration did not improve 11-deoxycortisol and worsened corticosterone and cortisone inter-laboratory comparability. Conclusions Method imprecision was variable. Inter-laboratory performance was reasonably good. However, cases with imprecision and total error above the acceptable limits were apparent for corticosterone and 11-deoxycortisol. Variability did not depend on calibration but apparently on imprecision, accuracy and specificity of individual methods. Tools for improving selectivity and accuracy are required to improve harmonization.
CRIS-Team WoS Importer:2022-11-11

Reproductive decision-making by women with X-linked hypohidrotic ectodermal dysplasia - Leo, B.; Schneider, Holm; Hammersen, J. (Journal of the European Academy of Dermatology and Venereology, 2022)
Background: In X-linked hypohidrotic ectodermal dysplasia (XLHED), ectodysplasin A1 (EDA1) deficiency results in malformation of hair, teeth and sweat glands. Lack of sweating which can cause life-threatening hyperthermia is amenable to intrauterine therapy with recombinant EDA1. Objectives: This study aimed at evaluating reproductive decision-making by women with XLHED and at clarifying the potential impact of a prenatal treatment option. Methods: In a retrospective cross-sectional analysis, a 75-item questionnaire filled in by 50 women with XLHED (age 19–49 years) was assessed. Results: Sixteen women (32%) prevented pregnancies because of the risk to pass on XLHED; 15 considered assisted reproduction for the same reason. Twelve women had a history of miscarriage, stillbirth or abortion, and three women reported on previous abortion of affected fetuses. When imagining to be pregnant, all except one showed interest in prenatal diagnosis of XLHED and in the possibility of treatment before birth. In 13 out of 50 women (26%), XLHED if detected prenatally would have impact on the continuation of pregnancy. Among 35 mothers of at least one affected child, XLHED had rarely been diagnosed during the first pregnancy (17%) but regularly during subsequent pregnancies (77%). Becoming aware of the condition before birth had caused a moral conflict for 50% of these women. Subjects with an affected child less frequently considered assisted reproduction to prevent XLHED (P < 0.05). In 69% of the women who reported an effect of XLHED on family planning, a prenatal treatment option for this disease would influence their decision-making. Conclusions: Many pregnant XLHED carriers who seek prenatal diagnosis experience moral conflicts. A prenatal treatment option would have strong impact on reproductive decisions, underlining the importance of adequate professional counselling.
CRIS-Team Scopus Importer:2022-06-17

Resection of dominant fusiform gyrus is associated with decline of naming function when temporal lobe epilepsy manifests after the age of five: A voxel-based lesion-symptom mapping study - Reindl, Caroline; Allgäuer, Andrea; Kleiser, Benedict; Onugoren, Müjgan Dogan; Lang, Johannes; Welte, Tamara; Stritzelberger, Jenny; Winder, Klemens; Schwarz, Michael; Gollwitzer, Stephanie; Trollmann, Regina; Rösch, Julie; et al. (NeuroImage: Clinical, 2022)
Objective: To determine patients’ characteristics and regions in the temporal lobe where resections lead to a decline in picture naming. Methods: 311 patients with left hemispheric dominance for language were included who underwent epilepsy surgery at the Epilepsy Center of Erlangen and whose picture naming scores (Boston Naming Test, BNT) were available preoperatively and 6-months postoperatively. Surgical lesions were mapped to an averaged template based on preoperative and postoperative MRI using voxel-based lesion-symptom mapping (VBLSM). Postoperative brain shifts were corrected. The relationship between lesioned brain areas and the presence of a postoperative naming decline was examined voxel-wise while controlling for effects of overall lesion size at first in the total cohort and then restricted to temporal lobe resections. Results: In VBLSM in the total sample, a decline in BNT score was significantly related to left temporal surgery. When only considering patients with left temporal lobe resections (n = 121), 40 (33.1%) significantly worsened in BNT postoperatively. VBLSM including all patients with left temporal resections generated no significant results within the temporal lobe. However, naming decline of patients with epilepsy onset after 5 years of age was significantly associated with resections in the left inferior temporal (extent of BNT decline range: 10.8− 14.4%) and fusiform gyrus (decline range: 12.1−18.4%). Significance: Resections in the posterior part of the dominant fusiform and inferior temporal gyrus was associated with a risk of deterioration in naming performance at six months after surgery in patients with epilepsy onset after 5 years of age but not with earlier epilepsy onset.
CRIS-Team Scopus Importer:2022-08-19
Keywords: Basal temporal language area; Epilepsy surgery; Gyrus fusiformis; Lesion localization; Naming; Neuropsychological outcome

Re-sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL-like association, and isolated anorectal malformation - Thiem, Corina E.; Stegmann, Jil D.; Hilger, Alina C.; Waffenschmidt, Lea; Bendixen, Charlotte; Köllges, Ricarda; Schmiedeke, Eberhard; Schäfer, Frank Mattias; Lacher, Martin; Kosch, Ferdinand; Grasshoff-Derr, Sabine; Kabs, Carmen; et al. (Birth Defects Research, 2022)
Background: The acronym VATER/VACTERL association describes the combination of at least three component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Individuals presenting two CFs have been termed VATER/VACTERL-like. Recently, FOXF1, HSPA6, HAAO, KYNU, TRAP1, and ZIC3 have been proposed as candidate genes for VATER/VACTERL, VATER/VACTERL-like, and ARM. Re-sequencing studies identified disease-causing variants in TRAP1 and ZIC3, the contribution of other genes was not independently investigated. One affected variant carrier in FOXF1 was previously identified. Here we re-sequenced FOXF1, HSPA6, HAAO, and KYNU in 522 affected individuals. Methods: Using molecular inversion probe (MIP) technology, re-sequencing was performed in 63 individuals with VATER/VACTERL association, 313 with VATER/VACTERL-like association, and 146 with ARM. All individuals were of European ethnicity. Variant filtering considered variants with a minor allele frequency (MAF) ≤0.01 for putative recessive disease-genes HSPA6, HAAO, and KYNU. For the putative dominant disease-gene FOXF1 we considered variants with a MAF ≤0.0001. In silico prediction tools were used for further prioritization. Results: Only two variants in FOXF1 in two independently affected individuals [c.443G>T, p.(Cys148Phe); c.850T>C, p.(Tyr284His)] passed our filter criteria. One individual presented with ARM, the second presented with TE and C comprising atrial and ventricular septal defects. Sanger sequencing confirmed both variants but also their inheritance from the healthy mother. Conclusion: Our analysis suggests that FOXF1, HSPA6, HAAO and KYNU do not play a major role in the formation of VACTER/VACTERL phenotypes or ARM.
CRIS-Team Scopus Importer:2022-04-15
Keywords: anorectal malformation; birth defects; candidate gene; penetrance; variants

Resistance to antibacterial therapy in pediatric febrile urinary tract infections—a single-center analysis - Raupach, Thomas; Held, Jürgen; Prokosch, Hans-Ulrich; Rascher, Wolfgang; Zierk, Jakob (Journal of Pediatric Urology, 2019)
Background: Febrile urinary tract infections (UTIs) are common serious bacterial infections in childhood and require early diagnosis and antibacterial therapy. However, considerable uncertainty exists regarding the optimal antibacterial agent for primary treatment of pediatric UTIs. Additionally, patterns of susceptibility and resistance change over time and microbiological in vitro resistance is not necessarily associated with treatment failure. Here, we analyzed uropathogens, their resistance patterns, and response to antibacterial treatment in children with acute pyelonephritis. Methods: We used billing codes (international classification of diseases) to identify all inpatients aged 0–18 years with febrile UTIs in a German university tertiary care center from 2009 until 2018. Microbial results were retrieved from the laboratory information system for all children, and treatment regimen and treatment response were analyzed in a subgroup of children. Results: We identified 907 children with acute pyelonephritis; in 590 cases (65%) an uropathogen was detected. Escherichia coli (60.8%), Enterococcus faecalis (13.2%), Klebsiella pneumoniae (7.0%), Proteus spp. (5.2%), and Pseudomonas aeruginosa (4.2%) were the most common pathogens. 353 of 436 E. coli isolates (81.0%) were susceptible or intermediate to aminopenicillin/β-lactamase-inhibitor (BLI) combinations. We examined 52 cases where E. coli was resistant to initial therapy with aminopenicillin/BLI combinations: Therapy was changed in 35 cases (67%) and left unchanged in 17 cases (33%), and we found no significant differences in C-reactive protein and leucocyte count in blood and urine between both groups after 3 days. Conclusions: We present the spectrum of uropathogens and susceptibility test results in pediatric UTIs in a tertiary care center. Our findings suggest a satisfactory response to first-line therapy with aminopenicillin/BLI combinations.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Antibiotic susceptibility/resistance; Escherichia coli; Febrile urinary tract infections; Pediatrics

Respiratory infections regulated blood cells IFN-β-PD-L1 pathway in pediatric asthma - Kölle, Julia; Haag, Patricia; Vuorinen, Tytti; Kiefer, Alexander; Rauh, Manfred; Zimmermann, Theodor; Papadopoulos, Nikolaos G.; Finotto, Susetta (Immunity, Inflammation and Disease, 2020)
Background: Respiratory infections, in general, and rhinovirus infection specifically are the main reason for asthma exacerbation in children and programmed cell death protein 1 ligand (PD-L1) expression inhibits T cell responses. Objective: Could the interferon (IFN) type I expression in peripheral blood mononuclear cells (PBMCs) improve disease exacerbation in pediatric asthma?. Results: Here we found increased level of PD-L1 messenger RNA (mRNA) in total blood cells isolated from preschool children with virus-induced asthma, with lower percentage of forced expiratory volume in 1 second and with high serum levels of the C-reactive-protein. Conclusions and Clinical Relevance: These data indicate that, in the presence of infection in the airways of preschool children, worse asthma is associated with induced PD-L1 mRNA expression in blood cells. Further, type I IFN, IFN-β, a cytokine that is involved in the clearance of infections, was found to be associated with a better lung function in asthmatic children. These data suggest that improving peripheral blood IFN type I expression in PBMCs in pediatric asthma could improve disease exacerbation due to suppressing PD-L1 expression in blood cells.
CRIS-Team Scopus Importer:2020-05-22
Keywords: human rhinovirus; IFNβ; PD-L1; pediatric asthma

