Frosted branch angiitis : Clinical findings and Spectralis OCT follow-up - Bergua, A.; Galiano, M.; Hohberger, B.; Rudolph, Michael (Ophthalmologe, 2016)
Frosted branch angiitis is a special form of retinal vasculitis, which has only rarely been reported in the literature. Although the majority of cases of frosted branch angiitis are idiopathic, a systematic clinical work-up should be done in order to exclude other causes, such as infectious and autoimmune diseases. The aim of this study was to correlate the clinical findings with the images obtained during follow-up by spectral domain optical coherence tomography (OCT).
EVALuna2:21248

Functional and clinical analysis of five EDA variants associated with ectodermal dysplasia but with a hard-to-predict significance - Goekdere, Sare; Schneider, Holm; Hehr, Ute; Willen, Laure; Schneider, Pascal; Maier-Wohlfart, Sigrun (Frontiers in Genetics, 2022)
Deficiency of ectodysplasin A1 (EDA1) due to variants of the gene EDA causes X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic condition characterized by abnormal development of ectodermal structures. XLHED is defined by the triad of hypotrichosis, hypo- or anhidrosis, and hypo- or anodontia. Anhidrosis may lead to life-threatening hyperthermia. A definite genetic diagnosis is, thus, important for the patients' management and amenability to a novel prenatal treatment option. Here, we describe five familial EDA variants segregating with the disease in three families, for which different prediction tools yielded discordant results with respect to their significance. Functional properties in vitro and levels of circulating serum EDA were compared with phenotypic data on skin, hair, eyes, teeth, and sweat glands. EDA1-Gly176Val, although associated with relevant hypohidrosis, still bound to the EDA receptor (EDAR). Subjects with EDA1-Pro389LeufsX27, -Ter392GlnfsX30, -Ser125Cys, and an EDA1 splice variant (c.924+7A > G) showed complete absence of pilocarpine-induced sweating. EDA1-Pro389LeufsX27 was incapable of binding to EDAR and undetectable in serum. EDA1-Ter392GlnfsX30, produced in much lower amounts than wild-type EDA1, could still bind to EDAR, and so did EDA1-Ser125Cys that was, however, undetectable in serum. The EDA splice variant c.924+7A > G resulted experimentally in a mix of wild-type EDA1 and EDA molecules truncated in the middle of the receptor-binding domain, with reduced EDA serum concentration. Thus, in vitro assays reflected the clinical phenotype in two of these difficult cases, but underestimated it in three others. Absence of circulating EDA seems to predict the full-blown phenotype of XLHED, while residual EDA levels may also be found in anhidrotic patients. This indicates that unborn subjects carrying variants of uncertain significance could benefit from an upcoming prenatal medical treatment even if circulating EDA levels or tests in vitro suggest residual EDA1 activity.
CRIS-Team WoS Importer:2022-08-12

Functional characterization of a novel CFTR mutation P67S identified in a patient with atypical cystic fibrosis - Kraus, Cornelia; Reis, André; Naehrlich, Lutz; Dötsch, Jörg; Korbmacher, Christoph; Rauh, Robert (Cellular Physiology and Biochemistry, 2007)
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR serves as a cAMP-stimulated chloride channel in a wide range of epithelial tissues and its dysfunction is a hallmark of CF. Over 1400 mutations in the CFTR gene are known, but functional data exist only for a minority of the mutant channels. The aim of the present study was to functionally characterize a novel CFTR mutation identified in a patient with atypical CF. Full length sequencing of the patient's CFTR gene revealed a homozygous C to T transition at nucleotide position 331 (CCT>TCT), which results in a P67S amino acid substitution. Mutant and wild-type CFTR were heterologously expressed in Xenopus laevis oocytes. CFTR whole-cell currents were studied using the two-electrode voltage-clamp technique. Channel surface expression was assessed by a chemiluminescence assay. Expression of P67S-CFTR resulted in functional CFTR chloride channels. However, the CFTR chloride conductance observed in oocytes expressing the mutant channel averaged only 24% of that in oocytes expressing wild-type CFTR. Similarly, surface expression of the mutant channel was reduced. In contrast, the mutation did not alter the anion selectivity of the channel, and Western blot analysis indicated a similar protein expression level of mutant and wild-type CFTR. Our findings indicate that the P67S mutation reduces CFTR chloride channel function by reducing channel surface expression. The mild disease phenotype of the patient indicates that the residual function of the mutant channel is sufficient to prevent the development of severe CF symptoms. Copyright © 2007 S. Karger AG.
UnivIS-Import:2015-04-14:Pub.2007.med.IPK.LPVP.functi
Keywords: CFTR; Chloride channel; Cystic fibrosis; Electrophysiology; P67S mutation; Pancreatic insufficiency; Surface expression; Xenopus laevis oocytes

Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta - Tagariello, Andreas; Breuer, C.; Birkner, Y.; Schmidt, Stefan; Koch, Anna Maria; Cesnjevar, Robert; Rueffer, A.; Dittrich, Sven; Schneider, H.; Winterpacht, Andreas; Sticht, Heinrich; Doetsch, J.; et al. (Current Molecular Medicine, 2012)
In patients with congenital heart defects, chromosomal anomalies are 100 times more frequent than in control subjects. Coarctation of the aorta can be detected in 15-20% of patients with Ullrich-Turner syndrome. By extensively reviewing literature involving breakpoint analysis of gonosomal deletions in Ullrich- Turner syndrome patients with and without coarctation of the aorta, we identified several gonosomal homolgous gene pairs of interest. Four of these homologous gene pairs were investigated by standard DNA sequencing in a cohort of 83 patients with non-syndromic coarctation of the aorta. Subsequently stability of mutant RNA and protein was analyzed to verify functional relevance of detected mutations. We identified two unreported missense mutations in Exon 8 (p.D69H) and 9 (p.R176W) of TBL1Y. Bioinformatic analysis and 3D modelling predicted that both mutations lead to TBL1Y loss of function. In RT-PCR and Western blot analyses of HEK293 cells transfected with a vector carrying the full-length TBL1Y (wild-type and mutant), we documented the predicted protein instability by showing protein decay for both mutant proteins. TBL1Y is similar to its gonosomal homologue, TBL1X, and its autosomal homologue, TBLR1, on chromosome 3. Both genes are part of co-repressor machineries and required for transcriptional activation by transcription factors that involve CtBP1/2, which contributes to Notch signaling. Several studies have shown that Notch signalling is important for proper development of the left ventricular outflow tract. Our findings suggest that TBL1Y is involved in the genesis of non-syndromic coarctation of the aorta.
EVALuna2:9136

Further delineation of SLC9A3-related congenital sodium diarrhea - Bogdanic, Ema; Mueller, Thomas; Heinz-Erian, Peter; Garczarczyk-Asim, Dorota; Janecke, Andreas R.; Rueckel, Aline (Molecular Genetics and Genomic Medicine, 2022)
Background: Congenital sodium diarrhea (CSD) is a rare enteropathy displaying both broad variability in clinical severity and genetic locus and allelic heterogeneity. Eleven CSD patients were reported so far with SLC9A3 variants that impair the function of the encoded intestinal sodium-proton exchanger 3 (NHE3). Methods: We report a 4-year-old patient, born prematurely in the 35th week of gestation, with antenatal polyhydramnios and dilated intestinal loops, and with diarrhea of congenital onset, 2–6 times a day, and with polydipsia. She thrived age-appropriately under a normal family diet. Serum sodium levels were repeatedly normal but urinary sodium excretion was low. Exome sequencing revealed compound heterozygous variants in SLC9A3 as the likely cause of the congenital diarrhea. Results: While exome sequencing did not reveal pathogenic or likely pathogenic variants in other genes that cause syndromic or non-syndromic forms of congenital and intractable diarrheas, we identified novel compound heterozygous variants in SLC9A3, a complex allele with two missense changes, NP_004165.2:p.[Ser331Leu;Val449Ile] and in-trans the missense variant p.(Phe451Ser). Conclusion: The clinical phenotype here appears to localize to the milder end of the known CSD spectrum, and the identified variants suggest that this is the twelfth patient reported to date with CSD due to mutations in SLC9A3.
CRIS-Team Scopus Importer:2022-07-08
Keywords: compound heterozygous; CSD; NHE3; parenteral nutrition; SLC9A3; urinary sodium

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice - Klepper, Simon; Jung, Susan; Dittmann, Lara; Geppert, Carol-Immanuel; Hartmann, Arndt; Beier, Nicole; Trollmann, Regina (International Journal of Molecular Sciences, 2022)
Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood-brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 mu g/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln(+) fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain.
CRIS-Team WoS Importer:2022-08-26

General Anesthesia in the First 36 Months of Life. - Schüttler, Christina; Münster, Tino; Gall, Christine; Trollmann, Regina; Schüttler, Jürgen (Deutsches Ärzteblatt international, 2021)
BACKGROUND: Experimental data have shown that the developing brain is especially vulnerable to exogenous noxious substances. The potential effects of anesthetic drugs on brain growth and development are a matter of concern. Clinical studies of children who underwent general anesthesia in their earliest years can make a major contribution to our understanding of the effects of anesthetic drugs on infants and toddlers (i.e., children under age 5). METHODS: Children born at term during the years 2007-2011 who were exposed to general anesthesia before their third birthday were included in the study. Data on general anesthesia were retrospectively evaluated, and the overall intelligence quotient (IQ) was determined prospectively as the primary target parameter. Children who had not been exposed to general anesthesia were recruited as a control group. The non-inferiority threshold was set at a difference of 5 IQ points out of a consideration of clinical relevance. RESULTS: 430 complete data sets were available from exposed children and 67 from members of the control group. The exposed group achieved a mean IQ score of 108.2, with a 95% confidence interval of [107; 109.4]; the corresponding values in the control group were 113 [110; 116.1]. Both groups achieved a mean score that was higher than the expected 100 points. After adjustment for age, socioeconomic status, and sex, the difference between the two groups was 2.9 points [0.2; 5.6], indicating a significantly better outcome in the control group than in the exposed group. The non-inferiority threshold of 5 IQ points was within the confidence interval; thus, non-inferiority was not demonstrated. CONCLUSION: The fact that both groups achieved a higher IQ score than the expected 100 points may be attributable, at least in part, to the restriction of the study to children born at term. The results indicate that general anesthesia in early childhood is not associated with markedly reduced intelligence in later years, although noninferiority could not be demonstrated.
EVALuna2:491351

Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia - Kowalczyk-Quintas, Christine; Willen, Laure; Anh Thu Dang,; Sarrasin, Heidi; Tardivel, Aubry; Hermes, Katharina; Schneider, Holm; Gaide, Olivier; Donze, Olivier; Kirby, Neil; Headon, Denis J.; Schneider, Pascal (Journal of Biological Chemistry, 2014)
Development of ectodermal appendages, such as hair, teeth, sweat glands, sebaceous glands, and mammary glands, requires the action of the TNF family ligand ectodysplasin A (EDA). Mutations of the X-linked EDA gene cause reduction or absence of many ectodermal appendages and have been identified as a cause of ectodermal dysplasia in humans, mice, dogs, and cattle. We have generated blocking antibodies, raised in Eda-deficient mice, against the conserved, receptor-binding domain of EDA. These antibodies recognize epitopes overlapping the receptor-binding site and prevent EDA from binding and activating EDAR at close to stoichiometric ratios in in vitro binding and activity assays. The antibodies block EDA1 and EDA2 of both mammalian and avian origin and, in vivo, suppress the ability of recombinant Fc-EDA1 to rescue ectodermal dysplasia in Eda-deficient Tabby mice. Moreover, administration of EDA blocking antibodies to pregnant wild type mice induced in developing wild type fetuses a marked and permanent ectodermal dysplasia. These function-blocking anti-EDA antibodies with wide cross-species reactivity will enable study of the developmental and postdevelopmental roles of EDA in a variety of organisms and open the route to therapeutic intervention in conditions in which EDA may be implicated.
EVALuna2:18884

Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study - Weiß, Claudia; Ziegler, Andreas; Becker, Lena Luise; Johannsen, Jessika; Brennenstuhl, Heiko; Schreiber, Gudrun; Flotats-Bastardas, Marina; Stoltenburg, Corinna; Hartmann, Hans; Illsinger, Sabine; Denecke, Jonas; Pechmann, Astrid; et al. (The Lancet Child & Adolescent Health, 2022)
Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8–59·0, IQR 9–23) and a mean weight of 9·1 kg (range 4·0–15·0, IQR 7·4–10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9–19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings. Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. Funding: None. Translation: For the German translation of the abstract see Supplementary Materials section.
CRIS-Team Scopus Importer:2021-12-24

Generic formulations of imatinib for treatment of Philadelphia chromosome-positive leukemia in pediatric patients - Suttorp, Meinolf; Metzler, Markus; Shimada, Hiroyuki; Bansal, Deepak; Gunes, Adalet Meral; Kalwak, Krzysztof; Sedlacek, Petr; Baruchel, Andre; Biondi, Andrea; Hijiya, Nobuko; Schultz, Kirk R.; Schrappe, Martin; et al. (Pediatric Blood & Cancer, 2018)
Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia.
EVALuna2:35822

Genetic Counseling for Birth Defects - Reutter, Heiko Martin (European Journal of Pediatric Surgery, 2021)
CRIS-Team WoS Importer:2021-12-31

Genetic Counseling for Bladder Exstrophy-Epispadias Complex - Reutter, Heiko Martin; Holmdahl, Gundela (European Journal of Pediatric Surgery, 2021)
Bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum and has profound impact on continence, sexual, and renal function. Treatment of BEEC is primarily surgical, and the main goals are safe closure of the abdominal wall, urinary continence while preserving renal function, and adequate cosmetic and functional genital reconstruction. Psychosocial and psychosexual outcomes and adequate health-related quality of life depend on long-term multidisciplinary care. The overall outcome is now considered very positive and affected individuals usually lead self-determined and independent lives with the desire to start their own families later in life. Certainty about the risk of recurrence and the provision of information about the current state of knowledge about the identified genetic causes with high penetrance will have an impact on family planning for healthy parents with an affected child and for affected individuals themselves. This review addresses this information and presents the current state of knowledge.
CRIS-Team WoS Importer:2021-12-31

Genetic modifiers of fetal hemoglobin affect the course of sickle cell disease in patients treated with hydroxyurea - Allard, Pierre; Alhaj, Nareen; Lobitz, Stephan; Cario, Holger; Jarisch, Andreas; Grosse, Regine; Oevermann, Lena; Hakimeh, Dani; Tagliaferri, Laura; Kohne, Elisabeth; Kopp-Schneider, Annette; Kulozik, Andreas E.; et al. (Haematologica, 2022)
The course of sickle cell disease (SCD) is modified by polymorphisms boosting fetal hemoglobin (HbF) synthesis. However, it has remained an open question how these polymorphisms affect patients who are treated with the HbF-inducing drug hydroxyurea/hydroxycarbamide. The German SCD registry offers the opportunity to answer this question, because >90% of patients are treated according to national guidelines recommending the use of hydroxyurea in all patients above 2 years of age. We analyzed the modifying effect of HbF-related genetic polymorphisms in 417 patients with homozygous SCD >2 years old who received hydroxyurea. HbF levels were correlated with higher total hemoglobin levels, lower rates of hemolysis, a lower frequency of painful crises and of red blood cell transfusions. The minor alleles of the polymorphisms in the γ-globin promoter (rs7482144), BCL11A (rs1427407) and HMIP (rs66650371) were strongly associated with increased HbF levels. However, these associations did not translate into lower frequencies of vaso-occlusive events which did not differ between patients either carrying or not carrying the HMIP and BCL11A polymorphisms. Patients on hydroxyurea carrying the γ-globin promoter polymorphism demonstrated substantially higher hemoglobin levels (P<10-4) but also higher frequencies of painful crises and hospitalizations (P<0.01) when compared to patients without this polymorphism. Taken together, these data indicate that the γ-globin, HMIP and BCL11A polymorphisms correlate with increased HbF in SCD patients on hydroxyurea. While HbF is negatively correlated with the frequency of painful crises and hospitalizations, this was not observed for the presence of known HbF-boosting alleles.
CRIS-Team Scopus Importer:2022-07-15

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature - Hauer, Nadine; Sticht, Heinrich; Boppudi, Sangamitra; Büttner, Christian; Kraus, Cornelia; Trautmann, Udo; Zenker, Martin; Zweier, Christiane; Wiesener, Antje; Abou Jamra, Rami; Wieczorek, Dagmar; Kelkel, Jaqueline; et al. (Scientific Reports, 2017)
Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of -3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature.
EVALuna2:9379

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts - Mayr, Bernhard; Schnabel, Dirk; Dörr, Helmuth-Günther; Schöfl, Christof (European Journal of Endocrinology, 2016)
The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.
EVALuna2:2068

Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group - Hettmer, Simone; Dachy, Guillaume; Seitz, Guido; Agaimy, Abbas; Duncan, Catriona; Jongmans, Marjolijn; Hirsch, Steffen; Kventsel, Iris; Kordes, Uwe; De Krijger, Ronald R.; Metzler, Markus; Michaeli, Orli; et al. (Familial Cancer, 2020)
Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Genetic counseling; Infantile myofibromatosis; PDGFRB variants; Surveillance

Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis - Maagdenberg, Hedy; Oosterom, Natanja; Zanen, Jolanda; Gemmati, Donato; Windsor, Rachael E.; Heil, Sandra G.; Esperón, Patricia; Jabeen, Shakila; Ruiz-Argüelles, Guillermo J.; Zolk, Oliver; Hörning, Susanne; Sleurs, Charlotte; et al. (Critical Reviews in Oncology Hematology, 2021)
Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0–2, OR 2.53, 95 %CI [1.48–4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16–3.73], FDR-corrected p-value 0.042).
CRIS-Team Scopus Importer:2021-05-21
Keywords: Adult; Cancer; Gastrointestinal toxicity; Methotrexate; Mucositis; Pediatric; Pharmacogenomics

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility - Machiela, Mitchell J.; Gruenewald, Thomas G. P.; Surdez, Didier; Reynaud, Stephanie; Mirabeau, Olivier; Karlins, Eric; Rubio, Rebeca Alba; Zaidi, Sakina; Grossetete-Lalami, Sandrine; Ballet, Stelly; Lapouble, Eve; Laurence, Valerie; et al. (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-04

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility - Machiela, Mitchell J.; Grunewald, Thomas G. P.; Surdez, Didier; Reynaud, Stephanie; Mirabeau, Olivier; Karlins, Eric; Rubio, Rebeca Alba; Zaidi, Sakina; Grossetete-Lalami, Sandrine; Ballet, Stelly; Lapouble, Eve; Laurence, Valerie; et al. (Nature Communications, 2018)
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.
EVALuna2:35825

GENOME-WIDE ASSOCIATION STUDY IN PATIENTS WITH ANATOMICAL OBSTRUCTIONS OF THE LOWER URINARY TRACT - Van Der Zanden, Loes F. M.; Maj, Carlo; Borisov, Oleg; Van Rooij, Iris A. L. M.; Quaedackers, Josine S. L. T.; Steffens, Martijn; Schierbaum, Luca; Schneider, Sophia; Waffenschmidt, Lea; Kiemeney, Lambert A. L. M.; De Wall, Liesbeth; Heilmann, Stefanie; et al. (PEDIATRIC NEPHROLOGY, 2022)
CRIS-Team WoS Importer:2022-09-30

Genome-wide association study in patients with posterior urethral valves - van der Zanden, Loes F.M.; Maj, Carlo; Borisov, Oleg; van Rooij, Iris A.L.M.; Quaedackers, Josine S.L.T.; Steffens, Martijn; Schierbaum, Luca; Schneider, Sophia; Waffenschmidt, Lea; Kiemeney, Lambertus A.L.M.; de Wall, Liesbeth L.L.; Heilmann, Stefanie; et al. (Frontiers in Pediatrics, 2022)
Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.
CRIS-Team Scopus Importer:2022-10-28
Keywords: BMP7; genome wide association study; lower urinary tract obstruction; obstructive uropathy; PCDH9; posterior urethral valves; SALL1

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations - Fabian, Julia; Dworschak, Gabriel C.; Waffenschmidt, Lea; Schierbaum, Luca; Bendixen, Charlotte; Heilmann-Heimbach, Stefanie; Sivalingam, Sugirthan; Buness, Andreas; Schwarzer, Nicole; Boemers, Thomas M.; Schmiedeke, Eberhard; Neser, Jorg; et al. (European Journal of Human Genetics, 2022)
Anorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted.
CRIS-Team Scopus Importer:2022-11-18

Genome-Wide Survey for Microdeletions or -Duplications in 155 Patients with Lower Urinary Tract Obstructions (LUTO) - Schierbaum, Luca M.; Schneider, Sophia; Herms, Stefan; Sivalingam, Sugirthan; Fabian, Julia; Reutter, Heiko Martin; Weber, Stefanie; Merz, Waltraut M.; Tkaczyk, Marcin; Miklaszewska, Monika; Sikora, Przemyslaw; Szmigielska, Agnieszka; et al. (Genes, 2021)
Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw intensity data were collected for CNVs detected in LUTO patients and 4.392 healthy controls using CNVPartition, QuantiSNP and PennCNV. Overlapping CNVs between patients and controls were discarded. Additional filtering implicated CNV frequency in the database of genomic variants, gene content and final visual inspection detecting 37 ultra-rare CNVs. After, prioritization qPCR analysis confirmed 3 microduplications, all detected in PUV patients. One microduplication (5q23.2) occurred de novo in the two remaining microduplications found on chromosome 1p36.21 and 10q23.31. Parental DNA was not available for segregation analysis. All three duplications comprised 11 coding genes: four human specific lncRNA and one microRNA. Three coding genes (FBLIM1, SLC16A12, SNCAIP) and the microRNA MIR107 have previously been shown to be expressed in the developing urinary tract of mouse embryos. We propose that duplications, rare or de novo, contribute to PUV formation, a male-limited phenotype.
CRIS-Team WoS Importer:2021-10-08

Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma - Krumbholz, Manuela; Hellberg, Julia; Steif, Benedikt; Bäuerle, Tobias; Gillmann, Clarissa; Fritscher, Torsten; Agaimy, Abbas; Frey, Benjamin; Juengert, Joerg; Wardelmann, Eva; Hartmann, Wolfgang; Juergens, Heribert; et al. (Clinical Cancer Research, 2016)
The application of the tumor-specific genomic fusion sequence as noninvasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated.EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic EWSR1-FLI1 copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. EWSR1 fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared with tumor volumes calculated from MRI or CT imaging studies.Kinetics of EWSR1 fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell-free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development.Genomic fusion sequences represent promising noninvasive biomarkers for improved therapy monitoring in EwS. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response. Clin Cancer Res; 22(17); 4356-65. ©2016 AACR.
EVALuna2:6851

Genotype, Clinical Course, and Therapeutic Decision Making in 76 Infants with Severe Generalized Junctional Epidermolysis Bullosa - Hammersen, Johanna; Has, Cristina; Naumann-Bartsch, Nora; Stachel, Daniel; Kiritsi, Dimitra; Söder, Stephan; Tardieu, Mathilde; Metzler, Markus; Bruckner-Tuderman, Leena; Schneider, Holm (Journal of Investigative Dermatology, 2016)
Severe generalized junctional epidermolysis bullosa, a lethal hereditary blistering disorder, is usually treated by palliative care. Allogeneic stem cell transplantation (SCT) has been proposed as a therapeutic approach, yet without clinical evidence. Decision making was evaluated retrospectively in 76 patients with severe generalized junctional epidermolysis bullosa born in the years 2000-2015. The diagnosis was based on the absence of laminin-332 in skin biopsies. With an incidence of 1 of 150,000, severe generalized junctional epidermolysis bullosa occurred more often than published previously. Eleven as yet unreported mutations in the laminin-332 genes were detected. Although patients homozygous for the LAMB3 mutation c.1903C>T lived longer than the others, life expectancy was greatly diminished (10.8 vs. 4.6 months). Most patients failed to thrive. In two patients with initially normal weight gain, the decision for SCT from haploidentical bone marrow or peripheral blood was made. Despite transiently increasing skin erosions, the clinical status of both subjects stabilized for several weeks after SCT, but finally deteriorated. Graft cells, but no laminin-332, were detected in skin biopsies. The patients died 96 and 129 days after SCT, respectively, one of them after receiving additional skin grafts. Treatment of severe generalized junctional epidermolysis bullosa by SCT is a last-ditch attempt still lacking proof of efficacy.
EVALuna2:6828

Genotype-phenotype correlation in boys with X-linked hypohidrotic ectodermal dysplasia - Burger, Kristin; Schneider, Anne-Theres; Wohlfart, Sigrun; Kiesewetter, Franklin; Huttner, Kenneth; Johnson, Ramsey; Schneider, Holm (American Journal of Medical Genetics Part A, 2014)
X-linked hypohidrotic ectodermal dysplasia (XLHED), the most frequent form of ectodermal dysplasia, is a genetic disorder of ectoderm development characterized by malformation of multiple ectodermal structures such as skin, hair, sweat and sebaceous glands, and teeth. The disease is caused by a broad spectrum of mutations in the gene EDA. Although XLHED symptoms show inter-familial and intra-familial variability, genotype-phenotype correlation has been demonstrated with respect to sweat gland function. In this study, we investigated to which extent the EDA genotype correlates with the severity of XLHED-related skin and hair signs. Nineteen male children with XLHED (age range 3-14 years) and seven controls (aged 6-14 years) were examined by confocal microscopy of the skin, quantification of pilocarpine-induced sweating, semi-quantitative evaluation of full facial photographs with respect to XLHED-related skin issues, and phototrichogram analysis. All eight boys with known hypomorphic EDA mutations were able to produce at least some sweat and showed less severe cutaneous signs of XLHED than the anhidrotic XLHED patients (e.g., perioral and periorbital eczema or hyperpigmentation, regional hyperkeratosis, characteristic wrinkles under the eyes). As expected, individuals with XLHED had significantly less and thinner hair than healthy controls. However, there were also significant differences in hair number, diameter, and other hair characteristics between the group with hypomorphic EDA mutations and the anhidrotic patients. In summary, this study indicated a remarkable genotype-phenotype correlation of skin and hair findings in prepubescent males with XLHED.
EVALuna2:18885

Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients - Riedl, Stefan; Roehl, Friedrich-Wilhelm; Bonfig, Walter; Braemswig, Juergen; Richter-Unruh, Annette; Fricke-Otto, Susanne; Bettendorf, Markus; Riepe, Felix; Kriegshaeuser, Gernot; Schoenau, Eckhard; Even, Gertrud; Hauffa, Berthold; et al. (Endocrine Connections, 2019)
Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80-90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.
CRIS-Team WoS Importer:2019-03-20

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. - Dörr, Helmuth-Günther; Schulze, Nadja; Bettendorf, Markus; Binder, Gerhard; Bonfig, Walter; Denzer, Christian; Dunstheimer, Desirée; Salzgeber, Kirsten; Schmidt, Heinrich; Schwab, Karl-Otfried; Voss, Egbert; Wabitsch, Martin; et al. (Molecular and Cellular Pediatrics, 2020)
BACKGROUND: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany. AIMS: Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7). CONCLUSION: Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.
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Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma - Desch, Ann Kathrin; Hartung, Kristin; Botzen, Ante; Brobeil, Alexander; Rummel, Mathias; Kurch, Lars; Georgi, Thomas; Jox, Theresa; Bielack, Stefan; Burdach, Stefan; Classen, Carl Friedrich; Claviez, Alexander; et al. (Leukemia, 2019)
We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.
CRIS-Team Scopus Importer:2019-08-27

Genotyp-Phänotyp-Korrelation bei Zwillingsmädchen mit nichtklassischem adrenogenitalem Syndrom und 21-Hydroxylase-Defekt - Dörr, Helmuth-Günther; Oppelt, Patricia (Gynakologische Endokrinologie, 2020)
CRIS-Team Scopus Importer:2020-03-06

Genotyp-Phänotyp-Korrelationen bei Kindern und Jugendlichen mit nichtklassischem adrenogenitalen Syndrom mit 21-Hydroxylase-Defekt - Dörr, Helmuth-Günther; Schulze, Nadja; Bettendorf, M.; Binder, G.; Bonfig, W.; Denzer, C.; Dunstheimer, D.; Salzgeber, K.; Schmidt, H.; Schwab, K. O.; Voss, E.; Wabitsch, M.; et al. (Monatsschrift Kinderheilkunde, 2020)
Background: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH) is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany. Objective: Description of the phenotype, evaluation of the diagnostics, genotype-phenotype correlation. Patients and methodology: Retrospective analysis of the data of 134 patients (age range 0.1–18.6 years) in a multicenter study covering 10 pediatric endocrinology centers in Bavaria and Baden-Württemberg. The data were collected on site from the medical records. In 126 patients 233 alleles with a mutation of the CYP21A2 gene were identified. A genotype-phenotype correlation of the mutation findings was undertaken (C1: severe/mild, C2: mild/mild). Individuals with a heterozygote mutation (C3) were also included in the analysis. The data were collected with the approval of the ethics committee of the University Hospital of Erlangen during the time period of 2014 and 2015. Results (MW ± SD): Out of 134 patients (115 female, 29 male) 117 were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-standard deviation score (SDS) on diagnosis was 0.8 ± 1.3 and the body mass index (BMI)-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17-hydroxyprogesterone (17-OHP) concentrations were 14.5 ± 19.1 ng/ml (18 patients <2 ng/ml). In total 58.1% mild and 34.7% severe mutations were found. The most common mutation (39.1%) was p.Val281Leu and 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the three mutation groups. The 17-OHP levels (basal and after ACTH) in the ACTH test were highest in group C1 and also significantly higher in group C2 than in group C3. The ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7). Conclusion: Most of the patients had symptoms of mild androgenization. Male patients were underdiagnosed. The diagnostics were not standardized. Differences between the types of mutations were found in the hormone concentrations but not in the phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.
CRIS-Team Scopus Importer:2020-07-24
Keywords: 17-OHP; ACTH stimulation test; Androgenisation; CYP21A2 gene mutations; Premature pubarche

German Registry for Cardiac Operations and Interventions in Patients with Congenital Heart Disease: Report 2020-Comprehensive Data from 6 Years of Experience - Beckmann, Andreas; Dittrich, Sven; Arenz, C.; Krogmann, O. N.; Horke, A.; Tengler, A.; Meyer, R.; Bauer, U. M. M.; Hofbeck, Michael (Thoracic and Cardiovascular Surgeon, 2021)
Background a Based on a quality assurance initiative of the German Society for Thoracic and Cardiovascular Surgery (DGTHG) and the German Society for Pediatric Cardiology and Congenital Heart Defects (DGPK), a voluntary registry was founded for assessment of treatment and outcomes of patients with congenital heart disease in Germany. This evaluation by the German Registry for cardiac operations and interventions in patients with congenital heart disease reports the data and the outcome over a 6-year period in patients undergoing invasive treatment. Methods a This real-world database collects clinical characteristics, in-hospital complications, and medium-term outcome of patients who underwent cardiac surgical and interventional procedures within the prospective, all-comers registry. Patients were followed-up for up to 90 days. Results a In the period from 2013 to 2018, a total of 35,730 patients, 39,875 cases, respectively 46,700 procedures were included at up to 31 German institutions. The cases could be subcategorized according to the treatment intention into 21,027 (52.7%) isolated operations, 17,259 (43.3%) isolated interventions, and 1,589 (4.0%) with multiple procedures. Of these, 4,708 (11.8%) were performed in neonates, 10,047 (25.2%) in infants, 19,351 (48.5%) in children of 1 to 18 years, and 5,769 (14.5%) in adults. Also, 15,845 (33.9%) cases could be allocated to so-called index procedures which underwent a more detailed evaluation to enable meaningful comparability. The mean unadjusted in-hospital mortality of all cases in our registry ranged from 0.3% in patients with isolated interventions and 2.0% in patients with surgical procedures up to 9.1% in patients undergoing multiple procedures. Conclusion a This annually updated registry of both scientific societies represents voluntary public reporting by accumulating actual information for surgical and interventional procedures in patients with congenital heart disease (CHD) in Germany. It describes advancements in cardiac medicine and is a basis for internal and external quality assurance for all participating institutions. In addition, the registry demonstrates that in Germany, both interventional and surgical procedures for treatment of CHD are offered with high medical quality.
CRIS-Team Scopus Importer:2021-03-19
Keywords: congenital heart disease; congenital heart surgery; multicenter registry; outcomes; pediatric cardiology

German Registry for Cardiac Operations and Interventions in Patients with Congenital Heart Disease: Report 2021 and 9 Years' Longitudinal Observations on Fallot and Coarctation Patients - Dittrich, Sven; Arenz, Claudia; Krogmann, Otto; Tengler, Anja; Meyer, Renate; Bauer, Ulrike; Hofbeck, Michael; Beckmann, Andreas; Horke, Alexander (Thoracic and Cardiovascular Surgeon, 2022)
BACKGROUND: The annual report of the German Quality Assurance of Congenital Heart Disease displays a broad overview on outcome of interventional and surgical treatment with respect to patient's age and risk categorization. Particular features of the German all-comers registry are the inclusion of all interventional and surgical procedures, the possibility to record repeated treatments with distinct individual patient assignment, and to record various procedures within one case. METHODS: International Pediatric and Congenital Cardiac Code terminology for diagnoses and procedures as well as classified adverse events, also recording of demographic data, key procedural performance indicators, and key quality indicators (mortality, adverse event rates). Surgical and interventional adverse events were classified according to the Society of Thoracic Surgeons and to the Congenital Heart Disease Adjustment for Risk Method of the congenital cardiac catheterization project on outcomes. Annual analysis of all cases and additional long-term evaluation of patients after repair of Fallot and primary treatment of native coarctation of the aorta were performed. RESULTS: In 2020, 5,532 patients with 6,051 cases (hospital stays) with 6,986 procedures were treated in 23 German institutions. Cases dispense on 618 newborns (10.2%), 1,532 infants (25.3%), 3,077 children (50.9%), and 824 adults (13.6%). Freedom from adverse events was 94.5% in 2,795 interventional cases, 67.9% in 2,887 surgical cases, and 42.9% in 336 cases with multiple procedures (without considering the 33 hybrid interventions). In-hospital mortality was 0.5% in interventional, 1.6% in surgical, and 5.7% in cases with multiple treatments. Long-term observation of 1,632 patient after repair of Fallot depicts the impact of previous palliation in 18% of the patients on the rate of 20.8% redo cases. Differentiated analysis of 1,864 patients with native coarctation picture clear differences of patient, age, and procedure selection and outcome. The overall redo procedure rate in this patient population is high with 30.8%. CONCLUSION: Improvement in quality of care requires detailed analysis of risks, performance indicators, and outcomes. The high necessity of redo procedures in patients with complex congenital heart disease underlines the imperative need of long-term observations.
CRIS-Team Scopus Importer:2022-10-14

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms - van Walree, Eva S.; Dombrowsky, Gregor; Jansen, Iris E.; Mirkov, Maša Umićević; Zwart, Rob; Ilgun, Aho; Guo, Dongchuan; Clur, Sally Ann B.; Amin, Ahmed S.; Savage, Jeanne E.; van der Wal, Allard C.; Waisfisz, Quinten; et al. (Genetics in Medicine, 2020)
Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370. These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
CRIS-Team Scopus Importer:2020-08-28
Keywords: cardiovascular defects; congenital heart defect; HEY2; thoracic aortic aneurysm

Germline variants in transcription factor HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms - Van Walree, E. S.; Dombrowsky, G.; Jansen, I. E.; Mirkov, M. Umicevic; Zwart, R.; Ilgun, A.; Guo, D.; Clur, S. B.; Amin, A. S.; Savage, J. E.; Van Der Wal, A. C.; Waisfisz, Q.; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2020)
CRIS-Team WoS Importer:2021-01-22

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma - Gähler, Alexander; Trufa, Denis; Chiriac, Mircea-Teodor; Tausche, Patrick; Hohenberger, Katja; Brunst, Ann-Kathrin; Rauh, Manfred; Geppert, Carol-Immanuel; Rieker, Ralf; Krammer, Susanne; Leberle, Anna; Neurath, Markus; et al. (Frontiers in Oncology, 2022)
BackgroundLung cancer is the second common cancer type in western countries and has a high mortality. During the development and progression of the tumor, the nutrients in its environment play a central role. The tumor cells depend crucially on glucose metabolism and uptake. Tumor cell metabolism is dominated by the Warburg effect, where tumor cells produce large amounts of lactate from pyruvate under aerobic conditions. We thus reasoned that, reducing carbohydrates in the diet might support anti-tumoral effects of current immunotherapy and additionally target tumor immune escape. ObjectivesThe link between reducing carbohydrates to improve current immunotherapy is not clear. We thus aimed at analyzing the effects of different glucose levels on the tumor development, progression and the anti-tumoral immune response. MethodsWe correlated the clinical parameters of our LUAD cohort with different metabolic markers. Additionally, we performed cell culture experiments with A549 tumor cell line under different glucose levels. Lastly, we investigated the effect of low and high carbohydrate diet in an experimental murine model of lung cancer on the tumor progression and different immune subsets. ResultsHere we found a positive correlation between the body mass index (BMI), blood glucose levels, reduced overall survival (OS) and the expression of Insulin-like growth factor-1 receptor (IGF1R) in the lung tumoral region of patients with lung adenocarcinoma (LUAD). Furthermore, increasing extracellular glucose induced IGF1R expression in A549 LUAD cells. Functional studies in a murine model of LUAD demonstrated that, glucose restricted diet resulted in decreased tumor load in vivo. This finding was associated with increased presence of lung infiltrating cytotoxic CD8+ T effector memory (TEM), tissue resident memory T (TRM) and natural killer cells as well as reduced IGFR mRNA expression, suggesting that glucose restriction regulates lung immunity in the tumor microenvironment. ConclusionsThese results indicate that, glucose restricted diet improves lung immune responses of the host and suppresses tumor growth in experimental lung adenocarcinoma. As glucose levels in LUAD patients were negatively correlated to postoperative survival rates, glucose-restricted diet emerges as therapeutic avenue for patients with LUAD.
CRIS-Team WoS Importer:2022-05-27

Goal-directed-perfusion in neonatal aortic arch surgery - Cesnjevar, Robert; Purbojo, Ariawan; Münch, Frank; Juengert, Joerg; Rueffer, Andre (Translational Pediatrics, 2016)
Reduction of mortality and morbidity in congenital cardiac surgery has always been and remains a major target for the complete team involved. As operative techniques are more and more standardized and refined, surgical risk and associated complication rates have constantly been reduced to an acceptable level but are both still present. Aortic arch surgery in neonates seems to be of particular interest, because perfusion techniques differ widely among institutions and an ideal form of a so called "total body perfusion (TBP)" is somewhat difficult to achieve. Thus concepts of deep hypothermic circulatory arrest (DHCA), regional cerebral perfusion (RCP/with cardioplegic cardiac arrest or on the perfused beating heart) and TBP exist in parallel and all carry an individual risk for organ damage related to perfusion management, chosen core temperature and time on bypass. Patient safety relies more and more on adequate end organ perfusion on cardiopulmonary bypass, especially sensitive organs like the brain, heart, kidney, liver and the gut, whereby on adequate tissue protection, temperature management and oxygen delivery should be visualized and monitored.
EVALuna2:34094

Größenwachstum und Knochengesundheit bei Erkrankungen der Wachstumsfuge und des Knochens: Möglichkeiten und Grenzen einer GH-Therapie - Wölfle, Joachim; Bettendorf, M.; Bechtold-Dalla Pozza, S.; Binder, G.; Grasemann, C.; Reinehr, T.; Semler, O.; Dörr, Helmuth-Günther (Monatsschrift Kinderheilkunde, 2020)
Background: Genetic, paracrine and endocrine factors influence longitudinal growth in the area of the epiphyseal plates and bone mineralization. Objective: The aim was to review the spontaneous longitudinal growth and bone health in patients with rare bone diseases. Can growth hormone (GH) treatment improve growth and bone health in these diseases? Material and methods: Findings of an expert workshop including literature search on bone health in bone disorders associated with stunted growth and the treatment options. Results: Most patients with osteogenesis imperfecta are of short stature. Additional administration of GH has no influence on adult height and is currently not used. Pseudohypoparathyroidism (PHP) patients with insufficient longitudinal growth and confirmed GH deficiency can be treated with GH and can benefit from the treatment. Children with X‑linked hereditary hypophosphatemic rickets show progressive disproportionate short stature under the current treatment with phosphate and calcitriol. Randomized GH treatment studies resulted in a temporary improvement in body height but not in a significant improvement of adult height. The use of GH is approved for treatment of SHOX-deficient children and is comparably effective as in girls with Turner’s syndrome (TS). Observational studies also suggest that GH treatment can lower the risk of bone fractures, known to be increased in TS. Inflammation, reduced physical activity and malnutrition can result in impaired growth with loss of muscle and bone mass in patients with juvenile idiopathic arthritis (JIA). Studies could demonstrate a positive impact of GH on longitudinal growth, density and geometry of bones and on bone metabolism as well as on muscular mass; however, GH treatment is not approved for patients with JIA. Conclusion: Regarding the various bone diseases mentioned above, all growth disorders have to be considered individually. Apart from longitudinal growth GH can have a positive impact on metabolism, bone mineral content and bone density depending on the indications. The only approved indications for GH treatment are GH deficiency in PHP and children born small for gestational age (SGA) and TS/SHOX deficiency. Apart from increased growth, improvements in bone health in children and adolescents should be discussed as an outcome measure for GH treatment.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Bone; Bone health; Growth; Growth hormone (GH); Growth plate