Response monitoring of infant acute myeloid leukemia treatment by quantification of the tumor specific MLL-FNBP1 fusion gene - Krumbholz, Manuela; Jung, Ronny; Bradtke, Jutta; Reinhardt, Dirk; Stachel, Daniel; Metzler, Markus (Leukemia & Lymphoma, 2015)
EVALuna2:18906

Results from an international multicenter trial evaluating the ease-of-use of and preference for a newly developed disposable injection pen for the treatment of growth hormone deficiency in treatment-naïve children and adults - Pleil, Andreas M.; Darendeliler, Feyza; Dörr, Helmuth-Günther; Hutchinson, Katherine; Wollmann, Hartmut A. (Medical Devices : Evidence and Research, 2014)
Previous research has reported that ease of use of and preference for a delivery device are associated with greater patient compliance - an important factor in achieving optimal therapeutic results. The objective of this study was to assess the ease-of-use of a new disposable pen (GoQuick(®), Pfizer, Inc.) versus the current reusable pen (GENOTROPIN Pen(®), Pfizer, Inc.) to inject a daily dose of recombinant DNA origin human growth hormone, Genotropin(®) (somatropin) in standard practice. In this randomized, crossover, multicenter, multinational, open-label study, ease-of-use of and preference for the two pens were assessed in three treatment-naïve populations: 1) parents of very young children; 2) parent-child dyads; and 3) adults via use of a validated self-report Injection Pen Assessment Questionnaire (IPAQ) after 2 months of at-home-use experience. The primary endpoint was the proportion of participants who reported the new disposable pen to be no different from or easier to use than the current reusable pen. Safety was also assessed and reported according to local legal requirements. Of the 120 screened patients, 119 were included in the ease-of-use analysis and all were included in the safety analyses. In all, 67.2% found the new somatropin disposable pen to be no different from or easier to use than the reusable pen (95% confidence interval: 58.8-75.7). Most adverse events were mild or moderate. No deaths or device- or treatment-related serious adverse events were reported. These results suggest that improvements made to the reusable somatropin pen are tangible and recognizable to treatment-naïve patients and their caregivers, child-caregiver dyads, and adults, and may positively impact continued compliance with therapy.ClinicalTrials.gov identifier: NCT01112865.
EVALuna2:18887

Reversing the Inflammatory Process—25 Years of Tumor Necrosis Factor-α Inhibitors - Muth, Katharina N.; Rech, Jürgen; Losch, Florian O.; Hörning, André (Journal of Clinical Medicine, 2023)
Immune-mediated inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, peripheral and/or axial spondyloarthritis, Crohn’s disease, and ulcerative colitis, are characterized by molecular and cellular changes in the immune system. Due to the systemic nature of these diseases, organs such as the liver or cardiovascular system are often affected by the inflammatory process. Tumor necrosis factor-α inhibitor therapy reduces the activation of pro-inflammatory signaling cascades, mitigates the chronic inflammatory process by restoring cellular balance, and alleviates clinical consequences, such as pain and tissue damage.
CRIS-Team Scopus Importer:2023-09-01
Keywords: cytokines; immune-mediated inflammatory diseases; inflammation; liver; rheumatoid arthritis; tumor necrosis factor alpha-inhibitors

Rezidivierende E.-coli-Meningitis in der Neonatalperiode - Dierl, Alexander; Hanslik, Gregor (Monatsschrift Kinderheilkunde, 2023)
Background: Due to heterogeneous data, case studies with a small study population and different clinical constellations, a generally valid statement about the duration of antibacterial treatment in cases of neonatal meningitis is difficult. Single case reports could be helpful to optimize the antibacterial treatment strategy. Objective: This study illustrates our experience in the treatment of a female preterm infant with recurrent episodes of meningitis in the neonatal period after initial Escherichia coli sepsis. Possible risk factors and suggestions for improvement of the treatment strategy as well as different diagnostic options to exclude anatomical or immunological risk factors are demonstrated. Material and methods: Case report of a female preterm infant of 35 + 3 weeks gestational age with 3 episodes of E. coli meningitis. Results: In this case an administration period of 6 weeks was necessary for successful infection treatment. No anatomical aberrations or immunodeficiencies were present as risk factors for the three episodes of E. coli meningitis with sepsis. Using magnetic resonance imaging (MRI) and positron emission tomography computed tomography (PET-CT) as well as repeated imaging with ultrasonography, the diagnosis could also be presented in cross-sectional imaging. Conclusion: The optimal duration of treatment of neonatal meningitis still needs to be selected based on the patient-related risk factors as well as the results of the microbial examination. In our case, the causative pathogen (E. coli) was identified as a significant risk factor for recurrent meningitis and the need for prolonged antibacterial treatment.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Cerebrospinal fluid; Neonate; Pleocytosis; Preterm; Sepsis

RHABDOID TUMOR PREDISPOSITION SYNDROME (RTPS) - FINDING EVIDENCE BY SYSTEMATIC ANALYSES - Nemes, Karolina; Bens, Susanne; Johann, Pascal D.; Steinbuegl, Mona; Gruhle, Miriam; Kachanov, Denis; Teleshova, Margarita; Hauser, Peter; Simon, Thorsten; Tippelt, Stephan; Eberl, Wolfgang; Woessmann, Wilhelm; et al. (NEURO-ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-09-02

Rhinovirus inhibits IL-17A and the downstream immune responses in allergic asthma - Graser, Anna; Ekici, Arif Bülent; Sopel, Nina; Melichar, V. O.; Zimmermann, Theodor; Papadopoulos, N. G.; Taka, S.; Ferrazzi, Fulvia; Vuorinen, T.; Finotto, Susetta (Mucosal Immunology, 2016)
The proinflammatory cytokine interleukin-17A (IL-17A) is known to mediate antimicrobial activity, but its role during rhinovirus (RV) infections and in asthma needs further investigation. Therefore, we addressed the role of IL-17A during allergic asthma and antiviral immune response in human and murine immunocompetent cells. In this study we found that asthmatic children with a RV infection in their upper airways have upregulated mRNA levels of the antiviral cytokine interferon type I (IFN)-? and the transcription factor T-box 21 (TBX21) and reduced levels of IL-17A protein in their peripheral blood mononuclear cells (PBMCs). We also found that IL-17A inhibited RV1b replication in infected human lung epithelial cells A549. Furthermore, by using gene array analysis we discovered that targeted deletion of Il17a in murine lung CD4(+) T cells impaired Oas1g mRNA downstream of Ifn?, independently from RV infection. Additionally, in PBMCs of children with a RV infection in their nasalpharyngeal fluid OAS1 gene expression was found downregulated. Finally RV1b inhibited IL-17A production in lung CD4(+) T cells in a setting of experimental asthma. These results indicate that the RV1b inhibits IL-17A in T helper type 17 cells and IL-17A clears RV1b infection in epithelial cells. In both cases IL-17A contributes to fend off RV1b infection by inducing genes downstream of interferon type I pathway.
EVALuna2:9312

Rhinovirus species/genotypes and interferon-λ: subtypes, receptor and polymorphisms - missing pieces of the puzzle of childhood asthma? - Bergauer, Annika; Sopel, Nina; Kro, Bettina; Vuorinen, Tytti; Xepapadaki, Paraskevi; Weiss, Scott T.; Blau, Ashley; Sharma, Himanshu; Kraus, Cornelia; Springel, Rebekka; Rauh, Manfred; Mittler, Susanne; et al. (European Respiratory Journal, 2017)
EVALuna2:25986

RIbench: A Proposed Benchmark for the Standardized Evaluation of Indirect Methods for Reference Interval Estimation - Ammer, Tatjana; Schuetzenmeister, Andre; Prokosch, Hans-Ulrich; Zierk, Jakob; Rank, Christopher M.; Rauh, Manfred (Clinical Chemistry, 2022)
Background Indirect methods leverage real-world data for the estimation of reference intervals. These constitute an active field of research, and several methods have been developed recently. So far, no standardized tool for evaluation and comparison of indirect methods exists. Methods We provide RIbench, a benchmarking suite for quantitative evaluation of any existing or novel indirect method. The benchmark contains simulated test sets for 10 biomarkers mimicking routine measurements of a mixed distribution of non-pathological (reference) values and pathological values. The non-pathological distributions represent 4 common distribution types: normal, skewed, heavily skewed, and skewed-and-shifted. To identify strengths and weaknesses of indirect methods, test sets have varying sample sizes and pathological distributions differ in location, extent of overlap, and fraction. For performance evaluation, we use an overall benchmark score and sub-scores derived from absolute z-score deviations between estimated and true reference limits. We illustrate the application of RIbench by evaluating and comparing the Hoffmann method and 4 modern indirect methods -TML (Truncated-Maximum-Likelihood), kosmic, TMC (Truncated-Minimum-Chi-Square), and refineR- against one another and against a nonparametric direct method (n = 120). Results For the modern indirect methods, pathological fraction and sample size had a strong influence on the results: With a pathological fraction up to 20% and a minimum sample size of 5000, most methods achieved results comparable or superior to the direct method. Conclusions We present RIbench, an open-source R-package, for the systematic evaluation of existing and novel indirect methods. RIbench can serve as a tool for enhancement of indirect methods, improving the estimation of reference intervals.
CRIS-Team WoS Importer:2022-11-04