Growth of hypoplastic mitral valves in hypoplastic left heart complex and similar constellations after anatomical left superior vena cava correction - Cesnjevar, Robert; Harig, Frank; Dietz, Moritz; Alkassar, Muhannad; Waellisch, Wolfgang; Rueffer, André; Dittrich, Sven; Purbojo, Ariawan (European Journal of Cardio-Thoracic Surgery, 2021)
OBJECTIVES: Left superior vena cava (LSVC)-related obstruction of mitral inflow is a rare finding in patients with complex cardiac anomalies like hypoplastic left heart complex. We report our experience by establishing a left superior to right superior caval vein continuity (innominate vein creation by direct LSVC-right superior vena cava end-to-side-anastomosis), and coronary sinus unroofing if indicated for LSVC-related mitral inflow obstruction. METHODS: Nineteen patients (median age: 1.0 ± 0.3 years; range: 7 days-4.8 years) underwent anatomical correction of LSVC without the use of foreign material in conjunction with repair or palliation of congenital anomalies in a single centre between April 2015 and November 2019. Indications for the procedure were LSVC-related obstruction of left ventricular inflow due to a dilated coronary sinus. Additional procedures included mitral (n = 7) or atrioventricular (n = 3) valve surgery, right ventricular to pulmonary artery conduit (n = 3), first stage palliation (n = 3) or biventricular repair (n = 5) of hypoplastic left heart complex. Three patients needed secondary mitral valve replacement (n = 3). RESULTS: All LSVC or coronary sinus-related obstructions were effectively relieved. No patient died early, 2 patients died late after the procedure. One patient needed stenting of the superior vena cava below the unobstructed cephalad vein anastomosis at the former right superior vena cava-cannulation-site. Follow-up was complete and demonstrated an 89.5% survival after 2.5 ± 0.4 years. Innominate vein patency was 100% documented by echocardiography (n = 19), cardiac catheterization (n = 6) or both. Mean mitral valve z-scores before the operation were -1.7 ± 0.2 (range -3.8 to 0.3) and increased to 0.7 ± 0.2 (range -0.7 to 1.9) after LSVC repair. CONCLUSIONS: Anatomical correction by surgical creation of an innominate vein is an effective method to relieve LSVC-related obstructions and promotes mitral valvar growth. Mitral ring sizes were at least normalized after surgery at the time of discharge. Further prospective follow-up studies to evaluate the growth potential of left-sided heart structures by reporting cardiac z-scores are needed to evaluate the true impact of coronary sinus unroofing.
CRIS-Team Scopus Importer:2021-01-29
Keywords: Congenital heart disease; Hypoplastic left heart complex; Left superior vena cava; Mitral valve growth; Mitral valve z-score

Guideline Adherence and Registry Recruitment of Congenital Primary Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (HypoDok) - Thomann, Julia; Tittel, Sascha R.; Voss, Egbert; Oeverink, Rudolf; Palm, Katja; Fricke-Otto, Susanne; Kapelari, Klaus; Holl, Reinhard W.; Wölfle, Joachim; Bettendorf, Markus (International Journal of Neonatal Screening, 2021)
Neonatal screening for congenital primary hypothyroidism (CH) is mandatory in Germany but medical care thereafter remains inconsistent. Therefore, the registry HypoDok of the German Society of Pediatric Endocrinology and Diabetology (DGKED) was analyzed to evaluate the implementation of evidence-based guidelines and to assess the number of included patients. Inclusion criteria were (i) date of birth between 10/2001 and 05/2020 and (ii) increased thyroid-stimulating hormone (TSH) at screening and/or confirmation. The cohort was divided into before (A) and after (B) guideline publication in 02/2011, to assess the guideline's influence on medical care. A total of 659 patients were analyzed as group A (n = 327) and group B (n = 332) representing 17.5% and 10.3% of CH patients identified in the German and Austrian neonatal screening program during the respective time period. Treatment start and thyroxine doses were similar in both groups and consistent with recommendations. Regular follow-ups were documented. In the first three years of life, less than half of the patients underwent audiometry; developmental assessment was performed in 49.3% (A) and 24.8% (B) (p < 0.01). Documentation of CH patient care by pediatric endocrinologists seemed to be established, however, it reflected only a minority of the affected patients. Therefore, comprehensive documentation as an important instrument of quality assurance and evidence-based medicine should be legally enforced and officially funded in order to record, comprehend, and optimize care and outcome in patients with rare diseases such as CH.
CRIS-Team WoS Importer:2021-04-16

Haematological characteristics and spontaneous haematological recovery in Pearson syndrome - Yoshimi, Ayami; Gruenert, Sarah C.; Cario, Holger; Fisch, Aron; Gross-Wieltsch, Ute; Timmermann, Kirsten; Kontny, Udo; Lobitz, Stephan; Odenthal, Helen S.; Schmid, Irene; Uetz, Barbara; Hoell, Tanja; et al. (British Journal of Haematology, 2021)
CRIS-Team Scopus Importer:2021-04-23
Keywords: hematological recovery; mitochondrial disease; Pearson syndrome; single large-scale mitochondrial DNA deletion

Health Problems and Quality of Life of Young Cancer Survivors in the Comprehensive Care for CAYA Program - Elmers, Simon; Beitzen-Heineke, Antonia; Von Grundherr, Julia; Jensen, Wiebke; Koch, Barbara; Mann, Julia; Salchow, Jannike; Sinn, Marianne; Straub, Lesley-Ann; Wegert, Luisa; Vettorazzi, Eik; Bergelt, Corinna; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany - Willems, Laurent M.; Schubert-Bast, Susanne; Grau, Janina; Hertzberg, Christoph; Kurlemann, Gerhard; Wiemer-Kruel, Adelheid; Bast, Thomas; Bertsche, Astrid; Bettendorf, Ulrich; Fiedler, Barbara; Hahn, Andreas; Hartmann, Hans; et al. (European Journal of Paediatric Neurology, 2021)
Objective: This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. Methods: Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4–18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. Results: The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. Conclusion: Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Angiomyolipoma; Depression; Epilepsy; Seizure; TSC

Hemoglobin A1c patterns of youth with type 1 diabetes 10 years post diagnosis from 3 continents - Sherr, Jennifer L.; Schwandt, Anke; Phelan, Helen; Clements, Mark A.; Holl, Reinhard W.; Benitez-Aguirre, Paul Z.; Miller, Kellee M.; Wölfle, Joachim; Dover, Thomas; Maahs, David M.; Fröhlich-Reiterer, Elke; Craig, Maria E. (Pediatrics, 2021)
Objectives: Distinct hemoglobin A1c (HbA1c) trajectories during puberty are identified in youth with established type 1 diabetes (T1D). We used data from 3 international registries to evaluate whether distinct HbA1c trajectories occur from T1D onset. Methods: Participants were <18 years old at diagnosis with at least 1 HbA1c measured within 12 months post diagnosis, along with ≥3 duration-year-aggregated HbA1c values over 10 years of follow-up. Participants from the Australasian Diabetes Data Network (n = 7292), the German-Austrian-Luxembourgian-Swiss diabetes prospective follow-up initiative (Diabetes Patienten Verlaufsdokumentation) (n = 39 226) and the US-based Type 1 Diabetes Exchange Clinic Registry (n = 3704) were included. With group-based trajectory modeling, we identified unique HbA1c patterns from the onset of T1D. Results: Five distinct trajectories occurred in all 3 registries, with similar patterns of proportions by group. More than 50% had stable HbA1c categorized as being either low stable or intermediate stable. Conversely, ∼15% in each registry were characterized by stable HbA1c >8.0% (high stable), and ∼11% had values that began at or near the target but then increased (target increase). Only ∼5% of youth were above the target from diagnosis, with an increasing HbA1c trajectory over time (high increase). This group differed from others, with higher rates of minority status and an older age at diagnosis across all 3 registries (P ≤ .001). Conclusions: Similar postdiagnostic HbA1c patterns were observed across 3 international registries. Identifying the youth at the greatest risk for deterioration in HbA1c over time may allow clinicians to intervene early, and more aggressively, to avert increasing HbA1c.
CRIS-Team Scopus Importer:2021-09-10

HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders - Reuter, Miriam; Sass, Joern Oliver; Leis, Thomas; Koehler, Julia; Mayr, Johannes A.; Feichtinger, Rene G.; Rauh, Manfred; Schanze, Ina; Baehr, Luzy; Trollmann, Regina; Uebe, Steffen; Ekici, Arif Bülent; et al. (American Journal of Medical Genetics Part A, 2014)
HIBCH (3-hydroxyisobutyryl-CoA hydrolase) deficiency (MIM #250620) is a rare autosomal recessive inborn error of metabolism, leading to a block in the catabolic pathway of the amino acid valine and presumably to accumulation of toxic valine metabolites in mitochondria. Only three families with HIBCH deficiency and biallelic HIBCH mutations have been described. We report on a further patient, first child of healthy consanguineous parents, with severe developmental delay, seizures, hyperintensities of the basal ganglia on magnetic resonance imaging (MRI), progressive brain atrophy, optic nerve atrophy, repeatedly elevated blood lactate, and respiratory chain complexes I, I + III and cytochrome c oxidase deficiencies with borderline depletion of mitochondrial DNA in muscle tissue. Laboratory findings in blood and skeletal muscle were inconsistent and did not allow a definite diagnosis, but supported the hypothesis of mitochondrial dysfunction. Homozygosity mapping and whole-exome sequencing revealed a homozygous one-base pair insertion in HIBCH. Deficiency of enzyme activity was confirmed in cultured fibroblasts. Although relatively unspecific, the clinical features were similar to those of the previously reported cases. Given the clinical variability and large number of differential diagnoses, the prevalence of HIBCH deficiency is probably underestimated. Next-generation sequencing approaches are an effective tool for identifying the underlying genetic basis in patients suspected of mitochondrial disorders. © 2014 Wiley Periodicals, Inc.
EVALuna2:9220

High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma - Koch, Raphael; Gelderblom, Hans; Haveman, Lianne; Brichard, Benedicte; Jürgens, Heribert; Cyprova, Sona; Van Den Berg, Henk; Hassenpflug, Wolf; Raciborska, Anna; Ek, Torben; Baumhoer, Daniel; Egerer, Gerlinde; et al. (Journal of Clinical Oncology, 2022)
PURPOSEEwing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS).METHODSPhase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method.RESULTSBetween 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P =.035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P =.016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3.CONCLUSIONIn patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.
CRIS-Team Scopus Importer:2022-06-10

High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations - Reutter, Heiko Martin (European Journal of Human Genetics, 2023)
CRIS-Team Scopus Importer:2023-01-13

High Platelet Counts, Thrombosis, Bleeding Signs, and Acquired Von Willebrand Syndrome at Diagnosis of Pediatric Chronic Myeloid Leukemia - Suttorp, Meinolf; Knoefler, Ralf; Deutsch, Helene; Paul, Franziska; Tiebel, Oliver; Metzler, Markus; Millot, Frederic (BLOOD, 2019)
CRIS-Team WoS Importer:2021-10-18

High-resolution label-free mapping of murine kidney vasculature by raster-scanning optoacoustic mesoscopy: an ex vivo study - Goebel, Colin A.; Brown, Emma; Fahlbusch, Fabian; Wagner, Alexandra; Buehler, Adrian; Raupach, Thomas; Hohmann, Martin; Späth, Moritz; Burton, Neal; Wölfle, Joachim; Schmidt, Michael; Hartner, Andrea; et al. (Molecular and Cellular Pediatrics, 2022)
Background: Chronic kidney disease (CKD) is a global burden affecting both children and adults. Novel imaging modalities hold great promise to visualize and quantify structural, functional, and molecular organ damage. The aim of the study was to visualize and quantify murine renal vasculature using label-free raster scanning optoacoustic mesoscopy (RSOM) in explanted organs from mice with renal injury. Material and methods: For the experiments, freshly bisected kidneys of alpha 8 integrin knock-out (KO) and wildtype mice (WT) were used. A total of n=7 female (n=4 KO, n=3 WT) and n=6 male animals (n=2 KO, n=4 WT) aged 6 weeks were examined with RSOM optoacoustic imaging systems (RSOM Explorer P50 at SWL 532nm and/or ms-P50 imaging system at 532 nm, 555 nm, 579 nm, and 606 nm). Images were reconstructed using a dedicated software, analyzed for size and vascular area and compared to standard histologic sections. Results: RSOM enabled mapping of murine kidney size and vascular area, revealing differences between kidney sizes of male (m) and female (f) mice (merged frequencies (MF) f vs. m: 52.42±6.24 mm2 vs. 69.18±15.96 mm2, p=0.0156) and absolute vascular area (MF f vs. m: 35.67±4.22 mm2 vs. 49.07±13.48 mm2, p=0.0036). Without respect to sex, the absolute kidney area was found to be smaller in knock-out (KO) than in wildtype (WT) mice (WT vs. KO: MF: p=0.0255) and showed a similar trend for the relative vessel area (WT vs. KO: MF p=0.0031). Also the absolute vessel areas of KO compared to WT were found significantly different (MF p=0.0089). A significant decrease in absolute vessel area was found in KO compared to WT male mice (MF WT vs. KO: 54.37±9.35 mm2 vs. 34.93±13.82 mm2, p=0.0232). In addition, multispectral RSOM allowed visualization of oxygenated and deoxygenated parenchymal regions by spectral unmixing. Conclusion: This study demonstrates the capability of RSOM for label-free visualization of differences in vascular morphology in ex vivo murine renal tissue at high resolution. Due to its scalability optoacoustic imaging provides an emerging modality with potential for further preclinical and clinical imaging applications.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Chronic kidney disease; Ex vivo kidney imaging; msRSOM; Optoacoustic; Photoacoustic; Raster scanning optoacoustic mesoscopy; RSOM

High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials - Zierk, Jakob; Baum, Hannsjörg; Bertram, Alexander; Boeker, Martin; Buchwald, Armin; Cario, Holger; Christoph, Jürgen; Frühwald, Michael C.; Groß, Hans Jürgen; Groening, Arndt; Gscheidmeier, Thomas; Hoff, Torsten; et al. (Clinical Chemistry and Laboratory Medicine, 2021)
Assessment of children's laboratory test results requires consideration of the extensive changes that occur during physiological development and result in pronounced sex- and age-specific dynamics in many biochemical analytes. Pediatric reference intervals have to account for these dynamics, but ethical and practical challenges limit the availability of appropriate pediatric reference intervals that cover children from birth to adulthood. We have therefore initiated the multi-center data-driven PEDREF project (Next-Generation Pediatric Reference Intervals) to create pediatric reference intervals using data from laboratory information systems. We analyzed laboratory test results from 638,683 patients (217,883-982,548 samples per analyte, a median of 603,745 test results per analyte, and 10,298,067 test results in total) performed during patient care in 13 German centers. Test results from children with repeat measurements were discarded, and we estimated the distribution of physiological test results using a validated statistical approach (kosmic). We report continuous pediatric reference intervals and percentile charts for alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl-transferase, total protein, albumin, creatinine, urea, sodium, potassium, calcium, chloride, anorganic phosphate, and magnesium. Reference intervals are provided as tables and fractional polynomial functions (i.e., mathematical equations) that can be integrated into laboratory information systems. Additionally, Z-scores and percentiles enable the normalization of test results by age and sex to facilitate their interpretation across age groups. The provided reference intervals and percentile charts enable precise assessment of laboratory test results in children from birth to adulthood. Our findings highlight the pronounced dynamics in many biochemical analytes in neonates, which require particular consideration in reference intervals to support clinical decision making most effectively.
CRIS-Team Scopus Importer:2021-03-05
Keywords: continuous reference intervals; data mining; indirect reference intervals; pediatric reference intervals; percentile charts

High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation - Kitada, Kento; Daub, Steffen; Zhang, Yahua; Klein, Janet D.; Nakano, Daisuke; Pedchenko, Tetyana; Lantier, Louise; Larocque, Lauren M.; Marton, Adriana; Neubert, Patrick; Schröder, Agnes; Rakova, Natalia; et al. (Journal of Clinical Investigation, 2017)
Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.
EVALuna2:34241

High sensitivity and clonal stability of the genomic fusion as single marker for response monitoring in ETV6-RUNX1-positive acute lymphoblastic leukemia - Hoffmann, Jana; Krumbholz, Manuela; Gutiérrez, Helia Pimentel; Fillies, Marion; Szymansky, Annabell; Bleckmann, Kirsten; zur Stadt, Udo; Köhler, Rolf; Kuiper, Roland P.; Horstmann, Martin; von Stackelberg, Arend; Eckert, Cornelia; et al. (Pediatric Blood & Cancer, 2019)
Background: Assessment of minimal residual disease (MRD) is an integral component for response monitoring and treatment stratification in acute lymphoblastic leukemia (ALL). We aimed to evaluate the genomic ETV6-RUNX1 fusion sites as a single marker for MRD quantification. Procedure: In a representative, uniformly treated cohort of pediatric relapsed ALL patients (n = 52), ETV6-RUNX1 fusion sites were compared to the current gold standard, immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements. Results: Primer/probe sets designed to ETV6-RUNX1 fusions achieved significantly more frequent a sensitivity and a quantitative range of at least 10 –4 compared to the gold standard with 100% and 73% versus 76% and 47%, respectively. The breakpoint sequence was identical at diagnosis and relapse in all tested cases. There was a high degree of concordance between quantitative MRD results assessed using ETV6-RUNX1 and the highest Ig/TCR marker (Spearman's 0.899, P <.01) with differences >½ log-step in only 6% of patients. A high proportion of ETV6-RUNX1-positive ALL relapses (40%) in our cohort showed a poor response to induction treatment at relapse, and therefore had an indication for hematopoietic stem cell transplantation, demonstrating the need of accurate identification of this subgroup. Conclusions: ETV6-RUNX1 fusion sites are highly sensitive and reliable MRD markers. Our data confirm that they are unaffected by clonal evolution and selection during front-line and second-line chemotherapy in contrast to Ig/TCR rearrangements, which require several markers per patient to compensate for the observed loss of target clones. In future studies, the genomic ETV6-RUNX1 fusion can be used as single MRD marker.
CRIS-Team Scopus Importer:2019-05-17
Keywords: acute lymphoblastic leukemia; fusion gene; genomic breakpoint; minimal residual disease; response monitoring

High Sodium Diet - Role in Renal Sympathodepression - Rodionova, Kristina; Ditting, Tilmann; Fahrmeier, Franziska; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (FASEB JOURNAL, 2020)
CRIS-Team WoS Importer:2020-10-16

Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration - Wolf, Ines; Fan, Zheng; Rauh, Manfred; Seufert, Sebastian; Hore, Nirjhar; Buchfelder, Michael; Savaskan, Nic E.; Eyupoglu, Ilker Y. (Scientific Reports, 2014)
Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter–i.e. in non-cancerously transformed cells too–as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.
EVALuna2:18895

Histopathological proof of the pathogenicity of a rare GFAP mutation in a patient with flaccid paraparesis - Brackmann, Florian; Coras, Roland; Rössler, Karl; Kraus, Cornelia; Rompel, Oliver; Trollmann, Regina (Brain & Development, 2017)
Infantile Alexander disease is a rare progressive leukodystrophy caused by autosomal dominant mutations in the (GFAP) gene typically presenting with psychomotor retardation, progressive macrocephaly and refractory epilepsy. Neuroradiological hallmarks are extensive white matter lesions with frontal preponderance as well as signal intensity changes of basal ganglia and medulla oblongata with variable contrast enhancement. Here, we report an atypical manifestation in a 21-month-old boy presenting with flaccid paraparesis and areflexia. Cognitive, visual as well as fine motor skills and muscular strength of the upper extremities were appropriate for age. Weight and height as well as head circumference were within normal range. Clinical or electroencephalographic signs of seizures were absent. Cranial MRI demonstrated bifrontal cystic tumorous lesions with partial contrast rims, as well as space-occupying focal lesions of the caudate nuclei. Spinal MRI revealed swelling of the lumbar and cervical spinal cord. CSF and blood chemistry showed normal results. Histopathology of a subcortical lesion showed large amounts of Rosenthal fibers and protein droplets characteristic of Alexander disease. Sequencing detected a heterozygous mutation of the GFAP gene (c.205G > A; p.(Glu69Lys)) that has been reported before as probably pathogenetic in another case of lower spinal involvement. This well documented case draws attention to atypical spinal manifestations of Alexander disease and gives histopathological proof of the pathogenetic role of a rare GFAP mutation with marked spinal involvement.
EVALuna2:9396

HIV-1 fusion is blocked through binding of GB Virus C E2D peptides to the HIV-1 gp41 disulfide loop - Eißmann, Kristin; Müller, Sebastian; Sticht, Heinrich; Jung, Susan; Zou, Peng; Jiang, Shibo; Gross, Andrea; Eichler, Jutta; Fleckenstein, Bernhard; Reil, Heide (PLoS ONE, 2013)
A strategy for antiviral drug discovery is the elucidation and imitation of viral interference mechanisms. HIV-1 patients benefit from a coinfection with GB Virus C (GBV-C), since HIV-positive individuals with long-term GBV-C viraemia show better survival rates than HIV-1 patients without persisting GBV-C. A direct influence of GBV-C on HIV-1 replication has been shown in coinfection experiments. GBV-C is a human non-pathogenic member of the flaviviridae family that can replicate in T and B cells. Therefore, GBV-C shares partly the same ecological niche with HIV-1. In earlier work we have demonstrated that recombinant glycoprotein E2 of GBV-C and peptides derived from the E2 N-terminus interfere with HIV entry. In this study we investigated the underlying mechanism. Performing a virus-cell fusion assay and temperature-arrested HIV-infection kinetics, we provide evidence that the HIV-inhibitory E2 peptides interfere with late HIV-1 entry steps after the engagement of gp120 with CD4 receptor and coreceptor. Binding and competition experiments revealed that the N-terminal E2 peptides bind to the disulfide loop region of HIV-1 transmembrane protein gp41. In conjunction with computational analyses, we identified sequence similarities between the N-termini of GBV-C E2 and the HIV-1 glycoprotein gp120. This similarity appears to enable the GBV-C E2 N-terminus to interact with the HIV-1 gp41 disulfide loop, a crucial domain involved in the gp120-gp41 interface. Furthermore, the results of the present study provide initial proof of concept that peptides targeted to the gp41 disulfide loop are able to inhibit HIV fusion and should inspire the development of this new class of HIV-1 entry inhibitors.
EVALuna2:8190

Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa - De Rosa, Laura; Enzo, Elena; Zardi, Giulia; Bodemer, Christine; Magnoni, Cristina; Schneider, Holm; De Luca, Michele (Frontiers in Genetics, 2021)
Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene LAMB3 has been the first genetic skin disease successfully tackled by ex vivo gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of LAMB3-related JEB. Autologous clonogenic keratinocytes will be isolated from patients’ skin biopsies, genetically corrected with a gamma-retroviral vector (γRV) carrying the full-length human LAMB3 cDNA and plated onto a fibrin support (144cm2). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with LAMB3 mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses. Clinical Trial Registration: EudraCT Number: 2018-000261-36.
CRIS-Team Scopus Importer:2021-10-01
Keywords: cell and gene therapy; clinical trial; epidermal stem cell; epidermolysis bullosa; genodermatoses; skin

Homozygous Biallelic KRT5 Mutations in Epidermolysis Bullosa Simplex, Including a Complete Human Keratin 5 "Knock-Out", in Families with Extensive Consanguinity - Vahidnezhad, H.; Youssefian, L.; Daneshpazhooh, M.; Mahmoudi, H.; Kariminejad, A.; Fischer, J.; Christiansen, J.; Schneider, Holm; Guy, A.; Liu, L.; Mcgrath, J. A.; Has, C.; et al. (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-09-27

Homozygous familial hypercholesterolemia with severe involvement of the aortic valve—A sibling-controlled case study on the efficacy of lipoprotein apheresis - Galiano, Matthias; Hammersen, Johanna; Sauerstein, Katja; Blessing, Holger; Rümmele, Petra; Purbojo, Ariawan; Schöber, Martin; Moosmann, Julia; Raffelsbauer, Gunter; Heibges, Andreas; Klingel, Reinhard (Journal of Clinical Apheresis, 2020)
Background: Homozygous familial hypercholesterolemia (hoFH) can cause severe atherosclerotic cardiovascular disease (ASCVD) in early infancy. Diagnosis and initiation of effective lipid-lowering therapy (LLT) are recommended as early as possible to prevent ASCVD-related morbidity and mortality. Methods: The clinical courses of a pair of siblings with an identical hoFH genotype, who exhibited major similarities of their clinical phenotype were analyzed in a case-control fashion including the family. Results: The older sibling was diagnosed with hoFH at the age of 4. Untreated LDL-cholesterol (LDL-C) was 17 mmol/L (660 mg/dL). LLT including lipoprotein apheresis (LA) was initiated and has been successful for 8 years now. A reduction of estimated cholesterol burden by 74% was achieved by LA and combined drug therapy including statins and ezetimibe. The efficacy of escalation of drug therapy was limited because the underlying LDL receptor (LDLR) mutation in the family resulted in substantially reduced receptor function. Treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9)-antibodies failed. His younger brother died at the age of 2 years shortly after the hoFH diagnosis of the elder sibling. Postmortem examination revealed advanced aortic root atheroma and aortic valve stenosis. In the older sibling, aortic valve stenosis and insufficiency were treated at the age of 9 years with mechanical aortic valve replacement. Conclusions: LLT including LA should be initiated as early as possible following the diagnosis of hoFH with very high LDL-C levels. With the same genotype, the phenotype of hoFH can exhibit similar patterns but outcome is substantially related to treatment.
CRIS-Team Scopus Importer:2020-03-27
Keywords: aortic valve stenosis; children; familial hypercholesterolemia; LDL-cholesterol; lipoprotein apheresis; prevention

Horn of plenty: Value of the international registry for pediatric chronic myeloid leukemia - Suttorp, Meinolf; Metzler, Markus; Millot, Frederic (World Journal of Clinical Oncology, 2020)
Chronic myeloid leukemia (CML) in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors (TKIs) since the year 2000. A majority of pediatricians will encounter one or two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care. Knowledge of response to TKIs and of age-specific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements. Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience. The International Registry on Pediatric CML (IR-PCML) was founded at Poitiers/France almost 10 years ago. Since then, the number of collaboration centers and in parallel of registered patients continuously increased (> 550 patients as of December 2019). Ideally, from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML. In the sense of quality assurance, the registry can offer dissemination of knowledge on state-of-the-art diagnostics (including reference appraisal), optimal treatment approaches, and follow-up procedures within a network that is exerting its strength via participation. With continuous growth during the recent years, very rare subgroups of patients could be identified (e.g., CML diagnosed at age < 3 years, children presenting with specific problems at diagnosis or during course of treatment) which had not been described before. Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease, among themselves and with their caregivers and clinicians. Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.
CRIS-Team WoS Importer:2020-08-28

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? - Bosch, A.; Ott, Christian; Jung, Susan; Striepe, Kristina; Karg, M. V.; Kannenkeril, D.; Dienemann, T.; Schmieder, Roland (EUROPEAN HEART JOURNAL, 2018)
CRIS-Team WoS Importer:2019-03-15

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial - Bosch, Agnes; Ott, Christian; Jung, Susan; Striepe, Kristina; Karg, Marina V.; Kannenkeril, Dennis; Dienemann, Thomas; Schmieder, Roland (Cardiovascular Diabetology, 2019)
BackgroundEmpagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness.MethodsOur analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial (http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis.ResultsAs previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.612.1 vs 118.612.9mmHg, p<0.001), central pulse pressure (39.1 +/- 10.2 vs 41.9 +/- 10.7mmHg, p=0.027) forward (27.1 +/- 5.69 vs 28.7 +/- 6.23mmHg, p=0.031) as well as reflected wave amplitude (18.9 +/- 5.98 vs 20.3 +/- 5.97mmHg, p=0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta=-0.259, p=0.054), sex (beta=0.292, p=0.040) and change in systolic 24-h ambulatory blood pressure (beta=0.364, p=0.019), the change of hsCRP (beta=0.305, p=0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta=0.347, p=0.017) on arterial stiffness parameters was found.Conclusion Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms.
CRIS-Team WoS Importer:2019-04-18

How often do SmPCs Contain Contraindications and Special Warnings that are Specific for the Paediatric Population - Wimmer, Stefan; Rascher, Wolfgang; Neubert, Antje (Klinische Pädiatrie, 2019)
BACKGROUND: 3.2-3.8% of all medicine prescriptions for minor outpatients are off-label only because of the patients' age group. The younger, the more patients are affected by this issue. Only one fifth of the most commonly used medicines for newborns are licensed for this age group. The aim of this study is to analyse all German SmPCs whether they contain contraindications and warnings that specifically concern paediatric patients. METHODS: All available SmPCs were processed to search the sections Contraindications and Special warnings and precautions for information on paediatric age groups. Results were evaluated for differences between age groups, ATC classification and routes of application. RESULTS: 13547 SmPCs (22863 medicinal products) were evaluated. For 3603 (15.8%) medicinal products the SmPC contained contraindications for at least one paediatric age group. For 9687 (42.4%) medicinal products contraindications or warnings were found, including 2833 (12.4%) where all patients below 18 years were affected. Preterms were particularly affected (n=9581, 41.9%) as well as the ATC therapeutic subgroups contrast media (89.0%), cough and cold preparations (86.2%) and Corticosteroids (topical 88.2%, systemic 86.6%). Concerning liquids for oral use the proportion was higher than average (58.2%). CONCLUSION: It can be assumed that for most medicinal products the contraindications for paediatrics result from a lack of data and age specific formulations rather than from pharmacokinetic or -dynamic differences in paediatric patients. The EU Paediatric Regulation did not significantly stimulate the conduction of paediatric studies in off-patent medicines to this day.
EVALuna2:206642

How to administer near-infrared spectroscopy in critically ill neonates, infants, and children - Bruns, Nora; Moosmann, Julia; Münch, Frank; Dohna-Schwake, Christian; Wölfle, Joachim; Cesnjevar, Robert; Dittrich, Sven; Felderhoff-Müser, Ursula; Müller, Hanna (Journal of Visualized Experiments, 2020)
Near infrared spectroscopy (NIRS) calculates regional tissue oxygenation (rSO2) using the different absorption spectra of oxygenated and deoxygenated hemoglobin molecules. A probe placed on the skin emits light that is absorbed, scattered, and reflected by the underlying tissue. Detectors in the probe sense the amount of reflected light: this reflects the organ-specific ratio of oxygen supply and consumption-independent of pulsatile flow. Modern devices enable the simultaneous monitoring at different body sites. A rise or dip in the rSO2 curve visualizes changes in oxygen supply or demand before vital signs indicate them. The evolution of rSO2 values in relation to the starting point is more important for interpretation than are absolute values. A routine clinical application of NIRS is the surveillance of somatic and cerebral oxygenation during and after cardiac surgery. It is also administered in preterm infants at risk for necrotizing enterocolitis, newborns with hypoxic ischemic encephalopathy and a potential risk of impaired tissue oxygenation. In the future, NIRS could be increasingly used in multimodal neuromonitoring, or applied to monitor patients with other conditions (e.g., after resuscitation or traumatic brain injury).
CRIS-Team Scopus Importer:2020-09-18

Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia - Garcia-Garcia, Ana; De Diego, Rebeca Perez; Flores, Carlos; Rinchai, Darawan; Sole-Violan, Jordi; Deya-Martinez, Angela; Garcia-Solis, Blanca; Lorenzo-Salazar, Jose M.; Hernandez-Brito, Elisa; Lanz, Anna-Lisa; Moens, Leen; Bucciol, Giorgia; et al. (Journal of Experimental Medicine, 2023)
X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.
CRIS-Team WoS Importer:2023-04-21

Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H2S homeostasis - Kožich, Viktor; Schwahn, Bernd C.; Sokolová, Jitka; Křížková, Michaela; Ditroi, Tamas; Krijt, Jakub; Khalil, Youssef; Křížek, Tomáš; Vaculíková-Fantlová, Tereza; Stibůrková, Blanka; Mills, Philippa; Clayton, Peter; et al. (Redox Biology, 2022)
Regulation of H2S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H2S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H2S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H2S synthesis from accumulating homocysteine, which suggests a control of H2S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H2S homeostasis.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Cystathionine β-synthase; Cystathionine γ-lyase; Molybdenum cofactor; Persulfide dioxygenase; Sulfide:quinone oxidoreductase; Sulfite oxidase

Hybrid reflected-ultrasound computed tomography versus B-mode-ultrasound for muscle scoring in spinal muscular atrophy - Danko, Vera; Jüngert, Jörg M.; Schüssler, Stephanie; Bühler, Adrian; Klett, Daniel; Federle, Anna; Roos, Andreas; Lochmüller, Hanns; Neurath, Markus; Wölfle, Joachim; Trollmann, Regina; Waldner, Maximilian; et al. (Journal of Neuroimaging, 2023)
Background and Purpose: Novel light- and sound-based technologies like multispectral optoacoustic tomography (MSOT) with co-registered reflected-ultrasound computed tomography (RUCT) could add additional value to conventional ultrasound (US) for disease phenotyping in pediatric spinal muscular atrophy (SMA). The aim of this study was to investigate the quality of RUCT compared to US for qualitative and quantitative assessment of imaging neuromuscular disorders. Methods: Subanalyzing the MSOT SMA study, 288 RUCT and 276 US images from 10 SMA patients (mean age 9.0 ± 3.7) and 10 gender- and age-matched healthy volunteers (HV; mean age 8.7 ± 4.3) were analyzed for quantitative (grayscale levels [GSLs]) and qualitative (echogenicity, distribution pattern, Heckmatt scale, and muscle texture) muscle changes. RUCT and US measures were further correlated with clinical standard motor outcomes. Results: Quantitative agreement using GSLs revealed significantly higher GSLs in muscles of SMA patients compared to healthy muscles in both techniques (US mean GSL [SD] SMA vs. HV: 110.70 [27.8] vs. 68.85 [19.2], p <.0001; RUCT mean GSL [SD] SMA vs. HV: 91.81 [21.8] vs. 59.86 [8.2], p <.0001) with good correlation with motor outcome tests, respectively. Qualitative agreement between methods for muscle composition was excellent for differentiation of pathological versus healthy muscles, echogenicity, and distribution pattern, moderate for Heckmatt scale, and poor for muscle texture. Conclusions: The data suggest that RUCT may allow the assessment of basic qualitative and quantitative measures for muscular diseases with comparable results to conventional US.
CRIS-Team Scopus Importer:2023-01-20
Keywords: neuromuscular disorders; optoacoustics; photoacoustics; spinal muscular atrophy; ultrasound

Hybrid ultrasound and single wavelength optoacoustic imaging reveals muscle degeneration in peripheral artery disease - Träger, Anna P.; Günther, Josefine; Raming, Roman; Paulus, Lars-Philip; Lang, Werner; Meyer, Alexander; Kempf, Julius; Caranovic, Milenko; Li, Yi; Wagner, Alexandra; Tan, Lina; Danko, Vera; et al. (Photoacoustics, 2024)
Peripheral arterial disease (PAD) leads to chronic vascular occlusion and results in end organ damage in critically perfused limbs. There are currently no clinical methods available to determine the muscular damage induced by chronic mal-perfusion. This monocentric prospective cross-sectional study investigated n = 193 adults, healthy to severe PAD, in order to quantify the degree of calf muscle degeneration caused by PAD using a non-invasive hybrid ultrasound and single wavelength optoacoustic imaging (US/SWL-OAI) approach. While US provides morphologic information, SWL-OAI visualizes the absorption of pulsed laser light and the resulting sound waves from molecules undergoing thermoelastic expansion. US/SWL-OAI was compared to multispectral data, clinical disease severity, angiographic findings, phantom experiments, and histological examinations from calf muscle biopsies. We were able to show that synergistic use of US/SWL-OAI is most likely to map clinical degeneration of the muscle and progressive PAD.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Muscle degeneration; Muscle imaging; Optoacoustics; Peripheral artery disease; Photoacoustics

Hydrocortisone dosing in children with classic congenital adrenal hyperplasia: Results of the german/austrian registry - Hoyer-Kuhn, Heike; Huebner, Angela; Richter-Unruh, Anette; Bettendorf, Markus; Rohrer, Tilman; Kapelari, Klaus; Riedl, Stefan; Mohnike, Klaus; Dörr, Helmuth-Günther; Roehl, Friedrich Wilhelm; Fink, Katharina; Holl, Reinhard W.; et al. (Endocrine Connections, 2021)
Objective: Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry. Design: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. Methods: A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. Results: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean (lower-upper quartiles) daily HC dose (mg/m² body surface area) was 19.4 (18.9–19.8) for patients <3 months (n = 329), 15.0 (14.6–15.3) for age ≥3–12 months (n = 463), 14.0 (13.7–14.3) for age 1–5.9 years (n = 745), 14.2 (14.0–14.5) for age 6 years to puberty entry (n = 669), and 14.9 (14.6–15.2) during puberty to 18 years (n = 801). Fludrocortisone was administered in 74.1% of patients with a median daily dosage of 88.8 µg. Conclusion: Our analyses showed that still a high proportion of children are treated with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.
CRIS-Team Scopus Importer:2021-06-11
Keywords: CYP21A2; fludrocortisone; glucocorticoids; treatment

Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome - Voelkl, Simon; Rensing-Ehl, Anne; Allgäuer, Andrea; Schreiner, Elisabeth; Lorenz, Myriam Ricarda; Rohr, Jan; Klemann, Christian; Fuchs, Ilka; Schuster, Volker; Von Bueren, Andre O.; Naumann-Bartsch, Nora; Gambineri, Eleonora; et al. (Blood, 2016)
Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCR??(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.
EVALuna2:25746

Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma - Hübner, Hanna; Strick, Reiner; Wachter, David Lukas; Kehl, Sven; Strissel, Pamela; Schneider-Stock, Regine; Rascher, Wolfgang; Horn, L. C.; Beckmann, Matthias; Rübner, Matthias; Fahlbusch, F. B.; Hartner, Andrea (Journal of Experimental & Clinical Cancer Research, 2017)
BACKGROUND: Human placental development resembles tumorigenesis, due to the invasive and fusogenic potential of trophoblasts. However, these features are tightly controlled in trophoblasts. Disturbance of this spatial and temporal regulation is thought to contribute to the rare formation of choriocarcinomas. Promoter hypermethylation and loss of the tumor suppressor Retinoic acid receptor responder 1 (RARRES1) were shown to contribute to cancer progression. Our study investigated the epigenetic and transcriptional regulation of RARRES1 in healthy human placenta in comparison to choriocarcinoma cell lines and cases. METHODS: Three choriocarcinoma cell lines (Jeg-3, JAR and BeWo) were treated with three different retinoic acid derivates (Am580, Tazarotene and all-trans retinoic acid) and 5-aza-2'-deoxycytidine. We analyzed RARRES1 promoter methylation by pyrosequencing and performed realtime-PCR quantification to determine RARRES1 expression in placental tissue and trophoblastic cell lines. Additionally, RARRES1 was stained in healthy placentas and in biopsies of choriocarcinoma cases (n = 10) as well as the first trimester trophoblast cell line Swan71 by immunofluorescence and immunohistochemistry. RESULTS: In the choriocarcinoma cell lines, RARRES1 expression could not be induced by sole retinoic acid treatment. Stimulation with 5-aza-2'-deoxycytidine significantly induced RARRES1 expression, which then could be further increased with Am580, Tazarotene and all-trans retinoic acid. In comparison to healthy placenta, choriocarcinoma cell lines showed a hypermethylation of the RARRES1 promoter, which correlated with a reduced RARRES1 expression. In concordance, RARRES1 protein expression was lost in choriocarcinoma tissue. Additionally, in the trophoblastic cell line Swan71, we found a significant induction of RARRES1 expression with increased cell density, during mitosis and in syncytial knots. CONCLUSIONS: Our findings showed that RARRES1 expression is absent in choriocarcinoma due to promoter methylation. Based on our analysis, we hypothesize that RARRES1 might exert tumor suppressive functions in multiple cellular processes (e.g. cell cycle regulation, adhesion, invasion and apoptosis).
EVALuna2:33950

Hypohidrotic Ectodermal Dysplasia: Breastfeeding Complications Due to Impaired Breast Development - Wahlbuhl-Becker, Mandy; Faschingbauer, Florian; Beckmann, Matthias; Schneider, Holm (Geburtshilfe und Frauenheilkunde, 2017)
Background X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common form of ectodermal dysplasia, is caused by mutations in the gene EDA. While only affected men develop the full-blown clinical picture, females who are heterozygous for an EDA mutation often also show symptoms such as hypodontia, hypotrichosis and hypohidrosis. These women may also suffer from malformations of the mammary gland which represent not just a cosmetic problem but can limit their breastfeeding capability. This paper summarizes the findings of the first systematic study on the impact of hypohidrotic ectodermal dysplasia on breastfeeding. Patients Thirty-eight adult female members of the German-Swiss-Austrian ectodermal dysplasia patient support group participated in a structured interview; most of them also agreed to a photodocumentation of their mammary region. Thirty-one women carried mutations in EDA (Group A) and seven were affected by other forms of hypohidrotic ectodermal dysplasia (Group B). Results 39 % of the women of Group A reported that their breasts were of different size or entirely absent on one side. In Group B, 86 % of the women reported differently sized or even absent breasts; two of these women lacked both breasts entirely. Most women described their nipples as exceptionally flat. 10 % of the women of Group A had more than two nipples. The high percentage of deviations from the norm was confirmed in the photodocumentation. Both groups had few or no sebaceous glands of Montgomery in the areolar region. Around 80 % of interviewed women had children and had attempted to breastfeed their first child. 67 % of the mothers in Group A had had difficulty in breastfeeding their infants and generally attributed this difficulty to their flat nipples. All of the mothers in Group B reported difficulties in breastfeeding; 60 % had not been able to breastfeed their first child. Conclusion Mothers with hypohidrotic ectodermal dysplasia very often have difficulty in breastfeeding because of their impaired breast development. This causal relationship needs to be taken into account in lactation counseling.
EVALuna2:34219