Risk Factor Analysis for Long-Term Graft Survival Following Pediatric Kidney Transplantation: The Importance of Pretransplantation Time on Dialysis and Donor/Recipient Age Difference - Marcou, Marios; Galiano, Matthias; Tzschoppe, Anja; Sauerstein, Katja; Wach, Sven; Taubert, Helge; Wullich, Bernd; Hirsch-Koch, Karin; Apel, Hendrik (Journal of Clinical Medicine, 2023)
Recognizing risk factors that may negatively affect long-term graft survival following pediatric kidney transplantation is a key element in the decision-making process during organ allocation. We retrospectively reassessed all cases of pediatric kidney transplantation performed in our center in the last 20 years with the aim of determining baseline characteristics that could be identified as prognostic risk factors for long-term graft survival. Between 2001 and 2020, a total of 91 kidney transplantations in children under the age of 18 years were undertaken in our center. Early graft failure was observed in six of the 91 patients (7%). The median follow-up of the remaining 85 children was 100 months, and the overall kidney graft survival rates at 5, 10, 15 and 20 years were 85.2%, 71.4%, 46.0% and 30.6%, respectively. Small children with a body surface area of <1 m2 were significantly associated with better long-term graft survival outcomes, while adolescents aged more than twelve years showed poorer graft survival rates than younger children. Body surface area of the recipient of ≥1 m2, pretransplantation duration of the recipient on dialysis ≥18 months, hemodialysis prior to transplantation and donor/recipient age difference of ≥25 years were significantly associated with poorer long-term graft survival.
CRIS-Team Scopus Importer:2023-12-08
Keywords: age difference; children; graft survival; kidney transplantation; renal dialysis

Risk factors for chylothorax and persistent serous effusions after congenital heart surgery - Raatz, Anna; Schöber, Martin; Zant, Robert; Cesnjevar, Robert; Rüffer, André; Purbojo, Ariawan; Dittrich, Sven; Alkassar, Muhannad (European Journal of Cardio-Thoracic Surgery, 2019)
OBJECTIVES: This study evaluated the various risk factors for chylothorax and persistent serous effusions (>7 days) after congenital heart surgery and developed equations to calculate the probability of their occurrence. METHODS: We performed a retrospective review of different medical databases at the University Hospital of Erlangen between January 2014 and December 2016. Full model regression analysis was used to identify risk factors, and prediction algorithms were set up to calculate probabilities. Discriminative power of the models was checked with the help of C-statistics. RESULTS: Of 745 operations on 667 patients, 68 chylothoraxes (9.1%) and 125 persistent pleural effusions (16.8%) were diagnosed. Lowest temperature [P = 0.043; odds ratio (OR) 0.899], trisomy 21 (P = 0.001; OR 5.548), a higher vasoactive inotropic score on the day of surgery (P = 0.001; OR 1.070) and use of an assist device (P = 0.001; OR 5.779) were significantly associated with chylothorax. Risk factors for persistent serous effusions were a given or possible involvement of the aortic arch during the operation (P = 0.000; OR 3.982 and 2.905), univentricular hearts (P = 0.019; OR 2.644), a higher number of previous heart operations (P = 0.014; OR 1.436), a higher vasoactive inotropic score 72 h after surgery (P = 0.019; OR 1.091), a higher central venous pressure directly after surgery (P = 0.046; OR 1.076) and an aortic cross-clamp time >86 min (P = 0.023; OR 2.223), as well as use of an assist device (P = 0.002; OR 10.281). The prediction models for both types of effusions proved to have excellent discriminative power. CONCLUSIONS: Persistent serous effusion is associated with a higher vasoactive inotropic score 72 h after surgery, an aortic cross-clamp time >86 min and elevated central venous pressure directly after surgery, which, in combination, potentially indicate cardiac stress. The developed logistic algorithm helps to estimate future likelihood.
CRIS-Team Scopus Importer:2019-11-29
Keywords: Cardiac insufficiency; Cardiac surgery; Chylothorax; Congenital heart disease; Persistent effusions; Risk factor

Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease. - Burgmaier, Kathrin; Kunzmann, Kevin; Ariceta, Gema; Bergmann, Carsten; Buescher, Anja Katrin; Burgmaier, Mathias; Dursun, Ismail; Duzova, Ali; Eid, Loai; Erger, Florian; Feldkoetter, Markus; Galiano, Matthias; et al. (Journal of Pediatrics, 2018)
OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.
EVALuna2:203368
Keywords: PKHD1; renal replacement therapy; oligohydramnios; ciliopathy

Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning - Wustrau, Katharina; Greil, Johann; Sykora, Karl-Walter; Albert, Michael H.; Burkhardt, Birgit; Lang, Peter; Meisel, Roland; Woessmann, Wilhelm; Beier, Rita; Schulz, Ansgar; Bader, Peter; Chada, Martin; et al. (Pediatric Blood & Cancer, 2020)
Background Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. Procedure Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. Results Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). Conclusion The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.
CRIS-Team WoS Importer:2020-07-17

RNA expression profiles and regulatory networks in human right ventricular hypertrophy due to high pressure load - Chouvarine, Philippe; Photiadis, Joachim; Cesnjevar, Robert; Scheewe, Jens; Bauer, Ulrike M. M.; Pickardt, Thomas; Kramer, Hans-Heiner; Dittrich, Sven; Berger, Felix; Hansmann, Georg (iScience, 2021)
Right ventricular hypertrophy (RVH) occurs in high pressure afterload, e.g., tetralogy of Fallot/pulmonary stenosis (TOF/PS). Such RVH is associated with alterations in energy metabolism, neurohormonal and epigenetic dysregulation (e.g., microRNA), and fetal gene reprogramming in animal models. However, comprehensive expression profiling of competing endogenous RNA in human RVH has not been performed. Here, we unravel several previously unknown circular, long non-coding, and microRNAs, predicted to regulate expression of genes specific to human RVH in the non-failing heart (TOF/PS). These genes are significantly overrepresented in pathways related to regulation of glucose and lipid metabolism (SIK1, FABP4), cell surface interactions (THBS2, FN1), apoptosis (PIK3IP1, SIK1), extracellular matrix composition (CTGF, IGF1), and other biological events. This is the first unbiased RNA sequencing study of human compensated RVH encompassing coding and noncoding RNA expression and predicted sponging of miRNAs by non-coding RNAs. These findings advance our understanding of adaptive RVH and highlight future therapeutic targets.
CRIS-Team WoS Importer:2021-04-16

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension - Menendez-Castro, Carlos; Cordasic, Nada; Fahlbusch, Fabian; Ekici, Arif Bülent; Kirchner, Philipp; Daniel, Christoph; Amann, Kerstin Ute; Velkeen, Roland; Wölfle, Joachim; Schiffer, Mario; Hartner, Andrea; Hilgers, Karl Friedrich (Journal of Molecular Medicine, 2021)
Abstract: In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. Key messages: The most severe hypertension-induced kidney injury occurs in malignant hypertension.In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades.Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.
CRIS-Team Scopus Importer:2021-09-24
Keywords: Complement activation; Inflammation; Kidney injury; Malignant hypertension; RNA-Seq; Two-kidney one-clip renovascular hypertension (2K1C)

Role of nuclear factor of activated T cells 2 (NFATc2) in allergic asthma - Jakobi, M.; Mirzakahni, H.; Kiefer, Alexander; Rauh, Manfred; Zimmermann, Theodor; Papadopoulos, N. G.; Raby, B. A.; Weiss, S. T.; Finotto, Susetta (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

Role of TGF-β in anti-rhinovirus immune responses in asthmatic patients - Bielor, Carina; Sopel, Nina; Maier, Anja; Blau, Ashley; Sharma, Himanshu; Vuorinen, Tytti; Kross, Bettina; Mittler, Susanne; Graser, Anna; Mousset, Stephanie; Melichar, Volker O.; Kiefer, Alexander; et al. (Journal of Allergy and Clinical Immunology, 2017)
EVALuna2:32796

Routine Surveillance of SARS-CoV-2 Serostatus in Pediatrics Allows Monitoring of Humoral Response - Wachter, Felix; Knieling, Ferdinand; Raming, Roman; Simon, David; Wölfle, Joachim; Hörning, André; Neubert, Antje; Rauh, Manfred; Regensburger, Adrian (Microorganisms, 2023)
The occurrence of SARS-CoV-2 infections during the pandemic was mainly based on PCR testing of symptomatic patients. However, with new variants, vaccinations, and the changing of the clinical disease severity, knowledge about general immunity is elusive. For public health systems, timely knowledge of these conditions is essential, but it is particularly scarce for the pediatric population. Therefore, in this study, we wanted to investigate the spike and nucleocapsid seroprevalence in pediatric patients using routine residual blood tests collected during the pandemic. This prospective observational study was conducted over seven one-month periods. Herein, the latest four time periods (November 2021, January 2022, March 2022, and May 2022) are depicted. Each patient of a tertiary-care center in Germany was anonymized after collection of clinical diagnosis (ICD-10) and then routinely tested for the respective spike and nucleocapsid SARS-CoV-2 antibody titer. A total of 3235 blood samples from four time periods were included. Spike seroprevalence rose from 37.6% to 51.9% to 70.5% to 85.1% and nucleocapsid seroprevalence from 11.6% to 17.0% to 36.7% to 58.1% in May 2022. In detail, significant changes in seroprevalence between age groups but not between sex or diagnosis groups were found. Quantitative measures revealed rising spike and constant nucleocapsid antibody levels over the pandemic with a half-life of 102 days for spike and 45 days for nucleocapsid antibodies. Routine laboratory assessment of SARS-CoV-2 in residual blood specimens of pediatric hospitals enables monitoring of the seroprevalence and may allow inferences about general immunity in this cohort.
EVALuna2:547467
Keywords: COVID-19; pediatrics; seroprevalence; SARS-CoV-2; Omicron; surveillance

Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity - Groß, Miriam; Speckmann, Carsten; May, Annette; Gajardo-Carrasco, Tania; Wustrau, Katharina; Maier, Sarah Lena; Panning, Marcus; Huzly, Daniela; Agaimy, Abbas; Bryceson, Yenan T.; Choo, Sharon; Chow, C. W.; et al. (Journal of Allergy and Clinical Immunology, 2021)
Background: Rubella virus–induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas. Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays. Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses. Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Cytotoxicity; granuloma; Griscelli syndrome type 2; hemophagocytic lymphohistiocytosis; live vaccine; primary immunodeficiency; rubella virus

RVAD implantation in a Fontan patient with protein-losing enteropathy as a bridge to transplant: Prêtre modification - Moosmann, Julia; Dittrich, Sven; Purbojo, Ariawan; Cesnjevar, Robert (Journal of Cardiac Surgery, 2020)
Fontan patients with protein-losing enteropathy (PLE) represent poor candidates for cardiac transplantation due to end-organ injury and severely impaired clinical condition. Ventricular assist device (VAD) therapy has evolved as a promising bridge to transplant strategy improving quality of life and survival on the waiting list. However, VAD therapy for the Fontan circulation remains challenging. For Fontan patients with preserved ventricular function implantation of a right ventricular assist device (RVAD) has been described by Prêtre et al as bridge to transplant. We present the second case of RVAD support in a Fontan patient with PLE.
CRIS-Team Scopus Importer:2020-06-30
Keywords: assist in Fontan; congenital heart disease; Fontan circulation; protein-losing enteropathy; right ventricular assist device

Safety and effectiveness of pediatric growth hormone therapy: Results from the full cohort in KIGS - Maghnie, Mohamad; Ranke, Michael B.; Geffner, Mitchell E.; Vlachopapadopoulou, Elpis; Dörr, Helmuth-Günther; Wikland, Kerstin Albertsson; Ibanez, Lourdes; Carlsson, Martin; Cutfield, Wayne; Rooman, Raoul; Gomez, Roy; Wajnrajch, Michael P.; et al. (HORMONE RESEARCH IN PAEDIATRICS, 2021)
CRIS-Team WoS Importer:2021-10-08

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort - Maghnie, Mohamad; Ranke, Michael B.; Geffner, Mitchell E.; Vlachopapadopoulou, Elpis; Ibanez, Lourdes; Carlsson, Martin; Cutfield, Wayne; Rooman, Raoul; Gomez, Roy; Wajnrajch, Michael P.; Linglart, Agnes; Stawerska, Renata; et al. (Journal of Clinical Endocrinology and Metabolism, 2022)
Context The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. Objective This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Methods Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (>= 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. Results The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Conclusion Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.
CRIS-Team WoS Importer:2022-10-14

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects - Körber, Iris; Klein, Ophir D.; Morhart, Patrick; Faschingbauer, Florian; Grange, Dorothy K.; Clarke, Angus; Bodemer, Christine; Maitz, Silvia; Huttner, Kenneth; Kirby, Neil; Durand, Caroline; Schneider, Holm (British Journal of Clinical Pharmacology, 2020)
In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.
CRIS-Team Scopus Importer:2020-05-02
Keywords: drug safety; ectodermal dysplasia; ectodysplasin A; immunogenicity; prenatal therapy; protein replacement

Safety of clonidine used for long-term sedation in paediatric intensive care: A systematic review - Eberl, Sonja; Ahne, Gabriele; Toni, Irmgard; Standing, Joseph; Neubert, Antje (British Journal of Clinical Pharmacology, 2020)
Aim: Although not approved, the alpha-adrenoceptor agonist clonidine is considered an option for long-term sedation protocols in paediatric intensive care. We reviewed adverse effects of clonidine occurring in this indication.
CRIS-Team WoS Importer:2021-01-15

Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia - Botzenhardt, Sebastian; Sing, Chor W; Wong, Ian C K; Chan, Godfrey Chi-Fung; Wong, Lisa Y L; Felisi, Mariagrazia; Rascher, Wolfgang; Ceci, Adriana; Neubert, Antje (Current Drug Safety, 2016)
UNLABELLED: There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. KEY POINTS: • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.
EVALuna2:34001

Safety profiles of iron chelators in young patients with haemoglobinopathies - Botzenhardt, Sebastian; Li, Niya; Chan, Esther W.; Sing, Chor Wing; Wong, Ian C. K.; Neubert, Antje (European Journal of Haematology, 2017)
BACKGROUND: This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies. METHODS: Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions. RESULTS: Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies. CONCLUSION: Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.
EVALuna2:34283

Sarcoma treatment in the era of molecular medicine - Grünewald, Thomas G.P.; Alonso, Marta; Avnet, Sofia; Banito, Ana; Burdach, Stefan; Cidre-Aranaz, Florencia; Di Pompo, Gemma; Distel, Martin; Dorado-Garcia, Heathcliff; Garcia-Castro, Javier; González-González, Laura; Grigoriadis, Agamemnon E.; et al. (Embo Molecular Medicine, 2020)
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
CRIS-Team Scopus Importer:2020-10-23
Keywords: bone sarcoma; molecular diagnostics; molecular medicine; soft tissue sarcoma; targeted therapy

SARS-CoV-2 Infection in Pregnancy and Incidence of Congenital Malformations - Is there a Correlation? Analysis of 8032 Pregnancies from the CRONOS Registry SARS-CoV-2-Infektion in der Schwangerschaft und Auftreten von angeborenen Fehlbildungen - Besteht ein Zusammenhang? Auswertung von 8032 Schwangerschaften aus dem CRONOS-Register - Hofbauer, Anna; Schneider, Holm; Kehl, Sven; Reutter, Heiko Martin; Pecks, Ulrich; Andresen, Kristin; Morhart, Patrick (Zeitschrift für Geburtshilfe und Neonatologie, 2024)
Background Based on single case reports, the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS) registry, sponsored by the German Society for Perinatal Medicine (DGPM), investigated the likelihood that SARS-CoV-2 infections of the mother in (early) pregnancy cause embryopathies and/or fetopathies. Material/Methods The CRONOS registry enrolled a total of 8032 women with confirmed SARS-CoV-2 infection during pregnancy at more than 130 participating hospitals from April 2020 to February 2023. Both maternal and fetal data were documented and the anonymized multicenter data were analyzed. Results Of 7142 fully documented pregnancies (including postnatal data), 140 showed congenital malformations. 8.57% of the mothers had had a SARS-CoV-2-infection in the 1st trimester and 36.43% in the 2nd trimester. In 66 cases with congenital malformations (47.14%), the malformation was only detected after the diagnosis of a maternal SARS-CoV-2 infection. The overall prevalence of congenital malformations in this cohort was 1.96%, compared to a prevalence of 2.39% reported in the EUROCAT (European network of population-based registries for the epidemiological surveillance of congenital anomalies) pre-pandemic registry between 2017-2019. Discussion Our multicenter data argue against a link between maternal SARS-CoV-2 infection in early pregnancy and congenital malformation.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Coronavirus; COVID-19; CRONOS-registry; embryopathy; fetopathy; malformations

Sclerosing epithelioid fibrosarcoma of the kidney: clinicopathologic and molecular study of a rare neoplasm at a novel location - Ohlmann, Carsten-Henning; Brecht, Ines B.; Junker, Kerstin; Van Der Zee, Jill A.; Nistor, Adriana; Bohle, Rainer M.; Stöckle, Michael; Metzler, Markus; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2015)
Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site.
EVALuna2:6701

Searching the web: a survey on the quality of advice on postnatal sequelae of intrauterine growth restriction and the implication of developmental origins of health and disease - Perzel, S.; Hübner, Hanna; Rascher, Wolfgang; Menendez-Castro, C.; Fahlbusch, F. B.; Hartner, Andrea (Journal of Developmental Origins of Health and Disease, 2017)
Intrauterine growth restriction (IUGR) and fetal growth restriction (FGR) are pregnancy complications associated with morbidity in later life. Despite a growing body of evidence from current research on developmental origins of health and disease (DOHaD), little information is currently provided to parents on long-term metabolic, cardiovascular and neurologic consequences. As parents strongly rely on internet-based health-related information, we examined the quality of information on IUGR/FGR sequelae and DOHaD in webpages used by laypersons. Simulating non-clinicians experience, we entered the terms 'IUGR consequences' and 'FGR consequences' into Google and Yahoo search engines. The quality of the top search-hits was analyzed with regard to the certification through the Health On the Net Foundation (HON), currentness of cited references, while reliability of information and DOHaD-related consequences were assessed via the DISCERN Plus score (DPS). Overall the citation status was not up-to-date and only a few websites were HON-certified. The results of our analysis showed a dichotomy between the growing body of evidence regarding IUGR/FGR-related sequelae and lack of current guidelines, leaving parents without clear directions. Furthermore, detailed information on the concept of DOHaD is not provided. These findings emphasize the responsibility of the individual physician for providing advice on IUGR/FGR-related sequelae, monitoring and follow-up.
EVALuna2:34005

Second International Conference on a classification of ectodermal dysplasias: development of a multiaxis model - Salinas, Carlos F.; Irvine, Alan D.; Itin, Peter H.; Di Giovanna, John J.; Schneider, Holm; Clarke, Angus J.; Mcgovern, Laura Sternesky; Fete, Mary (American Journal of Medical Genetics Part A, 2014)
Ectodermal dysplasias (EDs) comprise a large clinically and etiologically heterogeneous group of genetic disorders characterized by abnormalities in tissues derived from the embryonic ectoderm. Controversy exists over which syndromes should be classified as EDs and which should be excluded from the classification. The challenge will be to balance comprehensiveness within the classification with usability and accessibility so that the benefits truly serve the needs of researchers, health-care providers, and ultimately the individuals and families directly affected by EDs. The overarching goal of the Second International Conference was to develop a consensus on EDs classifications, with the ultimate goal of creating a system that integrates clinical and molecular knowledge, using an interactive Internet-based database that clinicians, researchers, and laymen can use. The Conference, brought together a group of experts from around the world, including a diverse health-care providers, researchers, patient advocate representatives, and administrators. The Conference was modeled after the 2008 conference, with plenary sessions, scientific updates, and small group discussions. Based on the present clinical knowledge, new molecular advances and both coupled with new bioinformatics developments, the participants agree to develop a multi-axis system approach for the classification of EDs. The multi-axis approach will include a clinical/phenotype axis, a gene-based axis, and a functional/pathways axis. The significance of the conference outcomes includes, a new classification approach that will foster a better understanding of EDs, open new fields of research and develop a nosologic approach that may have broad implications for classifying other hereditary conditions.
EVALuna2:18896