Hypothalamic-Pituitary Axis Dysfunction after Whole Brain Radiotherapy - A Cohort Study - Gebauer, Judith; Mehta, Preena; Fahlbusch, Fabian; Schmid, Sebastian M.; Rades, Dirk; Janssen, Stefan (Anticancer Research, 2020)
BACKGROUND/AIM: Hypothalamic-pituitary (HT-P) dysfunction is one of the most common endocrine late effects following cranial radiotherapy. However, there are currently no specific data describing this complication in adult-onset cancer patients after whole brain radiotherapy (WBRT). The present cohort study aims to establish the prevalence of HT-P axis dysfunction in this group of patients. PATIENTS AND METHODS: Twenty-six cancer patients previously treated with WBRT (median follow-up=20.5 months) received standardized endocrine check-up focusing on HT-P function. RESULTS: In 50% of the patients, impaired hypothalamic-pituitary function was detected during follow-up. While functional loss of a single hormonal axis was evident in 34.6% of patients, 7.7% showed an impairment of multiple endocrine axes, and one patient developed adrenocorticotropic hormone deficiency. Hypothalamic-pituitary dysfunction did not directly correlate with the applied WBRT total doses. CONCLUSION: In our cohort, hypothalamic-pituitary dysfunction appeared to be common after WBRT and was diagnosed as early as 6 months following radiation. This finding highlights the need for routine endocrine follow-up even in patients with limited life expectancy.
CRIS-Team Scopus Importer:2020-10-16
Keywords: cancer survivor; endocrine late effects; hypothalamic-pituitary dysfunction; Whole brain radiotherapy

Hypoxia in A Patient with Anti-p200 Pemphigoid under Combined Dapsone and Pantoprazole Treatment - Lang, Sebastian; Saenger, Philipp Wilhelm; Kocina, Sandra; Von Loeffelholz, Christian (Biomedicines, 2022)
A 70-year-old male patient was admitted to our dermatology outpatient clinic with newly developed personality changes and signs of hypoxemia. His anti-p200 Pemphigoid was treated with Dapsone for a few weeks. Due to generalized tonic-clonic seizure with a subsequent Glasgow Coma Scale of 5 points and a peripheral oxygen saturation not exceeding 88% under conditions of high-flow nasal cannula, he was intubated by the emergency team and transferred to the intensive care unit. Comprehensive tests were performed, but Dapsone-induced methemoglobinemia remained the exclusive explanation for the observed scenario, although arterial MetHb analysis showed a peak value of only 6%. The patient recovered shortly after repeated infusions of Methylene blue and Ascorbate, and cessation of Dapsone. We provide an overview of the pathophysiology, diagnostic procedures, and possible explanations for this case of Dapsone-induced methaemoglobinaemia. In conclusion, our case report provides evidence that even mild chronic methemglobinemia can induce severe clinical symptoms.
CRIS-Team Scopus Importer:2022-11-25
Keywords: CYP2C19; CYP2C9; G6PD-deficiency; hemolysis; NAFLD; proton pump inhibitors; sepsis

Hypoxia inducible factor stabilization improves defective ischemia-induced angiogenesis in a rodent model of chronic kidney disease - Schellinger, Isabel Nahal; Cordasic, Nada; Panesar, Julian; Buchholz, Björn; Jacobi, Johannes; Hartner, Andrea; Klanke, Bernd; Jakubiczka-Smorag, Joanna; Burzlaff, Nicolai; Heinze, Eva; Warnecke, Christina; Raaz, Uwe; et al. (Kidney International, 2017)
Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo: carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes (Vegf, Vegf-r1, Vegf-r2, Ho-1) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.
EVALuna2:3925
Keywords: cardiovascular disease; chronic kidney disease; hypoxia

Hypoxia Potentiates LPS-Mediated Cytotoxicity of BV2 Microglial Cells In Vitro by Synergistic Effects on Glial Cytokine and Nitric Oxide System - Frey, Daniel; Jung, Susan; Brackmann, Florian; Richter-Kraus, Mandy; Trollmann, Regina (Neuropediatrics, 2015)
Microglial activation due to a variety of stimuli induces secretion of neurotoxic substances including inflammatory cytokines and nitric oxide (NO). Clinical studies indicate a cross-link between inflammatory and hypoxia-regulated pathways suggesting that bacterial infections markedly sensitize the immature brain to hypoxic injury.The impact of inflammation and hypoxia on interleukin (IL)-1?, IL-6, tumor necrosis factor ? (TNF-?), and NO secretion and microglia-induced cytotoxicity was investigated exposing BV2 cells to lipopolysaccharides (LPS) and hypoxia (1% O2). Cytotoxicity, NO, and cytokine release was quantified by MTS and Griess assays and by enzyme-linked immunosorbent assays, respectively.LPS exposure of BV2 cells induced a significant, persistent production of NO, IL-1?, IL-6, and TNF-?. Even after LPS removal, ongoing NO and cytokine secretion was observed. Hypoxia mediated exclusively a significant, short-term IL-1? increase, but enhanced LPS-induced cytokine and NO secretion significantly. In addition, LPS-induced supernatants exhibited a stronger cytotoxic effect in glial and neuronal cells than LPS exposition (p < 0.001). Hypoxia potentiated LPS-induced cytotoxicity.Present data prove that LPS-induced soluble factors rather than LPS exposure mediate microglial toxicity under conditions of hypoxia in vitro. Apart from potential protective effects of the hypoxia-inducible transcription factor (HIF)-1? system, activation of proinflammatory pathways may markedly sensitize microglial cells to promote hypoxia-induced injuries of the developing brain.
EVALuna2:18925

Idiopathic Mast Cell Activation Syndrome With Associated Salicylate Intolerance - Rechenauer, Tobias; Raithel, Martin; Goetze, Thomas; Siebenlist, Gregor; Rueckel, Aline; Baenkler, Hanns-Wolf; Hartmann, Arndt; Haller, Florian; Hoerning, Andre (Frontiers in Pediatrics, 2018)
Idiopathic mast cell activation syndrome can be a rare cause for chronic abdominal pain in children. It remains a diagnosis by exclusion that can be particularly challenging due to the vast variety of possible clinical manifestations. We present a 13-year-old boy who suffered from a multitude of unspecific complaints over a long period of time. In this case, an assessment of mast cell-derived metabolites and immunohistochemical analysis of bioptic specimen was worthwhile. After ruling out, primary (oncologic) and secondary causes for mast cell activation, pharmacologic treatment adapted to the patient's salicylate intolerance resulted in a major relief of symptoms.
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IFN-α/IFN-λ responses to respiratory viruses in paediatric asthma - Bergauer, Annika; Sopel, Nina; Kross, 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, 2016)
We analysed the influence of rhinovirus (RV) in nasopharyngeal fluid (NPF) on type I and III interferon (IFN) responses (e.g. IFN-? and IFN -: ?) and their signal transduction, at baseline and during disease exacerbation, in cohorts of pre-school children with and without asthma.At the time of recruitment into the Europe-wide study PreDicta, and during symptoms, NPF was collected and the local RV colonisation was analysed. Peripheral blood mononuclear cells (PBMCs) were challenged in vitro with RV or not. RNA was analysed by quantitative real-time PCR and gene arrays. Serum was analysed with ELISA for IFNs and C-reactive protein.We found that PBMCs from asthmatic children infected in vitro with the RV1b serotype upregulated MYD88, IRF1, STAT1 and STAT2 mRNA, whereas MYD88, IRF1, STAT1 and IRF9 were predominantly induced in control children. Moreover, during symptomatic visits because of disease exacerbation associated with RV detection in NPF, IFN-? production was found increased, while IFN-? secretion was already induced by RV in asthmatic children at baseline.During asthma exacerbations associated with RV, asthmatic children can induce IFN-? secretion, indicating a hyperactive immune response to repeated respiratory virus infection.
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IFN-α/IFN-λ responses to respiratory viruses in paediatric asthma - Bergauer, Annika; Sopel, Nina; Kross, 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)
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IGF-I in cord blood is predictive of final height in monozygotic twins with intra-twin birth weight differences - Kasner, Charlotte; Schulte, Sandra; Schreiner, Felix; Fimmers, Rolf; Stoffel-Wagner, Birgit; Bartmann, Peter; Wölfle, Joachim; Gohlke, Bettina (Clinical Endocrinology, 2020)
Objective: Adverse prenatal conditions can exert a long-lasting impact on growth up to final height (FH). Due to different prenatal nutrient availability, monozygotic twin pairs with discordant birth weight (bw) provide an excellent model to examine the impact of genes and environment and to analyse the predictive value of bw, birth length (bl) and cord blood (cb) concentration of IGF-I on FH. Patients and Methods: Twenty eight monozygotic twin pairs with intra-twin bw-/bl-differences were studied at birth and longitudinally until FH. Intra-twin bw difference >1 SDS was defined “discordant” (n = 10 pairs). IGF-I was analysed in cord blood in all twins. Intra-twin differences (∆) in bw, bl and cord blood IGF-I were correlated with ∆FH. Results: Throughout growth and up until FH intra-twin length/height differences remained for all but two (26/28) twins and for all (10/10) discordant twins. In the discordant group, a highly significant intra-twin difference for FH-SDS was found with a mean intra-twin Δheight- SDS of 1.23 (range, 0.29-2.34). This corresponds to a mean Δintra-twin difference at FH of 7.9 cm (3.1 inch; range, 2-15 cm [0.79-5.9 inch]). Correlation coefficients were calculated to identify factors predicting FH: ∆bw (r =.678; P =.0005), ∆bl (r =.333; P =.0002) and ∆IGF-I in cb (r =.418; P =.0023). Interaction terms showed that IGF-I is an additional factor to the auxological data, leading to an improvement of the ∆FH modelling. Conclusion: Prenatal environment leading to bw-/bl- and cbIGF-I differences in monozygotic twins had a long-lasting impact on growth until FH. Both, anthropometric data at birth and cbIGF-I are predictive of FH.
CRIS-Team Scopus Importer:2020-06-19
Keywords: birth length; birth weight; final height; foetal programming; growth; IGF-I

IL-33/ST2 immune responses to respiratory bacteria in pediatric asthma - Hentschke, Isabell; Graser, Anna; Melichar, Volker O.; Kiefer, Alexander; Zimmermann, Theodor; Kross, Bettina; Haag, Patricia; Xepapadaki, Paraskevi; Papadopoulos, Nikolaos G.; Bogdan, Christian; Finotto, Susetta (Scientific Reports, 2017)
Here we investigated the relationship between local bacterial colonization and anti-bacterial immune responses in pre-school asthmatic and control children within the EU-wide study PreDicta. In this cohort of pre-school asthmatic children, nasopharyngeal colonization with Gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis was found to be associated with the highest interferon beta (IFN?) and IL-33 levels in the nasal pharyngeal fluids (NPF). IL33R-ST2 was found induced in the blood of asthmatic children with additional Gram + bacteria in the nasopharynx (Gr+/-). Furthermore, asthmatic children had more episodes of infection that required antibiotic therapy than the control group. Treatment with antibiotics associated with reduced ST2 in blood cells of both asthmatic and control children and reduced IL-33 levels in the airways of asthmatic children. In the absence of Staphylococcus (S.) aureus in NPF, antibiotic therapy associated with decreased IL-33 levels in the NPF and lower ST2 values in the blood of control children but not of asthmatic children. These data suggest that, in asthmatic children, Gram- bacteria, which persist after antibiotic therapy, contributes to IL-33 locally and associated with Gr + bacteria colonization in the airways, inhibited IFN-? and in the absence of Staphylococcus (S.) aureus, induced ST2 bearing cells in their blood.
EVALuna2:7728

IL-6 activated integrated BATF/IRF4 functions in lymphocytes are T-bet-independent and reversed by subcutaneous immunotherapy - Mousset, Stephanie; Koch, Sonja; Mousset, Stephanie; Graser, Anna; Reppert, Sarah; Uebel, Caroline; Reinhardt, Cornelia; Zimmermann, Theodor; Rieker, Ralf; Lehr, Hans A.; Finotto, Susetta (Scientific Reports, 2013)
IL-6 plays a central role in supporting pathological TH2 and TH17 cell development and inhibiting the protective T regulatory cells in allergic asthma. TH17 cells have been demonstrated to regulate allergic asthma in general and T-bet-deficiency-induced asthma in particular. Here we found an inverse correlation between T-bet and Il-6 mRNA expression in asthmatic children. Moreover, experimental subcutaneous immunotherapy (SIT) in T-bet((-/-)) mice inhibited IL-6, IL-21R and lung TH17 cells in a setting of asthma. Finally, local delivery of an anti-IL-6R antibody in T-bet((-/-)) mice resulted in the resolution of this allergic trait. Noteworthy, BATF, crucial for the immunoglobulin-class-switch and TH2,TH17 development, was found down-regulated in the lungs of T-bet((-/-)) mice after SIT and after treatment with anti-IL-6R antibody, indicating a critical role of IL-6 in controlling BATF/IRF4 integrated functions in TH2, TH17 cells and B cells also in a T-bet independent fashion in allergic asthma.

ILCOR 2022: notfallpharmakologische Implikationen - Dormann, Harald; Ittner, Karl Peter; Neubert, Antje; Böttiger, Bernd W. (Notarzt, 2023)
CRIS-Team Scopus Importer:2023-06-23

Immediate and Sustained Effect of Neonatal Teaching in a Perinatal Setting in Urban Laos - Hoehn, Thomas; Genet, Petra; Balan, Percy; Schramm, Dirk; Verde, Pablo Emilio; Phengsavanh, Alongkone (American Journal of Perinatology, 2020)
OBJECTIVE: This study aimed to quantify knowledge on neonatal topics among obstetricians and pediatricians participating in a perinatal teaching program aimed at reducing neonatal mortality in Laos. STUDY DESIGN: Obstetricians and pediatricians from Vientiane and the surrounding areas participated in a 1-week teaching program in obstetric and neonatal topics and responded to pre- and posttests questionnaires to quantify their knowledge. RESULTS: Although questions were predominantly related to neonatal topics, obstetricians performed significantly better than pediatricians during the pretest. Both groups increased their knowledge significantly as quantified by the results of the posttest. CONCLUSION: The teaching program was effective in improving knowledge on perinatal mortality related topics of the participants. These results may be related to the fact that most of the obstetricians had participated in a structured teaching program previously, whereas the pediatricians did not. We thus speculate that there is a sustained effect of even a 1-week teaching program in neonatology even several years after the initial teaching.
CRIS-Team Scopus Importer:2020-03-17

Immunoregulatory role of NFAT-interacting protein (NIP) 45 in adaptive and innate immune responses in allergic asthma - Koch, Sonja; Maeding, N.; Karwot, R.; Mirzakhani, H.; Springel, R.; Mittler, S.; Zimmermann, Theodor; Melichar, V. O.; Knipfer, Lisa; Wirtz, Stefan; Weiss, S. T. (2017)
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Impact of a computerized physician order entry system on medication safety in pediatrics-The AVOID study - Wimmer, Stefan; Toni, Irmgard; Botzenhardt, Sebastian; Trollmann, Regina; Rascher, Wolfgang; Neubert, Antje (Pharmacology Research and Perspectives, 2023)
BACKGROUND: One of the most critical steps in the medication process on pediatric wards is the medical prescription. This study aims to investigate the impact of a computerized physician order entry (CPOE) system on Adverse Drug Events (ADEs) and potentially harmful ADEs (pot ADEs) in comparison with paper-based documentation in a general pediatric ward at a German University hospital. METHODS: A prospective pre-post study was conducted. All patients aged 17 years or younger were observed during the study periods (5 months pre- and postimplementation). Issues Regarding Medication (IRM) were identified by intensive chart review. Events were assessed regarding causality (WHO), severity (WHO; Dean & Barber for MEs), and preventability (Shumock) and classified into (pot) ADEs, (pot) Medication errors (ME), Adverse drug Reactions (ADR), and Other incidents (OI) accordingly. RESULTS: Total of 333 patients with medication were included in the paper-based prescribing cohort (phase I) and 320 patients with medication in the electronic prescribing cohort (phase II). In each cohort, patients received a median number of four different drugs (IQR 5 and IQR 4). A total of 3966 IRM was observed. During the hospitalization, 2.7% (n = 9) patients in phase I and 2.8% (n = 9) in phase II experienced an ADE. Potentially harmful MEs were less often observed in the cohort with electronic prescribing (n = 228 vs. n = 562). The mean number per patient significantly decreased from 1.69 to 0.71 (p < .01). CONCLUSION: The implementation of a CPOE system resulted in a reduction of issues regarding medication, particularly MEs with the potential to harm patients decreased significantly.
CRIS-Team Scopus Importer:2023-06-02
Keywords: adverse drug event; adverse drug reaction; computerized physician order entry; electronic prescribing; medication error; medication safety; pediatrics

IMPACT OF BLOOD PRESSURE AND AGEING ON RETINAL NEURODEGENERATION ASSESSED BY SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY - Jung, Susan; Bosch, Agnes; Kohler, N.; Ott, Christian; Kannenkeril, D.; Dienemann, T.; Harazny, J. M.; Michelson, Georg; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Impact of Newborn Screening on Adult Height in Patients With Congenital Adrenal Hyperplasia (CAH) - Hoyer-Kuhn, Heike; Eckert, Alexander J.; Binder, Gerhard; Bonfig, Walter; Dübbers, Angelika; Riedl, Stefan; Wölfle, Joachim; Dörr, Helmuth-Günther; Holl, Reinhard W. (Journal of Clinical Endocrinology and Metabolism, 2023)
CONTEXT: Treatment of children with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is challenging. Linear growth and adult height are compromised according to recent publications. However, most of these data were obtained in the era before CAH newborn screening. DESIGN: Body height of patients with classical CAH diagnosed before and after the establishment of newborn screening were analyzed retrospectively. PATIENTS AND METHODS: We identified 600 patients with classical CAH (227 male) with data on near-adult height (NAH), target height (TH), and information on newborn screening from the electronic German CAH registry (German Society for Paediatric Endocrinology and Diabetology). Newborn screening was performed in 101 (16.8%) patients. All patients received hydrocortisone with or without fludrocortisone.To assess the effects of newborn screening, a linear regression model adjusted/stratified for sex and phenotype was used (SAS 9.4). RESULTS: TH corrected NAH (mean; 95% confidence interval) was closer to 0 in patients with CAH and newborn screening [-0.25 standard deviation score (SDS); -0.44 to -0.06] than in patients without newborn screening (-0.44 SDS; -0.52 to -0.36) (P = .069). Screening had no effect on NAH in female patients. In male patients, NAH was significantly better (P = .033) with screening than without screening. After stratifying for CAH phenotype, screening did not affect the NAH of patients with salt-wasting CAH. Patients with simple-virilizing CAH had a significantly better cNAH (P = .034) with screening (0.15 SDS; -0.28-0.59) than without screening (-0.35 SDS; -0.52 to -0.18). CONCLUSIONS: Our data suggest that newborn screening might be associated with improved NAH in male CAH patients and in patients with simple-virilizing CAH.
CRIS-Team Scopus Importer:2023-11-03
Keywords: congenital adrenal hyperplasia; CYP21A2; near adult height; newborn screening

Impact of premature birth on cardiopulmonary function in later life - Weigelt, Annika; Bleck, Steffen; Hübner, Matthias; Rottermann, Kathrin; Wällisch, Wolfgang; Morhart, Patrick; Abu-Tair, Tariq; Dittrich, Sven; Schöffl, Isabelle (European Journal of Pediatrics, 2023)
Pulmonary function is reduced in children after preterm birth. The variety of subgroups ranges from early to late preterm births. Limitations in pulmonary function can be observed even after late preterm birth without signs of bronchopulmonary dysplasia and/or history of mechanical ventilation. Whether this reduction in lung function is reflected in the cardiopulmonary capacity of these children is unclear. This study aims to investigate the impact of moderate to late premature birth on cardiopulmonary function. Cardiopulmonary exercise testing on a treadmill was performed by 33 former preterm infants between 8 and 10 years of age who were born between 32 + 0 and 36 + 6 weeks of gestation and compared with a control group of 19 children born in term of comparable age and sex. The former preterm children achieved comparable results to the term-born controls with respect to most of the cardiopulmonary exercise parameters (V˙O2peak43.9±6.6mlkgminminvs.41.9±8.8mlkg/min) . The only differences were in a slightly higher oxygen uptake efficiency slope (OUESof1.6±0.4vs1.4±0.4) and higher peak minute ventilation V˙Epeakof55.2±11.3ml/minvs.49.1ml±8.8/min) in the group of children born preterm. With respect to heart rate recovery (-35.3±13.8bpmvs.-37.2bpm±14.0after1min) and breathing efficiency (V˙E/V˙CO2of35.9±4.1vs34.0±4.6) , there were no significant differences. Conclusion: Children born preterm did not show limitations in cardiopulmonary function in comparison with matched controls. What is Known: • Preterm birth is associated with reduced pulmonary function in later life, this is also true for former late preterms. • As a consequence of being born premature, the lungs have not finished their important embryological development. Cardiopulmonary fitness is an important parameter for overall mortality and morbidity in children and adults and a good pulmonary function is therefore paramount. What is New: • Children born prematurely were comparable to an age- and sex-matched control group with regards to almost all cardiopulmonary exercise variables. • A significantly higher OUES, a surrogate parameter for VO 2 peak was found for the group of former preterm children, most likely reflecting on more physical exercise in this group. Importantly, there were no signs of impaired cardiopulmonary function in the group of former preterm children.
CRIS-Team Scopus Importer:2023-05-19
Keywords: Cardiopulmonary exercise testing; Habitual exercise; Premature birth; Sports