Seizure-induced neuronal apoptosis is related to dysregulation of the RNA-edited GluR2 subunit in the developing mouse brain - Jung, Susan; Ballheimer, Yili Elisabeth; Brackmann, Florian; Zoglauer, Daniel; Geppert, Carol-Immanuel; Hartmann, Arndt; Trollmann, Regina (Brain Research, 2020)
Ca2+-permeable AMPA receptors (AMPAR) which crucially modify maturational programs of the developing brain are involved in seizure-induced glutamate excitotoxicity and apoptosis. Regulatory effects on AMPAR subunit composition and RNA-editing in the developing brain and their significance as therapeutic targets are not well understood. Here, we analyzed acute effects of recurrent pilocarpine-induced neonatal seizures on age- and region-specific expression of AMPAR subunits and adenosine deaminases (ADAR) in the developing mouse brain (P10). After recurrent seizure activity and regeneration periods of 6–72 h cerebral mRNA levels of GluR (glutamate receptor subunit) 1, GluR2, GluR3, and GluR4 were unaffected compared to controls. However, ratio of GluR2 and GluR4 to pooled GluR1-4 mRNA concentration significantly decreased in seizure-exposed brains in comparison to controls. After a regeneration period of 24–72 h ADAR1 and ADAR2 mRNA expression was significantly lower in seizure-exposed brains than in those of controls. This was confirmed at the protein level in the hippocampal CA3 region. We observed a regionally increased apoptosis (TUNEL+ and CC3+ cells) in the hippocampus, parietal cortex and subventricular zone of seizure-exposed brains in comparison to controls. Together, present in vivo data demonstrate the maturational age-specific, functional role of RNA-edited GluR2 in seizure-induced excitotoxicity in the developing mouse brain. In response to recurrent seizure activity, we observed reduced expression of GluR2 and the GluR2 mRNA-editing enzymes ADAR1 and ADAR2 accompanied by increased apoptosis in a region-specific manner. Thus, AMPA receptor subtype-specific mRNA editing is assessed as a promising target of novel neuroprotective treatment strategies in consideration of age-related developmental mechanisms.
CRIS-Team Scopus Importer:2020-03-17
Keywords: ADAR; Adenosine deaminases; Apoptosis; Brain injury; Experimental seizure model; Neonatal brain; Neurodegeneration; Neuroprotection; Pilocarpine; RNA editing

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature - Schubert-Bast, Susanne; Wolff, Markus; Wiemer-Kruel, Adelheid; von Spiczak, Sarah; Trollmann, Regina; Reif, Philipp S.; Pritchard, Clive; Polster, Tilman; Neubauer, Bernd A.; Mayer, Thomas; Macdonald, Daniel; Kurlemann, Gerhard; et al. (Epilepsy & Behavior, 2019)
Objective: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. Methods: Patient use of routine AEDs and emergency medications over 3–6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. Results: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. Significance: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3–6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
CRIS-Team Scopus Importer:2019-07-16
Keywords: Antiepileptic drugs; Benzodiazepines; Epilepsy; Severe myoclonic epilepsy of infants

Self-medication in children under the aspect of medication safety Selbstmedikation bei Kindern unter dem Aspekt der Arzneimitteltherapiesicherheit - Neubert, Antje; Schulze, Christopher (Monatsschrift Kinderheilkunde, 2022)
Background: Self-medication, also known as over the counter (OTC) medication, is generally understood as the use of drugs that do not require a doctor’s prescription. It is very often used for colds or pain and fever; however, the OTC status does not mean, as is often assumed, that these drugs can be used completely uncritically. Especially in children and adolescents, serious side effects repeatedly occur. Objective: This article investigates which drugs are often used in self-medication and describes which problems can arise in association with different indications. Material and methods: The article is based on a search and analysis of the current literature. Results and discussion: The most commonly used OTC drugs are cough and cold medicines, medicines used to treat pain and fever and medicines used to treat nausea. Herbal preparations play an important role in self-medication for cold remedies; however, these multisubstance preparations are not always harmless and, especially with combination therapies, a doctor or pharmacist should always be consulted. In addition, the use of both herbal and synthetic preparations is based on very limited scientific evidence. Decongestant preparations for the nose and drugs against nausea (H1 antihistamines) have been and are repeatedly associated with serious adverse effects, especially in young children and should therefore be used strictly according to the license. Pain and fever can be treated very well with ibuprofen or paracetamol. Monotherapy should always be preferred for self-medication.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Adverse effects; Nonprescription drugs; Over the counter drugs; Plant preparations; Synthetic drugs

Sensor Fusion for the Robust Detection of Facial Regions of Neonates Using Neural Networks - Gleichauf, Johanna; Hennemann, Lukas; Fahlbusch, Fabian; Hofmann, Oliver; Niebler, Christine; Koelpin, Alexander (Sensors, 2023)
The monitoring of vital signs and increasing patient comfort are cornerstones of modern neonatal intensive care. Commonly used monitoring methods are based on skin contact which can cause irritations and discomfort in preterm neonates. Therefore, non-contact approaches are the subject of current research aiming to resolve this dichotomy. Robust neonatal face detection is essential for the reliable detection of heart rate, respiratory rate and body temperature. While solutions for adult face detection are established, the unique neonatal proportions require a tailored approach. Additionally, sufficient open-source data of neonates on the NICU is lacking. We set out to train neural networks with the thermal-RGB-fusion data of neonates. We propose a novel indirect fusion approach including the sensor fusion of a thermal and RGB camera based on a 3D time-of-flight (ToF) camera. Unlike other approaches, this method is tailored for close distances encountered in neonatal incubators. Two neural networks were used with the fusion data and compared to RGB and thermal networks. For the class “head” we reached average precision values of 0.9958 (RetinaNet) and 0.9455 (YOLOv3) for the fusion data. Compared with the literature, similar precision was achieved, but we are the first to train a neural network with fusion data of neonates. The advantage of this approach is in calculating the detection area directly from the fusion image for the RGB and thermal modality. This increases data efficiency by 66%. Our results will facilitate the future development of non-contact monitoring to further improve the standard of care for preterm neonates.
CRIS-Team Scopus Importer:2023-06-30
Keywords: face detection; neonates; neural network; non-contact monitoring; sensor fusion

Serial T2-Weighted Thoracic and Abdominal Lymphatic Imaging in Fontan Patients—New Insights into Dynamics of Lymphatic Abnormalities after Total Cavopulmonary Connection - Moosmann, Julia; Schroeder, Christian; Rompel, Oliver; Purbojo, Ariawan; Dittrich, Sven (Journal of Cardiovascular Development and Disease, 2022)
Lymphatic congestion in single-ventricle patients has been associated with increased morbidity and poor outcomes. Little is known about the dynamics of lymphatic abnormalities over time, on their association with clinical presentation or response to catheter interventions. This retrospective, single-center study describes Fontan patients who underwent at least two magnetic resonance imaging (MRI) studies. T2-weighted lymphatic imaging was used to classify thoracic and abdominal (para-aortic and portal-venous) lymphatic abnormalities. The relationship between lymphatic congestion and hemodynamic changes after cardiac catheter interventions, clinical presentation and MRI data was analyzed. A total of 33 Fontan patients underwent at least two cardiac MRI studies. Twenty-two patients had two, eight had three and three had four lymphatic imaging studies (total of 80 MRIs studies). No significant changes in lymphatic classification between MRI 1 and 2 were observed for thoracic (p = 0.400), para-aortic (0.670) and portal-venous (p = 0.822) abnormalities. No significant correlation between lymphatic classification and hemodynamic changes after intervention or MRI parameters was found. This study illustrates thoracic and abdominal lymphatic abnormalities in serial T2-weighted imaging after Fontan. Fontan patients did not demonstrate significant changes in their lymphatic perfusion, despite clinical or hemodynamic changes. We assume that lymphatic congestion might develop after total cavopulmonary connection (TCPC) and remain relatively stable, despite further intervention targeting hemodynamic parameters.
CRIS-Team Scopus Importer:2022-06-10
Keywords: Fontan; lymphatic abnormalities; magnetic resonance imaging; T2-weighted imaging

Serious Adverse Drug Reactions to Antipsychotics in Minors with Multiple Disabilities: Preventability and Potential Cost Savings by Therapeutic Drug Monitoring - Fekete, Stefanie; Guentzel, Tim; Egberts, Karin; Geissler, Julia; Neubert, Antje; Gerlach, Manfred; Romanos, Marcel; Taurines, Regina (Pharmacopsychiatry, 2022)
Introduction Children and adolescents with multiple disabilities and mental disorders (CAMD) are frequently treated with antipsychotic drugs. However, CAMD are particularly susceptible to serious adverse drug reactions (sADRs). This retrospective study examined the frequency of sADRs to antipsychotics in CAMD. Further, the potential preventability of these sADRs through therapeutic drug monitoring (TDM) and the potential socio-economic benefits of TDM were explored.Methods Routine clinical data of all patients treated at a specialized psychiatric clinic for CAMD between January 2017 and December 2018 were retrospectively examined. Data on the occurrence of sADRs (definition according to the European Medicines Agency), their causality with antipsychotics, as well as their preventability (Schumock criteria) were extracted from patient files. The prolongation of the hospital stay due to sADRs was calculated, and the cost savings were estimated if TDM had been applied. The data were based on a subsample of the KiDSafe project, supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021.Results One hundred two CAMD who were administered at least one antipsychotic drug during inpatient treatment were identified. Of these patients, 22 (21.6%) sADRs with a possible causal relationship with the antipsychotic treatment were documented. Eleven sADRs (50%) could potentially have been prevented through TDM. Mitigating sADRs through TDM likely would have prevented prolonged hospital stays and thus conferred considerable savings for health insurance companies.Discussion The routine implementation of TDM is urgently recommended for antipsychotic treatment in CAMD to increase drug therapy safety.
CRIS-Team WoS Importer:2022-11-25

Serum (1→3)-β-D-glucan and galactomannan levels in patients with cystic fibrosis: a retrospective cohort study - Traeger, Johannes; Melichar, Volker Otto; Meyer, Renate; Rauh, Manfred; Bogdan, Christian; Held, Jürgen (BMC Pulmonary Medicine, 2018)
BACKGROUND: Aspergillus fumigatus is frequently encountered in sputum samples of patients with cystic fibrosis (CF), which traditionally has been interpreted as saprophytic airway colonization. However, this mere bystander role has been challenged by recent data. There is now evidence that Aspergillus fumigatus accelerates the decline of pulmonary function. (1→3)-β-D-glucan (BDG) and galactomannan (GM) are highly sensitive fungal biomarkers that are used to diagnose invasive fungal disease. However, their diagnostic value in CF patients is largely unknown. METHODS: We conducted a retrospective cohort study on 104 CF patients to determine whether serum BDG and GM levels correlate with parameters such as Aspergillus-positive sputum cultures and lung function. RESULTS: Aspergillus fumigatus was persistently detected in 22 of the 104 CF patients (21%). Mean serum BDG and GM levels in the Aspergillus-positive patients were significantly higher than in those without persistent Aspergillus detection (89 versus 40 pg/ml [p = 0.022] and 0.30 versus 0.15 ODI [p = 0.013], respectively). 27 and 7 patients had elevated BDG (≥ 60 pg/ml) or GM levels (> 0.5 ODI), respectivly. BDG and GM levels showed a significant correlation (p = 0.004). Patients with increased serum concentrations of BDG were more frequently Aspergillus-positive (40.7 versus 14.3%, p = 0.004) and had a significantly lower forced expiratory volume in one second (FEV1) than patients with a normal BDG (61.6 versus 77.1%, p = 0.007). In the multivariate analysis, BDG but not GM or the growth of A. fumigatus, proved to be an independent predictor for the FEV1. CONCLUSIONS: CF patients with persistent Aspergillus detection have elevated BDG and GM levels which ranged between healthy and invasively infected patients. Serum BDG may be superior to GM and fungal culture in predicting an impaired lung function in CF patients.
EVALuna2:35821

Severe heart failure and the need for mechanical circulatory support and heart transplantation in pediatric patients with myocarditis: Results from the prospective multicenter registry “MYKKE” - Schubert, Stephan; Opgen-Rhein, Bernd; Boehne, Martin; Weigelt, Annika; Wagner, Robert; Mueller, Goetz; Rentzsch, Axel; Zu Knyphausen, Edzard; Fischer, Marcus; Papakostas, Konstantin; Wiegand, Gesa; Ruf, Bettina; et al. (Pediatric Transplantation, 2019)
Myocarditis represents an important cause for acute heart failure. MYKKE, a prospective multicenter registry of pediatric patients with myocarditis, aims to gain knowledge on courses, diagnostics, and therapy of pediatric myocarditis. The role of mechanical circulatory support (MCS) in children with severe heart failure and myocarditis is unclear. The aim of this study was to determine characteristics and outcome of patients with severe heart failure requiring MCS and/or heart transplantation. The MYKKE cohort between September 2013 and 2016 was analyzed. A total of 195 patients were prospectively enrolled by 17 German hospitals. Twenty-eight patients (14%) received MCS (median 1.5 years), more frequently in the youngest age group (0-2 years) than in the older groups (P < 0.001; 2-12 and 13-18 years). In the MCS group, 50% received a VAD, 36% ECMO, and 14% both, with a survival rate of 79%. The weaning rate was 43% (12/28). Nine (32%) patients were transplanted, one had ongoing support, and six (21%) died. Histology was positive for myocarditis in 63% of the MCS group. Patients within the whole cohort with age <2 years and/or ejection fraction <30% had a significantly worse survival with high risk for MCS, transplantation, and death (P < 0.001). Myocarditis represents a life-threatening disease with an overall mortality of 4.6% in this cohort. The fulminant form more often affected the youngest, leading to significantly higher rate of MCS, transplantation, and mortality. MCS represents an important and life-saving therapeutic option in children with myocarditis with a weaning rate of 43%.
CRIS-Team Scopus Importer:2019-07-23
Keywords: MCS; myocarditis; pediatric; transplantation

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) - Burgmaier, Kathrin; Ariceta, Gema; Bald, Martin; Buescher, Anja Katrin; Burgmaier, Mathias; Erger, Florian; Gessner, Michaela; Gokce, Ibrahim; König, Jens; Kowalewska, Claudia; Massella, Laura; Mastrangelo, Antonio; et al. (Scientific Reports, 2020)
To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4–15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.
CRIS-Team Scopus Importer:2020-10-16

Severe T-System Remodeling in Pediatric Viral Myocarditis - Fiegle, Dominik; Schober, Martin; Dittrich, Sven; Cesnjevar, Robert; Klingel, Karin; Volk, Tilmann; Alkassar, Muhannad; Seidel, Thomas (Frontiers in Cardiovascular Medicine, 2021)
Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 +/- 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 +/- 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 +/- 2.3% in AVSD and 12.2 +/- 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 +/- 0.05 mu m, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 +/- 0.02 mu m(2)) when compared with AVSD (0.90 +/- 0.02 mu m, p < 0.001; 0.52 +/- 0.02 mu m(2), n = 61, p < 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 +/- 1.4%) than in AVSD samples (24.4 +/- 0.8%, p < 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 +/- 0.04 mu m(2) vs. 0.72 +/- 0.05 mu m(2), p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 +/- 0.02 mu m(-3) vs. 0.05 +/- 0.01 mu m(-3), n = 9/10, p < 0.001), approaching values of AVSD (0.13 +/- 0.05 mu m(-3), n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 +/- 5.0% vs. 6.8 +/- 2.2%, p < 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.
CRIS-Team WoS Importer:2021-02-19

Sex chromosome DSD individuals with mosaic 45,X0 and aberrant Y chromosomes in 46,XY cells: distinct gender phenotypes and germ cell tumour risks§ - Vogt, Peter H.; Besikoglu, Banu; Bettendorf, Markus; Frank-Herrmann, Petra; Zimmer, Jutta; Bender, Urike; Knauer-Fischer, Sabine; Choukair, Daniela; Sinn, Peter; Dörr, Helmuth-Günther; Wölfle, Joachim; Heidemann, Peter H.; et al. (Systems Biology in Reproductive Medicine, 2022)
“Differences of Sexual Development (DSD),” individuals with rearranged Y chromosome breaks in their 46,XY cells are reported with male and female gender phenotypes and differences in germ cell tumour (GCT) risk. This raised the question of whether male or female gender and GCT risk depends on the site of the break and/or rearrangement of the individual´s Y chromosome. In this paper, we report molecular mapping of the breakpoint on the aberrant Y chromosome of 22 DSD individuals with a 45,X/46,XY karyotype reared with a different gender. Their Y chromosome breaks are found at different sites on the long and short Y arms. Our data indicate that gender rearing is, neither dependent on the site of Y breakage, nor on the amount of 45,X0 cells in the individuals' leukocytes. Most prominent are secondary rearrangements of the Y chromosome breaks forming di-centric Y-structures (“dic-Y”). Duplications of the short Y arm and the proximal part of the long Y arm are the results. A putative GCT risk has been analysed with immunohistochemical experiments on some dysgenetic gonadal tissue sections. With specific antibodies for OCT3/4 expression, we marked the pluripotent germ cell fraction being potential tumour precursor cells. With specific antibodies for DDX3Y, TSPY, and UTY we analyzed their putative Gonadoblastoma Y (GBY) tumour susceptibility function in the same specimen. We conclude GBY expression is only diagnostic for GCT development in the aberrant germ cells of these DSD individuals when strong OCT3/4 expression has marked their pluripotency.
CRIS-Team Scopus Importer:2022-05-27
Keywords: 45X/46XY mosaic DSD; di-centric Y chromosome; Germ cell tumour risk; OCT3/4 expression GBY expression

Sex differences in long-term kidney fibrosis following neonatal nephron loss during ongoing nephrogenesis - Menendez-Castro, Carlos; Cordasic, Nada; Fahlbusch, Fabian; Wölfle, Joachim; Hilgers, Karl Friedrich; Hartner, Andrea (Molecular and Cellular Pediatrics, 2023)
Background: Clinical studies suggest that female sex plays a protective role in the development and progression of kidney disease. Recent experimental studies indicate that in male rats early nephron loss under ongoing nephrogenesis is accompanied by severe long-term sequelae. In humans, nephron formation occurs mainly in the third trimester, ceasing with 36 weeks of gestation. Due to perinatal complications, preterm infants delivered during this vulnerable period may undergo acute nephron loss. In rats nephrogenesis persists until postnatal day 10, reflecting the situation of human preterms with persisting nephrogenesis. In our animal model of neonatal uninephrectomy, female and male rats were uninephrectomized at day 1 of life. Hypothesizing sex-dependent differences, long-term renal outcome was assessed after 1 year. Results: In both sexes, neonatal uninephrectomy was not followed by arterial hypertension at 1 year of age. Compensatory weight gain and glomerular hypertrophy of the remaining kidney occurred in uninephrectomized female and male animals. Selected markers of interstitial inflammation and fibrosis were regulated sex-dependently. The expression of monocyte chemoattractant protein-1 was increased in females, while tubulointerstitial infiltration by M1 macrophages was significantly higher in males after neonatal uninephrectomy. Neonatally uninephrectomized male rats had more glomerulosclerosis and podocyte damage compared to females, which was assessed by a semiquantitative score and desmin staining. RT-PCR revealed that after neonatal uninephrectomy in the remaining contralateral kidney of female rats the expression of candidate genes of renal development and function, i.e., wt-1, nephrin, synaptopodin, gdnf, and itga8 was higher than in males. Conclusions: Based on these observations we conclude that female sex is protective in the long-term response of the kidney to acute nephron loss under active nephrogenesis.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Kidney fibrosis; Neonatal nephron loss; Neonatal uninephrectomy; Nephrogenesis; Sex differences

Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8 - Marek, Ines; Canu, Maurizio; Cordasic, Nada; Rauh, Manfred; Volkert, Gudrun; Fahlbusch, Fabian B.; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea; Menendez-Castro, Carlos (Biology of Sex Differences, 2017)
BACKGROUND: Apoe-deficient (Apoe-/-) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe-/- mice deficient in the mesenchymal integrin chain Itga8 (Itga8-/-). Here, we used this Apoe-/-, Itga8-/- mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model. METHODS: Apoe-/- mice were backcrossed with Itga8-/- mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe-/-Itga8+/+ mice or Apoe-/-Itga8-/- mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed. RESULTS: When compared to male mice, Apoe-/-Itga8+/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe-/- mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different. CONCLUSIONS: In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.
EVALuna2:3958

Sharing of decision-making for infective endocarditis surgery: a narrative review of clinical and ethical implications - Pollari, Francesco; Spadaccio, Cristiano; Cuomo, Michela; Chello, Massimo; Nenna, Antonio; Fischlein, Theodor; Nappi, Francesco (Annals of Translational Medicine, 2020)
Infective endocarditis (IE) is nowadays one of the most challenging disease in cardiac surgery because of its multifaceted clinical and anatomical presentation. Despite the many clinical and surgical advances achieved in the past 60 years, there is a lack of evidence regarding the ideal strategy. The present review aims to investigate and highlight two main novel concepts for the decision-making of the best substitute. Firstly, the concept of an "endocarditis team": a coordinated multidisciplinary effort in the diagnostic work-up, especially in conditions of high risk of embolization or clinical deterioration. A good "endocarditis team" has the role to overcome such problem, in order to ensure a prompt and balanced strategy. Secondly, which ethical considerations are required to drive the choice of valvular substitute. The choice of best valve substitute is a relevant issue of debate, not only with operative but also prognostic and accordingly ethical aftermaths. Many different solutions have been developed to substitute the infected valve. Among these: mechanical prosthesis (MP), biological stented prosthesis (BP), sutureless bioprosthesis and cryopreserved homografts (CHs). Patients need to be informed in detail about the technical issues pertaining the use of these valve substitute. We will discuss the evidences regarding the risk of recurrent infections or future potentially severe calcification of aortic homograft valve and wall (in other words, the failure of the homograft) and the difficulties in managing the reoperation.
CRIS-Team WoS Importer:2021-01-15

Shedding light on pediatric diseases: multispectral optoacoustic tomography at the doorway to clinical applications. - Regensburger, Adrian; Wagner, Alexandra; Claussen, Jing; Waldner, Maximilian; Knieling, Ferdinand (Molecular and Cellular Pediatrics, 2020)
Optoacoustic imaging (OAI), or photoacoustic imaging (PAI), has fundamentally influenced basic science by providing high-resolution visualization of biological mechanisms. With the introduction of multispectral optoacoustic tomography (MSOT), these technologies have now moved closer to clinical applications. MSOT utilizes short-pulsed near-infrared laser light to induce thermoelastic expansion in targeted tissues. This results in acoustic pressure waves, which are used to resolve specific endo- and exogenous chromophores. Especially in the pediatric population, this non-invasive imaging approach might hold fundamental advantages compared to conventional cross-sectional imaging modalities. As this technology allows the visualization of quantitative molecular tissue composition at high spatial resolution non-invasively in sufficient penetration depth, it paves the way to personalized medicine in pediatric diseases.
EVALuna2:383218

Short and Long Term Outcome for Patients with Surgical Removal of Sacrococcygeal Teratoma in Newborns and Infancy - Ai, Maria; Schellerer, Vera; Besendörfer, Manuel (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Short Children with CHARGE Syndrome: Do They Benefit from Growth Hormone Therapy? - Dörr, Helmuth-Günther; Boguszewski, Margaret; Dahlgren, Jovanna; Dunger, David; Geffner, Mitchell E.; Hokken-Koelega, Anita C.; Lindberg, Anders; Polak, Michel; Rooman, Raoul (Hormone Research in Paediatrics, 2015)
The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome.We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 ?g/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years.Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged.Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.
EVALuna2:18915

Short-term adverse effects of testosterone used for priming in prepubertal boys before growth hormone stimulation test - Albrecht, Andrea; Penger, Theresa; Marx, Martin; Hirsch, Karin; Dörr, Helmuth-Günther (Journal of Pediatric Endocrinology & Metabolism, 2018)
BACKGROUND: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. METHODS: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. RESULTS: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. CONCLUSIONS: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.
EVALuna2:35502

Short-term response of metabolic hormones to coronary artery bypass surgery - Nemeth, Adam; Cziraki, Attila; Sulyok, Endre; Horvath, Ivan Gabor; Alotti, Nasri; Rauh, Manfred; Rascher, Wolfgang; Szabados, Sandor (Advances in Medical Sciences, 2014)
To explore the response pattern of plasma adipokine and ghrelin levels to coronary artery bypass graft (CABG) surgery in patients with (on-pump) and without (off-pump) cardiopulmonary bypass (CPB).Sixteen consecutive patients (age: 62 ± 10 years, male: 10) with obstructive coronary artery disease (CAD) who underwent elective CABG surgery with CPB and intraoperative GIK infusion were selected for on-pump group and 19 CAD patients (age: 63 ± 10 years, male: 16) were included in the off-pump group. Blood samples were taken before, during and after surgery. Intraoperative samples were withdrawn simultaneously for peripheral vein and sinus coronarius (SC). Plasma adipokine concentrations were measured by ELISA, those of ghrelin by RIA kits.In response to surgical intervention there was an early, transient fall in plasma levels of adiponectin (p<0.0001) and resistin (p=0.002) followed by an increase to approach their initial values. Plasma ghrelin also increased (p=0.045), this increase, however, was confined to the period of GIK supported CPB. Plasma insulin (p=0.003) and resistin (p=0.009) was significantly higher in the peripheral vein than in SC. The perioperative hormone profile of patients without CPB (off-pump) proved to be comparable to that of on-pump patients in spite of the insulin administration and greater oxidative and inflammatory stress.Adipose tissue-derived factors appear to mediate the metabolic and vascular changes that occur in patients with CABG surgery. Epicardial adipose tissue is unlikely to have major contribution to the development of CAD as adipokines are not elevated in SC independent of the mode of intervention.
EVALuna2:18893

Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany - Hahn, Andreas; Guenther, Rene; Ludolph, Albert; Schwartz, Oliver; Trollmann, Regina; Weydt, Patrick; Weiler, Markus; Neuland, Kathrin; Schwaderer, Martin Sebastian; Hagenacker, Tim (Orphanet Journal of Rare Diseases, 2022)
Background The oral, selective SMN2-splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients >= 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1-4 SMN2 gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy. Patients and methods Patients with SMA1/2, aged >= 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs). Results Between March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving >= 1 risdiplam dose, respectively. The median (range) age was 10.5 (3-52) years in the SMA1 cohort, and 26.5 (3-60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naive. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients. Conclusions We present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam.
CRIS-Team WoS Importer:2022-07-29

SIADH as presenting feature of foramen magnum stenosis in a 2-month-old infant with achondroplasia (ACH): case report and discussion on management of infants with ACH in order to reduce the risk of serious complications - Cebeci, Ayse Nurcan; Hébert, Steven; Reutter, Heiko Martin; Wölfle, Joachim (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Sickle cell disease in Germany: Results from a national registry - Kunz, Joachim B.; Lobitz, Stephan; Grosse, Regine; Oevermann, Lena; Hakimeh, Dani; Jarisch, Andrea; Cario, Holger; Beier, Rita; Schenk, Daniela; Schneider, Dominik; Gross-Wieltsch, Ute; Prokop, Aram; et al. (Pediatric Blood & Cancer, 2019)
Background Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. Procedure A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. Results Most patients had homozygous SCD (HbSS 75.1%, HbS/beta-thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6-4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/beta thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. Conclusion With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.
CRIS-Team WoS Importer:2020-01-07

Side effects of radiotherapy in breast cancer patients : The Internet as an information source - Janssen, S.; Kaesmann, L.; Fahlbusch, F. B.; Rades, D.; Vordermark, D. (Strahlentherapie und Onkologie, 2018)
AIM: Breast cancer is the most common cancer type among women necessitating adjuvant radiotherapy. As the Internet has become a major source of information for cancer patients, this study aimed to evaluate the quality of websites giving information on side effects of radiotherapy for breast cancer patients. METHODS: A patients' search for the English terms "breast cancer - radiotherapy - side effects" and the corresponding German terms "Brustkrebs - Strahlentherapie - Nebenwirkungen" was carried out twice (5 months apart) using the search engine Google. The first 30 search results each were evaluated using the validated 16-question DISCERN Plus instrument, the Health on the Net Code of Conduct (HONcode) certification and the Journal of the American Medical Association (JAMA) benchmark criteria. The overall quality (DISCERN score) of the retrieved websites was further compared to queries via Bing and Yahoo search engines. RESULTS: The DISCERN score showed a great range, with the majority of websites ranking fair to poor. Significantly superior results were found for English websites, particularly for webpages run by hospitals/universities and nongovernmental organizations (NGO), when compared to the respective German categories. In general, only a minority of websites met all JAMA benchmarks and was HONcode certified (both languages). We did not determine a relevant temporal change in website ranking among the top ten search hits, while significant variation occurred thereafter. Mean overall DISCERN score was similar between the various search engines. CONCLUSION: The Internet can give breast cancer patients seeking information on side effects of radiotherapy an overview. However, based on the currently low overall quality of websites and the lack of transparency for the average layperson, we emphasize the value of personal contact with the treating radio-oncologist in order to integrate and interpret the information found online.
EVALuna2:34297