IMPAIRED GENE-EXPRESSION AND EPIGENETIC REGULATION OF RETINOIC ACID RECEPTOR RESPONDER 1 IN PREECLAMPSIA AND CHORIOCARCINOMA - Hübner, Hanna; Fahlbusch, Fabian B.; Strissel, Pamela; Strick, Reiner; Wachter, David; Beckmann, Matthias; Rübner, Matthias (2016)
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Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction - Menendez-Castro, Carlos; Toka, Okan; Fahlbusch, Fabian; Cordasic, Nada; Wachtveitl, Rainer; Hilgers, Karl Friedrich; Rascher, Wolfgang; Hartner, Andrea (Pediatric Research, 2014)
Intrauterine growth restriction (IUGR) is an important risk factor for cardiovascular disease. Previous studies revealed altered myocardial matrix composition after IUGR. We hypothesized that IUGR is accompanied by compromised myocardial performance independently from arterial hypertension.IUGR was induced in Wistar rats by maternal protein restriction, and hearts of male offspring were studied using echocardiography, immunohistochemistry, real-time PCR, and western blot analysis.At day 70 of life, in the absence of arterial hypertension (mean arterial blood pressure: 101.3 ± 7.1 mmHg in IUGR vs. 105.3 ± 4.6 mmHg in controls, not significant (NS)), echocardiography showed a reduced contractility (ejection fraction: 65.4 ± 1.8% in IUGR vs. 82.2 ± 1.5% in controls, P < 0.001) of a more distensible myocardium in IUGR rats. Altered expression patterns of myosin chains and titin isoforms and increased expression levels of atrial natriuretic peptide, Na/K-ATPase, and ?-adrenergic receptor 1 were detected. A higher number of cardiac fibroblasts and vascular cross-sections were observed in IUGR rats, accompanied by elevated expression of hypoxia inducible factor 1 target genes, such as vascular endothelial growth factor and its receptors.We observed a blood pressure-independent impairment of myocardial function after IUGR, which possibly favors cardiovascular disease later in life. Some IUGR-induced myocardial changes (e.g., sarcomeric components) may partly explain the compromised cardiac performance, whereas others (e.g., elevated vascular supply) reflect compensatory mechanisms.
EVALuna2:3704

Impaired Neovascularization and Reduced Capillary Supply in the Malignant vs. Non-malignant Course of Experimental Renovascular Hypertension - Jagusch, Lisa Gudrun; Cordasic, Nada; Amann, Kerstin Ute; Veelken, Roland; Jacobi, Johannes; Hilgers, Karl Friedrich; Hartner, Andrea (Frontiers in Physiology, 2016)
Malignant hypertension develops in some cases of hypertension but not in others. We hypothesized that an impaired neovascularization and a reduced capillary supply characterizes the malignant course of experimental hypertension. Two-kidney, one-clip renovascular hypertension was induced in rats; controls (sham) were sham operated. To distinguish malignant hypertension from non-malignant hypertension, we considered two factors: weight loss, and the number of typical vascular lesions (onion skin lesions and fibrinoid necroses) per kidney section of the nonclipped kidney. Animals in the upper half for both criteria were defined as malignant hypertensives. After 5 weeks, mean arterial blood pressure was elevated to the same degree in malignant hypertension and non-malignant hypertension whereas plasma renin and aldosterone were significantly higher in malignant hypertensives. The expression of plasminogen activator inhibitor-1 was elevated (up to 14-fold) in non-malignant but significantly more increased (up to 36-fold) in malignant hypertensive rats, compared to sham. As a bioassay for neovascularization, the area of granulation tissue ingrowth in polyvinyl discs (implanted subcutaneously) was reduced in malignant hypertension compared to non-malignant hypertension and sham, while there was no difference between non-malignant hypertension and sham. The number of renal and left ventricular capillaries was significantly lower in malignant hypertension compared to non-malignant hypertension, as was the number of proliferating endothelial cells. We conclude that an impaired neovascularization and capillarization occurs in malignant renovascular hypertension but not in the non-malignant course of the disease despite comparable blood pressure levels. This might contribute to the unique vascular lesions and progressive target organ damage observed in malignant hypertension.
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Important aspects of medication safety in pediatric emergencies Wichtige Aspekte zur Medikamentensicherheit bei Kindernotfällen - Kaufmann, Jost; Neubert, Antje; Hoffmann, Florian; Jung, Philipp (Monatsschrift Kinderheilkunde, 2021)
Medication errors represent a threat to patients of all ages. Errors occur more frequently with children than with adults because age group-specific features must be considered, an individual calculation of the dose is necessary and the emergency team cannot be familiar with the dose to be administered. Especially in emergency situations, it is necessary to administer drugs with the high potential for life-threatening complications within a short period of time. Even the wrong placing of a comma when calculating a dose of epinephrine leads to a life-threatening tenfold error. Preclinically, it is often impossible to provide specialized pediatric teams. This CME article analyses the process of drug administration with the typical pitfalls, presents successful interventions and the recommendations of the S2k guidelines on medication safety in pediatric emergencies coordinated by the Association of the Scientific Medical Societies in Germany (AWMF).
CRIS-Team Scopus Importer:2021-10-22
Keywords: Medication errors; Off-label use; Patient safety; Safety management; Weight estimation

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study - Pechmann, Astrid; Behrens, Max; Dörnbrack, Katharina; Tassoni, Adrian; Wenzel, Franziska; Stein, Sabine; Vogt, Sibylle; Zöller, Daniela; Bernert, Günther; Hagenacker, Tim; Schara-Schmidt, Ulrike; Walter, Maggie C.; et al. (Orphanet Journal of Rare Diseases, 2022)
Background: The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods: SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results: Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion: Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Later-onset; Nusinersen; Sitter; SMArtCARE; Spinal muscular atrophy

Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study - Pechmann, Astrid; Behrens, Max; Dörnbrack, Katharina; Tassoni, Adrian; Wenzel, Franziska; Stein, Sabine; Vogt, Sibylle; Zöller, Daniela; Bernert, Günther; Hagenacker, Tim; Schara-Schmidt, Ulrike; Walter, Maggie C.; et al. (Journal of Neuromuscular Diseases, 2023)
BACKGROUND AND OBJECTIVES: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. METHODS: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. RESULTS: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. CONCLUSION: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.
CRIS-Team Scopus Importer:2023-01-20
Keywords: ambulant; nusinersen; SMArtCARE; Spinal muscular atrophy; walker

Improving the Safety of Drug Therapy through a Hospital-Internal Reporting System - Analysis of Reports over 15 Years from a Children's Hospital - Toni, Irmgard; Neubert, Antje; Rascher, Wolfgang (Klinische Pädiatrie, 2020)
BackgroundPatient safety is a major challenge and has high priority in the inpatient care. Notably, drug therapy is considered critical after surgery. The medication process is particularly difficult and problematic in newborns and children. Method In a retrospective analysis, hospital-internal spontaneous reports on Drug-related Problems (DRP) from a children's hospital were analysed, which were reported between 2000 and 2014. Results229 spontaneous reports on DRP were considered for analysis. 72.5% of these were due to a Medication Error. Nearly half of the DRP occurred during drug dispensing (44.5%), followed by problems during administration (38.0%) and prescribing (11.4%). 61.4% of Medication Errors were dispensing errors (esp. confusion of patients, wrong dose). Almost all Other Incidents happened during drug administration (mainly extravasations). 40.6% of DRP reports were associated with clinically relevant patient harm and occurred particularly during drug administration. ConclusionThese results show that drug therapy in paediatrics is a complex and hazardous process. The system of hospital-internal spontaneous reports has led to regular training and raising awareness of the employees for critical situations. In addition, it fosters a safety culture to report mistakes. Spontaneous reporting is suitable for increasing the safety of drug therapy in paediatrics.
CRIS-Team WoS Importer:2020-09-11

Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie - Shai, Sonu; Perez-Becker, Ruy; Andres, Oliver; Bakhtiar, Shahrzad; Bauman, Ulrich; von Bernuth, Horst; Classen, Carl Friedrich; Dückers, Gregor; El-Helou, Sabine M.; Gangfuß, Andrea; Ghosh, Sujal; Grimbacher, Bodo; et al. (Journal of Clinical Immunology, 2020)
Purpose: Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. Methods: The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). Results: Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. Conclusions: SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
CRIS-Team Scopus Importer:2020-06-02
Keywords: SCID surveillance newborn screening paediatric incidence

Incidence of Secondary Malignancies After TBI/VP16 Conditioning for Childhood All - Results of the Prospective ALL-SCT-BFM-2003 Trial - Eichinger, Anna; Glogova, Evgenia; Beier, Rita; Guengoer, Tayfun; Stachel, Daniel; Stachel, Daniel; Lang, Peter; Sauer, Martin; Strahm, Brigitte; Schulz, Ansgar; Gruhn, Bernd; Wawer, Angela; et al. (BONE MARROW TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2021-01-22

Incidence of subsequent malignancies after total body irradiation-based allogeneic HSCT in children with ALL - long-term follow-up from the prospective ALL-SCT 2003 trial - Eichinger, Anna; Poetschger, Ulrike; Glogova, Evgenia; Bader, Peter; Basu, Oliver; Beier, Rita; Burkhardt, Birgit; Classen, Carl-Friedrich; Claviez, Alexander; Corbacioglu, Selim; Deubzer, Hedwig E.; Greil, Johann; et al. (Leukemia, 2022)
Total body irradiation (TBI)-based conditioning is associated with superior leukemia-free survival in children with ALL undergoing HSCT. However, the risk for subsequent malignant neoplasms (SMN) remains a significant concern. We analyzed 705 pediatric patients enrolled in the prospective ALL-SCT-BFM-2003 trial and its subsequent registry. Patients >2 years received conditioning with TBI 12 Gy/etoposide (n = 558) and children <= 2 years of age or with contraindications for TBI received busulfan/cyclophosphamide/etoposide (n = 110). The 5- and 10-year cumulative incidence of SMN was 0.02 +/- 0.01 and 0.13 +/- 0.03, respectively. In total, 39 SMN (34 solid tumors, 5 MDS/AML) were diagnosed in 33 patients at a median of 5.8 years (1.7-13.4), exclusively in the TBI group. Of 33 affected patients, 21 (64%) are alive at a median follow-up of 5.1 years (0-9.9) after diagnosis of their first SMN. In univariate analysis, neither age at HSCT, donor type, acute GVHD, chronic GVHD, nor CMV constituted a significant risk factor for SMN. The only significant risk factor was TBI versus non-TBI based conditioning. This analysis confirms and quantifies the increased risk of SMN in children with ALL after conditioning with TBI. Future strategies to avoid TBI will need careful tailoring within prospective, controlled studies to prevent unfavorable outcomes.
CRIS-Team WoS Importer:2022-09-23

Increased expression of nuclear factor of activated T cells 1 drives IL-9-mediated allergic asthma - Koch, Sonja; Graser, Anna; Mirzakhani, Hooman; Zimmermann, Theodor; Melichar, Volker O.; Woelfel, Marco; Croteau-Chonka, Damien C.; Raby, Benjamin A.; Weiss, Scott T.; Finotto, Susetta (Journal of Allergy and Clinical Immunology, 2016)
EVALuna2:25981

Increased Rat Placental Fatty Acid, but Decreased Amino Acid and Glucose Transporters Potentially Modify Intrauterine Programming - Nuesken, Eva; Gellhaus, Alexandra; Kuehnel, Elisabeth; Swoboda, Isabelle; Wohlfarth, Maria; Vohlen, Christina; Schneider, Holm; Doetsch, Joerg; Nuesken, Kai-Dietrich (Journal of Cellular Biochemistry, 2016)
Regulation of placental nutrient transport significantly affects fetal development and may modify intrauterine growth restriction (IUGR) and fetal programming. We hypothesized that placental nutrient transporters are differentially affected both by utero-placental insufficiency and prenatal surgical stress. Pregnant rats underwent bilateral uterine artery and vein ligation (LIG), sham operation (SOP) or no operation (controls, C) on gestational day E19. Placentas were obtained by caesarean section 4 h (LIG, n=20 placentas; SOP, n=24; C, n=12), 24 h (LIG, n=28; SOP, n=20; C, n=12) and 72 h (LIG, n=20; SOP, n=20; C, n=24) after surgery. Gene and protein expression of placental nutrient transporters for fatty acids (h-FABP, CD36), amino acids (SNAT1, SNAT2) and glucose (GLUT-1, Connexin 26) were examined by qRT-PCR, western blot and immunohistochemistry. Interestingly, the mean protein expression of h-FABP was doubled in placentas of LIG and SOP animals 4, 24 (SOP significant) and 72 h (SOP significant) after surgery. CD36 protein was significantly increased in LIG after 72 h. SNAT1 and SNAT2 protein and gene expressions were significantly reduced in LIG and SOP after 24 h. Further significantly reduced proteins were GLUT-1 in LIG (4 h, 72 h) and SOP (24 h), and Connexin 26 in LIG (72 h). In conclusion, placental nutrient transporters are differentially affected both by reduced blood flow and stress, probably modifying the already disturbed intrauterine milieu and contributing to IUGR and fetal programming. Increased fatty acid transport capacity may affect energy metabolism and could be a compensatory reaction with positive effects on brain development. J. Cell. Biochem. 117: 1594-1603, 2016. © 2015 Wiley Periodicals, Inc.
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Increased risk of chronic fatigue and hair loss following COVID-19 in individuals with hypohidrotic ectodermal dysplasia - Hennig, Verena; Schuh, Wolfgang; Neubert, Antje; Mielenz, Dirk; Jäck, Hans-Martin; Schneider, Holm (Orphanet Journal of Rare Diseases, 2021)
Background: Hypohidrotic ectodermal dysplasia (HED) is a group of genodermatoses in which deficient ectodysplasin A signalling leads to maldevelopment of skin appendages, various eccrine glands, and teeth. Individuals with HED often have disrupted epithelial barriers and, therefore, were suspected to be more susceptible to coronavirus infection. Methods: 56 households with at least one member who had coronavirus disease of 2019 (COVID-19) were enrolled in a longitudinal study to compare the course of illness, immune responses, and long-term consequences of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in HED patients (n = 15, age 9–52 years) and control subjects of the same age group (n = 149). Results: In 14 HED patients, mild or moderate typical COVID-19 symptoms were observed that lasted for 4–45 days. Fever during the first days sometimes required external cooling measures. The course of COVID-19 was similar to that in control subjects if patients developed antibodies blocking the SARS-CoV-2 spike protein. Five out of six HED patients with completely abrogated ectodysplasin A signalling (83%) suffered from chronic, in two cases very severe fatigue following COVID-19, while only 25% of HED patients with residual activity of this pathway and 21% of control subjects recovering from COVID-19 experienced postinfectious fatigue. Hair loss after COVID-19 was also more frequent among HED patients (64%) than in the control group (13%). Conclusions: HED appears to be associated with an increased risk of long-term consequences of a SARS-CoV-2 infection. Preventive vaccination against COVID-19 should be recommended for individuals affected by this rare genetic disorder.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Chronic fatigue; COVID-19; Hair loss; Hypohidrotic ectodermal dysplasia; SARS-CoV-2

Increased salt consumption induces body water conservation and decreases fluid intake - Rakova, Natalia; Kitada, Kento; Lerchl, Kathrin; Dahlmann, Anke; Birukov, Anna; Daub, Steffen; Kopp, Christoph; Pedchenko, Tetyana; Zhang, Yahua; Beck, Luis; Johannes, Bernd; Marton, Adriana; et al. (Journal of Clinical Investigation, 2017)
BACKGROUND: The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. METHODS: Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. RESULTS: A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. CONCLUSION: Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. FUNDING: Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
EVALuna2:34240

Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis - Schnell, Alexander; Jüngert, Jörg M.; Klett, Daniel; Hober, Hannah; Kaiser, Natalie; Ruppel, Renate; Geppert, Annika; Tremel, Christina; Sobel, Julia; Plattner, Erika; Schmitt-Grohe, Sabina; Zirlik, Sabine; et al. (Liver International, 2023)
Background: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor—ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF. Methods: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy. Results: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97). Conclusions: ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.
CRIS-Team Scopus Importer:2023-03-17
Keywords: ARFI; bile acids; CFLD; cystic fibrosis

Indirect determination of hematology reference intervals in adult patients on Beckman Coulter UniCell DxH 800 and Abbott CELL-DYN Sapphire devices - Zierk, Jakob; Arzideh, Farhad; Haeckel, Rainer; Rauh, Manfred; Metzler, Markus; Ganslandt, Thomas; Krause, Stefan (Clinical Chemistry and Laboratory Medicine, 2018)
Background Conventional establishment of reference intervals for hematological analytes is challenging due to the need to recruit healthy persons. Indirect methods address this by deriving reference intervals from clinical laboratory databases which contain large datasets of both physiological and pathological test results. Methods We used the "Reference Limit Estimator" (RLE) to establish reference intervals for common hematology analytes in adults aged 18-60 years. One hundred and ninety-five samples from 44,519 patients, measured on two different devices in a tertiary care center were analyzed. We examined the influence of patient cohorts with an increasing proportion of abnormal test results, compared sample selection strategies, explored inter-device differences, and analyzed the stability of reference intervals in simulated datasets with varying overlap of pathological and physiological test results. Results Reference intervals for hemoglobin, hematocrit, red cell count and platelet count remained stable, even if large numbers of pathological samples were included. Reference intervals for red cell indices, red cell distribution width and leukocyte count were sufficiently stable, if patient cohorts with the highest fraction of pathological samples were excluded. In simulated datasets, estimated reference limits shifted, if the pathological dataset contributed more than 15%-20% of total samples and approximated the physiological distribution. Advanced sample selection techniques did not improve the algorithm's performance. Inter-device differences were small except for red cell distribution width. Conclusions The RLE is well-suited to create reference intervals from clinical laboratory databases even in the challenging setting of a adult tertiary care center. The procedure can be used as a complement for reference interval determination where conventional approaches are limited.
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Indirect determination of serum creatinine reference intervals in a Pakistani pediatric population using big data analytics - Ahmed, Sibtain; Zierk, Jakob; Siddiqui, Imran; Khan, Aysha Habib (World Journal of Clinical Pediatrics, 2021)
BACKGROUND The indirect methods of reference intervals (RI) establishment based on data mining are utilized to overcome the ethical, practical challenges and the cost associated with the conventional direct approach. AIM To generate RIs for serum creatinine in children and adolescents using an indirect statistical tool. METHODS Data mining of the laboratory information system was performed for serum creatinine analyzed from birth to 17 years for both genders. The timeline was set at six years from January 2013 to December 2018. Microsoft Excel 2010 and an indirect algorithm developed by the German Society of Clinical Chemistry and Laboratory Medicine’s Working Group on Guide Limits were used for the data analysis. RESULTS Data were extracted from 96104 samples and after excluding multiple samples for the same individual, we calculated RIs for 21920 males and 14846 females, with stratification into six discrete age groups. CONCLUSION Serum creatinine dynamics varied significantly across gender and age groups.
CRIS-Team Scopus Importer:2021-08-06
Keywords: Creatinine; Data mining; Indirect; Pakistan; Pediatric; Reference intervals

INFANTS AND NEWBORNS WITH ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) AND EXTRACRANIAL MALIGNANT RHABDOID TUMORS: A UNIQUE AND CHALLENGING POPULATION - Nemes, Karolina; Johann, Pascal D.; Steinbuegl, Mona; Gruhle, Miriam; Bens, Susanne; Kachanov, Denis; Teleshova, Margarita; Peter, Hauser; Simon, Thorsten; Tippelt, Stephan; Eberl, Wolfgang; Chada, Martin; et al. (NEURO-ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-09-02

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population - Nemes, Karolina; Johann, Pascal D.; Steinbügl, Mona; Gruhle, Miriam; Bens, Susanne; Kachanov, Denis; Teleshova, Margarita; Hauser, Peter; Simon, Thorsten; Tippelt, Stephan; Eberl, Wolfgang; Chada, Martin; et al. (Cancers, 2022)
Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k/850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.
CRIS-Team Scopus Importer:2022-05-13
Keywords: atypical teratoid rhabdoid tumors; EU-RHAB registry; extracranial malignant rhabdoid tumor; germline mutation; RTPS1; RTPS2; SMARCB1

Infliximab therapy of relapsing tracheal stenosis in a pediatric patient with granulomatosis with polyangiitis: a case report - Schnell, Alexander; Ruppel, Renate; Tremel, Christina; Galiano, Matthias; Meßbacher, Maria-Elena; Krickau, Tobias (Journal of Medical Case Reports, 2022)
Background: Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases. Case presentation: We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters. Conclusions: The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Children; Granulomatosis with polyangiitis; TNF-α inhibitor; Tracheal stenosis