Significant advantages for first line treatment with TNF-alpha inhibitors in pediatric patients with inflammatory bowel disease – Data from the multicenter CEDATA-GPGE registry study - Claßen, Merle; de Laffolie, Jan; Claßen, Martin; Schnell, Alexander; Sohrabi, Keywan; Hörning, André (Frontiers in Pediatrics, 2022)
Background and aims: In recent years, biological agents, such as anti-TNF-α blockers, have been introduced and have shown efficacy in pediatric patients with inflammatory bowel disease (IBD). Here, the prescription mode differentiated into a first/second line application, and efficacy and side effects are evaluated beginning from 2004 until today. Methods: Statistical analyses of the prospective and ongoing CEDATA multicenter registry data from the Society of Pediatric Gastroenterology and Nutrition (GPGE) were performed for patients receiving a biological agent at least once during the period from June 2004 until November 2020 (n = 487). The analyzed parameters were patient demographics, disease extent and behavior, prior or concurrent therapies, duration and outcome of biological therapy, disease-associated complications, drug-related complications, laboratory parameters and treatment response as determined by the Physician’s Global Assessment. Results: Crohn’s disease (CD) was present in 71.5% of patients, and 52% were boys. Patients showed high disease activity when receiving a first-line TNF-α blocker. After 2016, patients who failed to respond to anti-TNF-α induction therapy were treated with off-label biologics (vedolizumab 4.3% and ustekinumab 2.1%). Propensity score matching indicated that patients with CD and higher disease activity benefitted significantly more from early anti-TNF-α therapy. This assessment was based on a clinical evaluation and lab parameters related to inflammation compared to delayed second-line treatment. Additionally, first-line treatment resulted in less treatment failure and fewer extraintestinal manifestations during TNF-α blockade. Conclusion: First-line treatment with anti-TNF-α drugs is effective and safe. An earlier start significantly reduces the risk of treatment failure and is associated with fewer extraintestinal manifestations during longitudinal follow-up.
CRIS-Team Scopus Importer:2022-11-04
Keywords: anti-TNF-α inhibitor therapy; Crohn’s disease; first-line therapy; pediatric inflammatory bowel disease (IBD); ulcerative colitis

Simulation of cardiac electromechanics of a rat left ventricle - Duong, Minh Tuan; Holz, David; Ach, Theresa; Binnewitt, Svea Vanessa; Stegmann, Hedwig; Dittrich, Sven; Alkassar, Muhannad; Leyendecker, Sigrid (Proc. Appl. Math. Mech. (PAMM), 2018)

SIRT1 regulates Mxd1 during malignant melanoma progression - Meliso, Fabiana M.; Micali, Danilo; Silva, Camila T.; Sabedot, Thais S.; Coetzee, Simon G.; Koch, Anna Maria; Fahlbusch, Fabian B.; Noushmehr, Houtan; Schneider-Stock, Regine; Jasiulionis, Miriam G. (Oncotarget, 2017)
In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.
EVALuna2:33949

Sleep-Disordered Breathing in Children with Prader-Willi Syndrome in Relation to Growth Hormone Therapy Onset - Zimmermann, Maja; Laemmer, Constanze; Wölfle, Joachim; Fimmers, Rolf; Gohlke, Bettina (Hormone Research in Paediatrics, 2020)
Objective: The aim of this study was to consider sleep apnea in Prader-Willi syndrome (PWS) children depending on age at growth hormone (GH) therapy onset. Study Design: We analyzed longitudinally cardiorespiratory polygraphy of 62 PWS children (aged 0-2.5 years at baseline). Twenty-one children (Group A) started GH-therapy during and 41 children (Group B) after their first year of life. Data were acquired before, at 3 and 6 months, then 1.2, 2.2, and 3.2 years after GH onset. Outcomes were determined with the obstructive apnea hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), and by measuring obstructive sleep apnea (OSA) and peripheral blood oxygen saturation (SpO2). Results: We observed no significant differences in OAHI, CAI, ODI, and SpO2 depending on treatment onset. At baseline, 5/21 patients (23.8%) in Group A versus 15/41 patients (36.6%) in Group B showed pathological sleep apnea (OAHI ≥1.5). Pathological OSA increased significantly in Group A during the first 3 months of therapy but dropped below baseline after 1 year in both groups. ODI changed during GH therapy in both groups (from 4.0 to 2.6 in Group A, and 3.6 to 1.6 in Group B; baseline to 3.2 years; p < 0.05). Conclusions: OSA in PWS children appears to develop independently of treatment onset. Treatment may therefore safely be initiated early but should be accompanied by regular sleep analysis.
CRIS-Team Scopus Importer:2020-07-10

Sleep quality, anxiety, symptoms of depression, and caregiver burden among those caring for patients with Dravet syndrome: a prospective multicenter study in Germany - Maltseva, Margarita; Schubert-Bast, Susanne; Zöllner, Johann Philipp; Bast, Thomas; Mayer, Thomas; von Spiczak, Sarah; Ruf, Susanne; Trollmann, Regina; Wolff, Markus; Hornemann, Frauke; Klotz, Kerstin A.; Jacobs, Julia; et al. (Orphanet Journal of Rare Diseases, 2023)
Background: This study measured sleep quality among caregivers of patients with Dravet syndrome (DS) and assessed the impacts of mental health problems and caregiver burden on sleep quality. Methods: This multicenter, cross-sectional study of patients with DS and their caregivers throughout Germany consisted of a questionnaire and a prospective 4-week diary querying disease characteristics, demographic data, living conditions, nocturnal supervision, and caregivers’ work situations. Sleep quality was assessed using the Pittsburgh Sleeping Quality Index (PSQI). The Hospital Anxiety and Depression Scale (HADS) and the Burden Scale for Family Caregivers (BSFC) were used to measure anxiety, symptoms of depression, and caregiver burden. Results: Our analysis included 108 questionnaires and 82 four-week diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 ± 10.0 years. Caregivers were 92.6% (n = 100) female, with a mean age of 44.7 ± 10.6 years. The overall mean PSQI score was 8.7 ± 3.5, with 76.9% of participants (n = 83) scoring 6 or higher, indicating abnormal sleep quality. The HADS for anxiety and depression had overall mean scores of 9.3 ± 4.3 and 7.9 ± 3.7, respectively; 61.8% and 50.9% of participants scored above the cutoff value of 8 for anxiety and depression, respectively. Statistical analyses revealed caregiver anxiety levels and patients’ sleep disturbances as major factors influencing PSQI scores. The overall mean BSFC score of 41.7 ± 11.7 indicates a moderate burden, with 45.3% of caregivers scoring 42 or higher. Conclusions: Sleep quality is severely affected among caregivers of patients with DS, correlating with anxiety, comorbidities, and patients’ sleep disturbances. A holistic therapeutic approach should be implemented for patients with DS and their caregivers, focusing on the sleep quality and mental health of caregivers. Trial registration: German Clinical Trials Register (DRKS), DRKS00016967. Registered 27 May 2019, http://www.drks.de/DRKS00016967
CRIS-Team Scopus Importer:2023-05-12
Keywords: Encephalopathy; Epilepsy; Quality of life; Seizure

Social inequalities in the participation and activity of children and adolescents with leukemia, brain tumors, and sarcomas (SUPATEEN): a protocol for a multicenter longitudinal prospective observational study - Roick, Julia; Berner, Reinhard; Bernig, Toralf; Erdlenbruch, Bernhard; Escherich, Gabriele; Faber, Jörg; Klein, Christoph; Bochennek, Konrad; Kratz, Christian; Kühr, Joachim; Längler, Alfred; Lode, Holger N.; et al. (BMC Pediatrics, 2020)
BACKGROUND: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents. METHODS: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods. DISCUSSION: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04101123.
CRIS-Team Scopus Importer:2020-02-11
Keywords: Brain tumors; Cancer; Children and adolescents; Leukemia; Patient reported outcomes; Sarcomas; Social participation

SOCIO-ECONOMIC IMPACT OF DRAVET SYNDROME IN GERMANY: A REAL-WORLD STUDY - Irwin, J.; Strzelczyk, A.; Kalski, M.; Bast, T.; Wiemer-Kruel, A.; Bettendorf, U.; Kieslich, M.; Kluger, G.; Kurlemann, G.; Mayer, T.; Neubauer, B. A.; Polster, T.; et al. (VALUE IN HEALTH, 2018)
CRIS-Team WoS Importer:2019-03-15

Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner - Royzman, Dmytro; Andrev, Darja; Stich, Lena; Rauh, Manfred; Bäuerle, Tobias; Ellmann, Stephan; Boon, Louis; Kindermann, Markus; Peckert, Katrin; Bozec, Aline; Schett, Georg; Steinkasserer, Alexander; et al. (Frontiers in Immunology, 2019)
Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFN gamma, IL-6, and TNF alpha within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-beta antibodies further revealed that also TGF-beta is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-beta dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.
CRIS-Team WoS Importer:2019-04-12

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

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

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

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

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 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 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 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, D.; 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, D.; 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 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

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, D.; 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 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

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