Influence of factor XIII activity on post-operative transfusion in congenital cardiac surgery-A retrospective analysis - Fahlbusch, Fabian B.; Heinlein, Thomas; Rauh, Manfred; Dittrich, Sven; Cesnjevar, Robert; Moosmann, Julia; Nadal, Jennifer; Schmid, Matthias; Münch, Frank; Schroth, Michael; Rascher, Wolfgang; Topf, Hans-Georg (PLoS ONE, 2018)
OBJECTIVES: Coagulation factor XIII (FXIII) plays a key role in fibrin clot stabilization-an essential process for wound healing following cardiothoracic surgery. However, FXIII deficiency as a risk for post-operative bleeding in pediatric cardiac surgery involving cardiopulmonary bypass (CPB) for congenital heart disease (CHD) is controversially discussed. Thus, as primary outcome measures, we analyzed the association of pre-operative FXIII activity and post-operative chest tube drainage (CTD) loss with transfusion requirements post-operatively. Secondary outcomes included the influence of cyanosis and sex on transfusion. METHODS: Our retrospective analysis (2009-2010) encompassed a single center series of 76 cardio-surgical cases with CPB (0-17 years, mean age 5.61 years) that were post-operatively admitted to our pediatric intensive care unit (PICU). The observational period was 48 hours after cardiac surgery. Blood cell counts and coagulation status, including FXIII activity were routinely performed pre- and post-operatively. The administered amount of blood products and volume expanders was recorded electronically, along with the amount of CTD loss. Uni- and multivariate logistic regression analysis was performed to calculate the associations (odds ratios) of variables with post-operative transfusion needs. RESULTS: FXIII activities remained stable following CPB surgery. There was no association of pre- and post-operative FXIII activities and transfusion of blood products or volume expanders in the first 48 hours after surgery. Similarly, FXIII showed no association with CTD loss. Cyanosis and female sex were associated with transfusion rates. CONCLUSIONS: Although essentially involved in wound healing and clotting after surgery, FXIII activity does not serve as a valid predictor of post-operative transfusion need.
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Influence of labor on direct and indirect determinants of placental 11beta-hydroxysteroid dehydrogenase activity - Hübner, Hanna; Heussner, Kirsten; Rübner, Matthias; Schmid, Matthias; Nadal, Jennifer; Wölfle, Joachim; Hartner, Andrea; Menendez-Castro, Carlos; Rauh, Manfred; Beckmann, Matthias; Kehl, Sven; Fahlbusch, Fabian (Archives of Gynecology and Obstetrics, 2020)
Purpose: Labor is a complex process involving multiple para-, auto- and endocrine cascades. The interaction of cortisol, corticotropin-releasing hormone (CRH) and progesterone is essential. The action of cortisol on the human feto-placental unit is regulated by 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2/HSD11B2) that converts cortisol into inactive cortisone. The majority of studies on the assessment of placental 11β-HSD2 function determined indirect activity parameters. It remains elusive if indirect measurements correlate with enzymatic function and if these parameters are affected by potential confounders (e.g., mode of delivery). Thus, we compared determinants of indirect 11β-HSD2 tissue activity with its direct enzymatic turnover rate in placental samples from spontaneous births and cesarean (C)-sections. Methods: Using LC–MS/MS, we determined CRH, cortisol, cortisone, progesterone and 17-hydroxy(OH)-progesterone in human term placentas (spontaneous birth vs. C-section, n = 5 each) and measured the enzymatic glucocorticoid conversion rates in placental microsomes. Expression of HSD11B1, 2 and CRH was determined via qRT-PCR in the same samples. Results: Cortisol–cortisone ratio correlated with direct microsomal enzymatic turnover. While this observation seemed independent of sampling site, a strong influence of mode of delivery on tissue steroids was observed. The mRNA expression of HSD11B2 correlated with indirect and direct cortisol turnover rates in C-section placentas only. In contrast to C-sections, CRH, cortisol and cortisone levels were significantly increased in placental samples following spontaneous birth. Conclusion: Labor involves a series of complex hormonal processes including activation of placental CRH and glucocorticoid metabolism. This has to be taken into account when selecting human cohorts for comparative analysis of placental steroids.
CRIS-Team Scopus Importer:2020-09-11
Keywords: 11beta-hydroxysteroid dehydrogenase; CRH; LC–MS/MS; Mode of delivery; Placenta

Influence of Low Protein Diet-Induced Fetal Growth Restriction on the Neuroplacental Corticosterone Axis in the Rat - Schmidt, Marius; Rauh, Manfred; Schmid, Matthias C.; Hübner, Hanna; Rübner, Matthias; Wachtveitl, Rainer; Cordasic, Nada; Rascher, Wolfgang; Menendez-Castro, Carlos; Hartner, Andrea; Fahlbusch, Fabian B. (Frontiers in Endocrinology, 2019)
Objectives: Placental steroid metabolism is linked to the fetal hypothalamus-pituitary-adrenal axis. Intrauterine growth restriction (IUGR) might alter this cross-talk and lead to maternal stress, in turn contributing to the pathogenesis of anxiety-related disorders of the offspring, which might be mediated by fetal overexposure to, or a reduced local enzymatic protection against maternal glucocorticoids. So far, direct evidence of altered levels of circulating/local glucocorticoids is scarce. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) allows quantitative endocrine assessment of blood and tissue. Using a rat model of maternal protein restriction (low protein [LP] vs. normal protein [NP]) to induce IUGR, we analyzed fetal and maternal steroid levels via LC-MS/MS along with the local expression of 11beta-hydroxysteroid- dehydrogenase (Hsd11b).
CRIS-Team WoS Importer:2019-03-20

Influence of passive mechanical properties in healthy and infarcted rat myocardium on the cardiac cycle - Martonová, Denisa; Alkassar, Muhannad; Seufert, Julia; Holz, David; Duong, Minh Tuan; Reischl, Barbara; Friedrich, Oliver; Leyendecker, Sigrid (Proc. Appl. Math. Mech. (PAMM), 2021)

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants - Thome, Ulrich H.; Dreyhaupt, Jens; Genzel-Boroviczeny, Orsolya; Bohnhorst, Bettina; Schmid, Manuel; Fuchs, Hans; Rohde, Oliver; Avenarius, Stefan; Topf, Hans-Georg; Zimmermann, Andrea; Faas, Dirk; Timme, Katharina; et al. (Neonatology, 2018)
BACKGROUND: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. OBJECTIVES: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. METHODS: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. RESULTS: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). CONCLUSIONS: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.
EVALuna2:35728

Influence of prenatal environment and genetic background on glucocorticoid steroid metabolism in monozygotic twins with intra-twin birthweightdifferences - Schulte, Sandra; Schreiner, Felix; Plamper, Michaela; Kasner, Charlotte; Gruenewald, Mathias; Bartmann, Peter Bartmann; Fimmers, Rolf; Hartmann, Michaela F.; Wudy, Stefan A.; Wölfle, Joachim; Gohlke, Bettina (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Influence of Prenatal Environment on Androgen Steroid Metabolism In Monozygotic Twins With Birthweight Differences - Schulte, Sandra; Schreiner, Felix; Plamper, Michaela; Kasner, Charlotte; Gruenewald, Mathias; Bartmann, Peter; Fimmers, Rolf; Hartmann, Michaela F.; Wudy, Stefan A.; Stoffel-Wagner, Birgit; Wölfle, Joachim; Gohlke, Bettina (Journal of Clinical Endocrinology and Metabolism, 2020)
OBJECTIVE: Although low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, little is known about their impact on steroid metabolism. We studied genetically identical twins with intra-twin bw-differences from birth to adolescence to analyze the long-term impact of bw on steroid metabolism. METHODS: 68 monozygotic twin pairs with a bw-difference of <1 standard deviation score (SDS; concordant; n = 41) and ≥1 SDS (discordant; n = 27) were recruited. At 14.9 years (mean age), morning urine samples were collected and analyzed with gas chromatography-mass-spectrometry. RESULTS: No significant differences were detected in the concordant group. In contrast, in the smaller twins of the discordant group, we found significantly higher concentrations not only of the dehydroepiandrosterone sulfate (DHEAS) metabolite 16α-OH-DHEA (P = 0.001, 656.11 vs 465.82 µg/g creatinine) but also of cumulative dehydroepiandrosterone and downstream metabolites (P = 0.001, 1650.22 vs 1131.92 µg/g creatinine). Relative adrenal (P = 0.002, 0.25 vs 0.18) and overall androgen production (P = 0.001, 0.79 vs 0.65) were significantly higher in the formerly smaller discordant twins. All twin pairs exhibited significant intra-twin correlations for all individual steroid metabolites, sums of metabolites, indicators of androgen production, and enzyme activities. Multiple regression analyses of the smaller twins showed that individual steroid concentrations of the larger co-twin were the strongest influencing factor among nearly all parameters analyzed. CONCLUSION: In monozygotic twin pairs with greater intra-twin bw-differences (≥1 SDS), we found that bw had a long-lasting impact on steroid metabolism, with significant differences regarding DHEAS metabolites and relative androgen production. However, most parameters showed significant intra-twin correlations, suggesting a consistent interrelationship between prenatal environment, genetic background, and steroid metabolism.
CRIS-Team Scopus Importer:2020-09-04
Keywords: androgens; androgen production; fetal programming; low birthweight; steroid hormones; twin-to-twin transfusion syndrome

Influence of the autotaxin-lysophosphatidic acid axis on cellular function and cytokine expression in different breast cancer cell lines - Hauck, Theresa; Kadam, Sheetal; Heinz, Katharina; Garcia Peraza, Maria; Schmid, Rafael; Kremer, Andreas; Wolf, Katharina; Bauer, Alina; Horch, Raymund E.; Arkudas, Andreas; Kengelbach-Weigand, Annika (Scientific Reports, 2022)
Previous studies provide high evidence that autotaxin (ATX)-lysophosphatidic acid (LPA) signaling through LPA receptors (LPAR) plays an important role in breast cancer initiation, progression, and invasion. However, its specific role in different breast cancer cell lines remains to be fully elucidated to offer improvements in targeted therapies. Within this study, we analyzed in vitro the effect of LPA 18:1 and the LPAR1, LPAR3 (and LPAR2) inhibitor Ki16425 on cellular functions of different human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, BT-474, SKBR-3) and the human breast epithelial cell line MCF-10A, as well as Interleukin 8 (IL-8), Interleukin 6 (IL-6) and tumor necrosis factor (TNF)-alpha cytokine secretion after LPA-incubation. ATX-LPA signaling showed a dose-dependent stimulatory effect especially on cellular functions of triple-negative and luminal A breast cancer cell lines. Ki16425 inhibited the LPA-induced stimulation of triple-negative breast cancer and luminal A cell lines in variable intensity depending on the functional assay, indicating the interplay of different LPAR in those assays. IL-8, IL-6 and TNF-alpha secretion was induced by LPA in MDA-MB-468 cells. This study provides further evidence about the role of the ATX-LPA axis in different breast cancer cell lines and might contribute to identify subtypes suitable for a future targeted therapy of the ATX-LPA axis.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Cancer; Medical research; Molecular medicine

Influence of Timing of Antenatal Corticosteroid Administration on Morbidity of Preterm Neonates - Morhart, Patrick; Gärtner, Janis; Weiss, Christel; Stumpfe, Florian; Dammer, Ulf; Faschingbauer, Florian; Fahlbusch, Fabian; Beckmann, Matthias; Kehl, Sven (In Vivo, 2022)
Background/Aim: We investigated the impact of the timing of antenatal corticosteroid (ACS) administration on the clinical outcome of preterm infants. Patients and Methods: Two hundred and fifty-five preterm infants between 28+0 and 34+0 weeks of gestation were retrospectively assigned to one of two groups: In the first group, ACS was given within 7 days before birth; the second group, did not receive ACS during that period. The primary outcome parameter was respiratory failure (defined by need for continuous positive airway pressure or mechanical ventilation) due to grade 1-4 respiratory distress syndrome (RDS). Secondary outcomes included the rates of intraventricular hemorrhage (IVH), periventricular leukomalacia, and necrotizing enterocolitis. Results: The rate of RDS was significantly higher in the no ACS group (40% vs. 62%, p=0.0009), especially of the more severe grades 24 (n=37 vs. n=48, p=0.0121). In addition, IVH (1% vs. 9%, p=0.0041) and neonatal infections (72% vs. 89%, p=0.0025) were significantly increased. Univariable and multivariable regression analyses showed a lower likelihood of RDS in the ACS group [odds ratio (OR)=0.295] in infants born closer to term (OR=0.907) and following preterm onset of labor (OR=0.495). Similarly, we observed a lower probability of IVH in the ACS group (OR=0.098), with a higher probability of occurrence of IVH in pre-eclampsia/HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count) (OR=7.914). Conclusion: ACS treatment within the last 7 days before birth significantly reduced the risk of RDS and IVH in preterm. These data emphasize that the timing of ACS administration determines its success.
CRIS-Team WoS Importer:2022-07-15

Influence of Turkish origin on hematology reference intervals in the German population - Mayr, Franz Xaver; Bertram, Alexander; Cario, Holger; Frühwald, Michael C.; Groß, Hans Jürgen; Groening, Arndt; Grützner, Stefanie; Gscheidmeier, Thomas; Hoffmann, Reinhard; Krebs, Alexander; Ruf, Hans Georg; Torge, Antje; et al. (Scientific Reports, 2021)
Reference intervals for laboratory test results have to be appropriate for the population in which they are used to be clinically useful. While sex and age are established partitioning criteria, patients’ origin also influences laboratory test results, but is not commonly considered when creating or applying reference intervals. In the German population, stratification for ethnicity is rarely performed, and no ethnicity-specific hematology reference intervals have been reported yet. In this retrospective study, we investigated whether specific reference intervals are warranted for the numerically largest group of non-German descent, individuals originating from Turkey. To this end, we analyzed 1,314,754 test results from 167,294 patients from six German centers. Using a name-based algorithm, 1.9% of patients were identified as originating from Turkey, in line with census data and the algorithm’s sensitivity. Reference intervals and their confidence intervals were calculated using an indirect data mining approach, and Turkish and non-Turkish reference limits overlapped completely or partially in nearly all analytes, regardless of age and sex, and only 5/144 (3.5%) subgroups’ reference limits showed no overlap. We therefore conclude that the current practice of using common reference intervals is appropriate and allows correct clinical decision-making in patients originating from Turkey.
CRIS-Team Scopus Importer:2021-11-05

Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis - Avouac, Jerome; Palumbo, Katrin; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Horn, Angelika; Maurer, Britta; Akhmetshina, Alfiya; Beyer, Christian; Sadowski, Anika; Schneider, Holm; Shiozawa, Shunichi; et al. (Arthritis and Rheumatism, 2012)
Objective To investigate whether c-Jun and c-Fos contribute to the pathologic activation of fibroblasts in systemic sclerosis (SSc) and to evaluate the antifibrotic potential of selective activator protein 1 (AP-1) inhibition. Methods Expression of c-Jun and c-Fos was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis. Fibroblasts were stimulated with transforming growth factor β (TGFβ) and incubated with T-5224, a small-molecule inhibitor of AP-1, or were transfected with small interfering RNA (siRNA) duplexes against c-Jun and c-Fos. Collagen synthesis was quantified by real-time PCR and hydroxyproline assay. Differentiation of resting fibroblasts into myofibroblasts was assessed by staining for α-smooth muscle actin and stress fibers. The antifibrotic potential of T-5224 was evaluated in mouse models of dermal fibrosis induced by bleomycin or by adenoviral overexpression of a constitutively active TGFβ receptor type I. Results Up-regulation of c-Jun and c-Fos was detected in mouse models of SSc and in the skin and dermal fibroblasts of patients with SSc. Stimulation of healthy fibroblasts with TGFβ induced the expression of c-Jun and c-Fos. Treatment with T-5224 or nucleofection with siRNA directed against c-Jun and c-Fos abrogated the profibrotic effects of TGFβ. T-5224 decreased the release of collagen selectively in SSc fibroblasts. T-5224 was well tolerated and prevented dermal fibrosis induced by bleomycin or by adenoviral activation of TGFβ signaling. Conclusion AP-1 is up-regulated in a TGFβ-dependent manner in SSc. The selective AP-1 inhibitor T-5224 reduced collagen synthesis selectively in SSc fibroblasts and efficiently prevented the development of experimental dermal fibrosis. Thus, AP-1 might be a promising new molecular target for the treatment of SSc. Copyright © 2012 by the American College of Rheumatology.
CRIS-Team Scopus Importer:2020-07-01

Inhibition of sumoylation prevents experimental fibrosis - Khodzhigorova, Aisa; Distler, Alfiya; Lang, Veronika; Dees, Clara; Schneider, Holm; Beyer, Christian; Gelse, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2012)
Objectives: Fibrosis is a predominant cause of death in systemic sclerosis (SSc). First epigenetic modifications have recently been shown to contribute to activation of SSc fibroblasts. Here, we investigated inhibition of sumoylation as a novel antifibrotic approach. Methods: Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation. The effects of knockdown of Ubc9 were analysed in bleomycin-induced dermal fibrosis, and in the model of fibrosis induced by overexpression of a constitutively active TGF-beta receptor type I (TBR). SUMO-1 and phosphorylated Smad3 were detected by immunohistochemistry. Results: Increased staining for SUMO-1 was detected in patients with SSc and in experimental fibrosis. Inhibition of sumoylation exerted potent antifibrotic effects and prevented dermal thickening, myofibroblast differentiation and accumulation of collagen induced by bleomycin, or by overexpression of constitutively active TBR. Moreover, knockdown of Ubc9 reduced the accumulation of phosphorylated Smad3 in experimental fibrosis indicating that inhibition of sumoylation may normalise canonical TGF-β signalling in vivo. Conclusions: We demonstrate that inhibition of sumoylation reduces canonical TGF-β signalling and prevents experimental fibrosis in different preclinical models. These data provide first evidence that targeting of aberrant sumoylation may be a novel therapeutic approach for fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

Inhibition of tgf-β signaling and decreased apoptosis in iugr-associated lung disease in rats - Alcazar, Miguel Angel Alejandre; Morty, Rory E.; Lendzian, Lisa; Vohlen, Christina; Oestreicher, Iris; Plank, Christian Georg; Schneider, Holm; Doetsch, Joerg (PLoS ONE, 2011)
Intrauterine growth restriction is associated with impaired lung function in adulthood. It is unknown whether such impairment of lung function is linked to the transforming growth factor (TGF)-β system in the lung. Therefore, we investigated the effects of IUGR on lung function, expression of extracellular matrix (ECM) components and TGF-β signaling in rats. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day (P) 70. Pulmonary activity of the TGF-β system was determined at P1 and P70. TGF-β signaling was blocked in vitro using adenovirus-delivered Smad7. At P70, respiratory airway compliance was significantly impaired after IUGR. These changes were accompanied by decreased expression of TGF-β1 at P1 and P70 and a consistently dampened phosphorylation of Smad2 and Smad3. Furthermore, the mRNA expression levels of inhibitors of TGF-β signaling (Smad7 and Smurf2) were reduced, and the expression of TGF-β-regulated ECM components (e.g. collagen I) was decreased in the lungs of IUGR animals at P1; whereas elastin and tenascin N expression was significantly upregulated. In vitro inhibition of TGF-β signaling in NIH/3T3, MLE 12 and endothelial cells by adenovirus-delivered Smad7 demonstrated a direct effect on the expression of ECM components. Taken together, these data demonstrate a significant impact of IUGR on lung development and function and suggest that attenuated TGF-β signaling may contribute to the pathological processes of IUGR-associated lung disease. © 2011 Alejandre Alcázar et al.
CRIS-Team Scopus Importer:2020-07-01

Initial experience with cinematic rendering for the visualization of extracardiac anatomy in complex congenital heart defects - Röschl, Florian; Purbojo, Ariawan; Rüffer, André; Cesnjevar, Robert; Dittrich, Sven; Glöckler, Martin (Interactive Cardiovascular and Thoracic Surgery, 2019)
OBJECTIVES: Detailed anatomical information is essential for planning of surgical therapy in patients with congenital heart disease. We wanted to determine whether cinematic rendering, the novel 3-dimensional visualization technique, could help paediatric cardiac surgeons achieve better preoperative visualization of the extracardiac anatomy in patients with complex congenital heart defects. Therefore, cinematic rendering was compared to the traditional volume rendering technique by means of a questionnaire with predefined criteria. METHODS: Picture sets from 20 infant patients (mean age = 17 days) were generated from computed tomography data with both the cinematic rendering and the volume rendering techniques. These were presented side by side in a digital high-resolution portfolio without labelling them. Three experienced paediatric cardiac surgeons were provided with these portfolios and a questionnaire. They were asked to evaluate the images individually in predefined categories on a 4-point Likert scale from 1 = 'fully acceptable' to 4 = 'unacceptable'. RESULTS: Cinematic rendering scored significantly better values on the Likert scale in 7 of 9 categories, namely 'spatial impression in general', 'depth perception', 'delineation of the atrial appendages/pulmonary veins/peripheral pulmonary arteries', 'assessability of the anterior interventricular sulcus' and 'assessability of the aortic arch branches'. CONCLUSIONS: Cinematic rendering is a valuable software tool, and our data suggest that it provides significantly better visualization than volume rendering. The surgeons appraised improved depth perception and delineation of structures adjacent to the heart as the most significant advantages.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Cinematic rendering; Computed tomography; Congenital heart disease; Three-dimensional

Inosine Released from Dying or Dead Cells Stimulates Cell Proliferation via Adenosine Receptors - Chen, Jin; Chaurio, Ricardo A.; Maueröder, Christian; Derer, Anja; Rauh, Manfred; Kost, Andriy; Liu, Yi; Mo, Xianming; Hueber, Axel; Bilyy, Rostyslav; Herrmann, Martin; Zhao, Yi; et al. (Frontiers in Immunology, 2017)
Many antitumor therapies induce apoptotic cell death in order to cause tumor regression. Paradoxically, apoptotic cells are also known to promote wound healing, cell proliferation, and tumor cell repopulation in multicellular organisms. We aimed to characterize the nature of the regenerative signals concentrated in the micromilieu of dead and dying cells.Cultures of viable melanoma B16F10 cells, mouse fibroblasts, and primary human fibroblast-like synoviocytes (FLS) in the presence of dead and dying cells, their supernatants (SNs), or purified agonists and antagonists were used to evaluate the stimulation of proliferation. Viable cell quantification was performed by either flow cytometry of harvested cells or by crystal violet staining of adherent cells. High-performance liquid chromatography and liquid chromatography coupled with mass spectrometry of cell SNs were deployed to identify the nature of growth-promoting factors. Coimplantation of living cells in the presence of SNs collected from dead and dying cells and specific agonists was used to evaluate tumor growth in vivo.The stimulation of proliferation of few surviving cells by bystander dead cells was confirmed for melanoma cells, mouse fibroblasts, and primary FLS. We found that small soluble molecules present in the protein-free fraction of SNs of dead and dying cells were responsible for the promotion of proliferation. The nucleoside inosine released by dead and dying cells acting via adenosine receptors was identified as putative inducer of proliferation of surviving tumor cells after irradiation and heat treatment.Inosine released by dead and dying cells mediates tumor cell proliferation via purinergic receptors. Therapeutic strategies surmounting this pathway may help to reduce the rate of recurrence after radio- and chemotherapy.
EVALuna2:13419

In Reply - Rascher, Wolfgang (Deutsches Ärzteblatt international, 2016)
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Insights into the infiltrative behavior of adamantinomatous craniopharyngioma in a new xenotransplant mouse model - Stache, Christina; Hoelsken, Annett; Schlaffer, Sven-Martin; Heß, Andreas; Metzler, Markus; Frey, Benjamin; Fahlbusch, Rudolf; Flitsch, Joerg; Buchfelder, Michael; Buslei, Rolf (Brain Pathology, 2015)
Adamantinomatous craniopharyngiomas (adaCP) cause hypothalamic pituitary dysfunction. Elucidation of pathomechanisms underlying tumor progression is essential for the development of targeted chemotherapeutic treatment options. In order to study the mechanisms of tumor outgrowth, we implanted human primary adaCP tissue from three different surgical specimens stereotactically into the brain of immunodeficient mice (n = 20). Three months after tumor inoculation, magnetic resonance imaging and histology confirmed tumor engraftment in all 20 mice (100%) that obtained tissue transplants. The lesions invaded adjoining brain tissue with micro finger-shaped protrusions. Immunohistochemical comparison of the primary tumor and xenotransplants revealed a similar amount of proliferation (Mib-1) and cytokeratin expression pattern (KL-1). Whole tumor reconstruction using serial sections confirmed whirl-like cell clusters with nuclear ?-catenin accumulations at the tumor brain border. These whirls were surrounded by a belt of Claudin-1 expressing cells, showed an activated epidermal growth factor receptor (EGFR) and distinct CD133 as well as p21(WAF1/Cip1) positivity, indicating a tumor stem cell phenotype. Consistent with our previous in vitro studies, intracranial xenotransplants of adaCP confirmed cells with nuclear ?-catenin and activated EGFR being the driving force of tumor outgrowth. This model provides the possibility to study in vivo tumor cell migration and to test novel treatment regimens targeting this tumor stem cell niche.
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Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease - Audain, Enrique; Wilsdon, Anna; Breckpot, Jeroen; Izarzugaza, Jose M.G.; Fitzgerald, Tomas W.; Kahlert, Anne Karin; Sifrim, Alejandro; Wünnemann, Florian; Perez-Riverol, Yasset; Abdul-Khaliq, Hashim; Bak, Mads; Bassett, Anne S.; et al. (PLoS Genetics, 2021)
Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parentoffspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
CRIS-Team Scopus Importer:2021-08-13

Integrin α8 Is Abundant in Human, Rat, and Mouse Trophoblasts - Herdl, Sebastian; Hübner, Hanna; Volkert, Gudrun; Marek, Ines; Menendez-Castro, Carlos; Nögel, Stephanie; Rübner, Matthias; Rascher, Wolfgang; Hartner, Andrea; Fahlbusch, Fabian B. (Reproductive Sciences, 2017)
OBJECTIVE: Integrins exert regulatory functions in placentogenesis. Null mutation of certain integrin α subunits leads to placental defects with subsequent fetal growth restriction or embryonic lethality in mice. So far, the placental role of α8 integrin remains to be determined. METHODS: Localization of α8 integrin and its ligands, fibronectin (FN) and osteopontin (OPN), was studied by immunohistochemistry in human, rat, and mouse placenta. The vascularization of the placental labyrinth layer of α8 integrin-deficient mice was determined by CD31 staining. In humans, α8 integrin expression was assessed via real-time polymerase chain reaction in healthy placentas, in the placental pathologies such as intrauterine growth restriction (IUGR), preeclampsia, and HELLP-syndrome (hemolysis, elevated liver enzymes, low platelet count), as well as in primary extravillous trophoblasts (EVT) and villous trophoblasts. RESULTS: In humans, α8 integrin was detected in first and third trimester syncytiotrophoblast and EVT. Although OPN showed the same localization, FN was observed in EVT only. No expressional changes in α8 integrin were detected in the placental pathologies studied. Rodent placenta showed α8 integrin expression in giant cells and in the labyrinth layer. The localization of OPN and FN, however, showed species-specific differences. Knockout of α8 integrin in mice did not cause IUGR, despite some reduction in labyrinth layer vascularization. CONCLUSION: α8 Integrin is expressed in functional placental compartments among its ligands, OPN and/or FN, across species. Although this may point to a regulatory role in trophoblast function, our data from α8 integrin-deficient mice indicated only mild placental pathology. Thus, the lack of placental α8 integrin seems to be largely compensated for.
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Interaction of the mechano-electrical feedback with passive mechanical models on a 3D rat left ventricle: a computational study - Duong, Minh Tuan; Holz, David; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (Frontiers in Physiology, 2019)
In this paper, we are investigating the interaction between different passive material models and the mechano-electrical feedback (MEF) in cardiac modelling. Various types of passive mechanical laws (nearly incompressible/compressible, polynomial/exponential-type, transversally isotropic/orthotropic material models) are integrated in a fully coupled electromechanical model in order to study their specific influence on the overall MEF behaviour. Our computational model is based on a three-dimensional (3D) geometry of a healthy rat left ventricle reconstructed from magnetic resonance imaging (MRI). The electromechanically coupled problem is solved using a fully implicit finite element-based approach. The effects of different passive material models on the MEF are studied with the help of numerical examples. It turns out that there is a significant difference between the behaviour of the MEF for compressible and incompressible material models. Numerical results for the incompressible models exhibit that a change in the electrophysiology can be observed such that the transmembrane potential (TP) is unable to reach the resting state in the repolarisation phase and this leads to non-zero relaxation deformations. The most significant and strongest effects of the MEF on the rat cardiac muscle response are observed for the exponential passive material law.<br
Keywords: Electromechanics; Excitation-contraction; Mechano-electrical feedback; passive mechanics; rat left ventricle; FEM; Compressible; Incompressible; Exponential; Polynomial; Orthotropic; Transversely isotropic

Interactive virtual stent planning for the treatment of coarctation of the aorta - Neugebauer, Mathias; Glöckler, Martin; Goubergrits, Leonid; Kelm, Marcus; Kuehne, Titus; Hennemuth, Anja (International Journal of Computer Assisted Radiology and Surgery, 2016)
The coarctation of the aorta (CoA), a local narrowing of the aortic arch, accounts for 7 % of all congenital heart defects. Stenting is a recommended therapy to reduce the pressure gradient. This procedure is associated with complications such as the development of adverse flow conditions. A computer-aided treatment planning based on flow simulations can help to predict possible complications. The virtual stent planning is an important, intermediate step in the treatment planning pipeline. We present a novel approach that automatically suggests a stent setup and provides a set of intuitive parameters that allow for an interactive adaption of the suggested stent placement and induced deformation.A high-quality mesh and a centerline are automatically generated. The stent-induced deformation is realized through a deformation of the centerline and a vertex displacement with respect to the deformed centerline and additional stent parameters. The parameterization is automatically derived from the underlying data and can be optionally altered through a condensed set of clinically sound parameters.The automatic deformation can be generated in about 25 s on a consumer system. The interactive adaption can be performed in real time. Compared with manual expert reconstructions of the stented vessel section, the mean difference of vessel path and diameter is below 1 mm.Our approach enables a medical user to easily generate a plausibly deformed vessel mesh which is necessary as input for a simulation-based treatment planning of CoA.
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Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice - Haep, Lisa; Britzen-Laurent, Nathalie; Weber, Thomas G.; Naschberger, Elisabeth; Schäfer, Amrei; Kremmer, Elisabeth; Försch, Sebastian; Scheuer, Werner; Wirtz, Stefan; Waldner, Maximilian; Stürzl, Michael; Vieth, Michael (Inflammatory Bowel Diseases, 2015)
Interferon (IFN)-? is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN-? in IBD have been predominantly investigated. Based on previous studies showing that IFN-? acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN-? on the vascular system in IBD.Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy.We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN-? were more strongly upregulated in colitis tissues. IFN-? exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN-?-induced guanylate binding protein 1 (GBP-1). Neutralization of IFN-? in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability.The dissection of the pleiotropic activities of IFN-? in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.
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Interventions for reducing medication errors in children in hospital - Maaskant, Jolanda M.; Vermeulen, Hester; Apampa, Bugewa; Fernando, Bernard; Ghaleb, Maisoon A.; Neubert, Antje; Thayyil, Sudhin; Soe, Aung (Cochrane Database of Systematic Reviews, 2015)
Many hospitalised patients are affected by medication errors (MEs) that may cause discomfort, harm and even death. Children are at especially high risk of harm as the result of MEs because such errors are potentially more hazardous to them than to adults. Until now, interventions to reduce MEs have led to only limited improvements.To determine the effectiveness of interventions aimed at reducing MEs and related harm in hospitalised children.The Effective Practice and Organisation of Care Group (EPOC) Trials Search Co-ordinator searched the following sources for primary studies: The Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL), the Economic Evaluation Database (EED) and the Health Technology Assessments (HTA) database; MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Proquest Dissertations & Theses, Web of Science (citation indexes and conference proceedings) and the EPOC Register of Studies. Related reviews were identified by searching the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects (DARE). Review authors searched grey literature sources and trial registries. They handsearched selected journals, contacted researchers in the field and scanned reference lists of relevant reviews. They conducted searches in November 2013 and November 2014. They applied neither language nor date limits.Randomised controlled trials, controlled before-after studies and interrupted time series investigating interventions to improve medication safety in hospitalised children (<= 18 years). Participants were healthcare professionals authorised to prescribe, dispense or administer medications. Outcome measures included MEs, (potential) patient harm, resource utilisation and unintended consequences of the interventions.Two review authors independently selected studies, extracted data and assessed study quality using the EPOC data collection checklist. We evaluated the risk of bias of included studies and used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to assess the quality of the body of evidence. We described results narratively and presented them using GRADE tables.We included seven studies describing five different interventions: participation of a clinical pharmacist in a clinical team (n = 2), introduction of a computerised physician order entry system (n = 2), implementation of a barcode medication administration system (n = 1), use of a structured prescribing form (n = 1) and implementation of a check and control checklist in combination with feedback (n = 1).Clinical and methodological heterogeneity between studies precluded meta-analyses. Although some interventions described in this review show a decrease in MEs, the results are not consistent, and none of the studies resulted in a significant reduction in patient harm. Based on the GRADE approach, the overall quality and strengfh of the evidence are low.Current evidence on effective interventions to prevent MEs in a paediatric population in hospital is limited. Comparative studies with robust study designs are needed to investigate interventions including components that focus on specific paediatric safety issues.
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Intracerebral gene therapy of aromatic L-amino acid decarboxylase deficiency with eladocagene exuparvovec. Statement of the Society for Neuropediatrics (GNP), the Working Group on Pediatric Metabolic Disorders (APS), the German Society of Neurosurgery (DGNC) and the German Society of Pediatrics and Adolescent Medicine (DGKJ) - Opladen, Thomas; Brennenstuhl, Heiko; Kuseyri Huebschmann, Oya; Call, Debora; Green, Kim; Schara, Ulrike; Rascher, Wolfgang; Hoevel, Annegret; Assmann, Birgit; Koelker, Stefan; Westhoff, Jens H.; Walter, Magdalena; et al. (Monatsschrift Kinderheilkunde, 2021)
Background: The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) causes a severe combined deficiency of dopamine, serotonin and catecholamines. The clinical picture is characterized by truncal hypotonia, delayed or absent achievement of motor milestones, and oculogyric crises from infancy onwards. The response to conventional drug treatment is very limited, especially in severe cases. The intracerebral application of eladocagene exuparvovec, an AAV2-based gene therapy, which is expected to be approved in mid-2021, is the first available causal therapeutic approach.
CRIS-Team WoS Importer:2021-07-16

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

Intrauterine Growth Restriction (IUGR) Induces Signs of Subclinical Atherosclerosis in 6-Year-Old Infants Despite Absence Of Excessive Growth - Tzschoppe, Anja; Von Kries, Ruediger; Struwe, Ellen; Rascher, Wolfgang; Dörr, Helmuth-Günther; Juengert, Joerg; Rauh, Manfred; Beckmann, Matthias; Schild, Ralf; Goecke, Tamme W.; Doetsch, Joerg (Klinische Pädiatrie, 2017)
Background Postnatal catch-up growth and rapid weight gain after intrauterine growth restriction (IUGR) seem to increase the risk for later disease. This study aimed to compare features of the metabolic syndrome early in life between IUGR and appropriate for gestational age (AGA) infants. Patients Data for 9 infants with IUGR defined by a birth weight<10th percentile and ultrasound-proven placental insufficiency and 11 AGA children were available. Method Postnatal growth, auxological, cardiovascular, and metabolic parameters up to a chronological age of 6 years were assessed: Fasting serum concentrations of LDL-cholesterol, insulin, leptin, IGF-I, DHEAS, skinfold thicknesses, blood pressure, and mean carotid intima-media thickness (cIMT). Results All IUGR infants showed catch-up growth, although mean BMI SDS and total subcutaneous fat mass at the age of 6 years were still slightly lower compared to the AGA cohort. Reduced serum leptin concentrations were observed in IUGR infants (p=0.02), whereas no significant difference was found for IGF-I, insulin, LDL-cholesterol and DHEAS concentrations. Mean cIMT was significantly higher in IUGR infants (p<0.05). Mean arterial pressure did no differ. Discussion and Conclusion In 6-year-old IUGR infants with catch-up growth, who still had a slightly reduced BMI SDS compared to the AGA group, signs of subclinical atherosclerosis were detectable suggesting that cardiovascular risk in IUGR may be present even in the absence of excessive growth.
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Investigating significant health trends in growth hormone treatments registry: rationale, aims and design of a nationwide prospective registry (study protocol) - Schnabel, Dirk; Kreitschmann-Andermahr, Ilonka J.; Strasburger, Christian; Pittrow, David; Pausch, Christine; Wölfle, Joachim; Nsights-Ght Study Grp, (Orphanet Journal of Rare Diseases, 2023)
Background: Somatropin treatment is indicated in a variety of disorders including growth hormone (GH) deficiency, Prader–Willi and Turner syndrome, chronic renal insufficiency and others. To date, almost all studies have been limited to single GH products, and no independent registry across indications and somatropin products was ever established. Aim: The present investigator-initiated registry named INSIGHTS-GHT aims to provide comprehensive information on various aspects of somatropin treatment in Germany in approved indications within routine clinical practice: drug utilization, effectiveness (including real final height, body composition), tolerability, quality of life, other patient related outcomes (PRO), and health economic variables. Methods: Registry (prospective observational study) in specialised pediatric and adult endocrinology centres in Germany. Patients of any age are eligible for documentation, if they are on ongoing or newly initiated treatment with any approved somatropin or somatropin-related product within the labelling, available for long term follow-up documentation, and if they provided informed consent. Subjects may switch, discontinue/interrupt or initiate somatropin products at any time. They are followed up for at least 3 years (minimal study duration). Documentation is planned once or twice per year to record somatropin utilisation (product, dosing), other medications, laboratory status (glucose, lipids, GH function including stimulation tests, IGF-I, IGFBP3), if applicable, pubertal development, auxological parameters, body composition and bone age. Patient reported outcome (PRO) measures include, but are not limited to, Short Form 12 in adults and adolescents aged 14 years and over. Safety reporting includes adverse events. Conclusions: The registry documents children and adults in one joint registry, includes, at present, patients in Germany and allows documentation of patients on all approved somatropin and other growth hormone preparations. It will allow to describe the transition of subjects from adolescence to adulthood (treatment and height), to describe switches between somatotropin preparations, to perform responder analyses, and to analyse differences and similarities of somatropin utilization (by age group, sex, setting, and PRO instrument). INSIGHTS-GHT offers a broad, comprehensive research platform to assess multiple relevant aspects of somatropin treatment and outcomes (including the transition of subjects from adolescence to adulthood), allows the documentation of all GH products including long-acting GH preparations after their introduction, and will evaluate the data independently of funders. Trial registration BfArM Nr. NIS7492, DRKS registry DRKS00027394.
CRIS-Team Scopus Importer:2023-05-26
Keywords: Adults; Children; Growth hormone deficiency; Human growth hormone; Observational; Somatropin

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

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

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

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

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

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

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

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

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

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

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

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

Late complete atrioventricular block after closure of an atrial septal defect with a gore septal occluder (GSO(TM)) - Dittrich, Sven; Sigler, Matthias; Priessmann, Helga (Catheterization and Cardiovascular Interventions, 2016)
Temporary intermittent complete heart block (CHB) occurred the day after interventional closure of an ASD with a 30 mm Gore Septal Occluder (GSO(TM)) in a 2 years and 11-month-old female. CHB disappeared without further treatment and stable sinus rhythm recovered within 3 days. Only short episodes of 2nd degree AV-block (Wenckebach periodicity) at rare intervals were documented in Holter-monitors the following 2 months. Eleven months after device implantation the patient suffered from long lasting episodes of CHB. Surgical removal of the device resulted in incomplete recovery of AV-conduction. Histopathological work-up of the explanted GSO showed complete endothelialization of the device and regular scar formation. One year after surgery, the child had sinus rhythm during daytime but needed VVI-pacing while sleeping. Young age, inferior localization of the defect, and use of a large device have been individual risk factors for CHB in this patient. Clinical course and histologic findings indicate that mechanical compression was the only cause for CHB. The cumulative number of reports of CHB after use of different ASD-devices supports the recommendation to postpone the intervention in asymptomatic patients to preschool-age. Early removal of a pushing device may increase the chance of complete recovery from CHB.
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Latency duration of preterm premature rupture of membranes and neonatal outcome: a retrospective single-center experience - Mueller, Hanna; Staehling, Ann-Christin; Bruns, Nora; Weiss, Christel; Ai, Maria; Koeninger, Angela; Felderhoff-Mueser, Ursula (European journal of pediatrics, 2021)
In preterm premature rupture of membranes (PPROM), a decision between early delivery with prematurity complications and pregnancy prolongation bearing the risk of chorioamnionitis has to be made. To define disadvantages of delayed prolongation, latency duration of PPROM in expectantly managed pregnancies was investigated. We included those PPROMs > 48 h leading to preterm birth prior 37 weeks’ gestation and retrospectively analyzed 84 preterm infants fulfilling these criteria. The association between latency duration/appearance of PPROM and respiratory outcome (primary outcomes) and neurological outcome (secondary outcomes) was investigated. The study showed that latency duration of PPROM is not associated with clinical or histological chorioamnionitis (p = 0.275; p = 0.332). As the numerous clinical parameters show multicollinearity between each other, we performed a multiple regression analysis to consider this fact. Respiratory distress syndrome is significantly associated with gestational age at PPROM (p < 0.001), and surfactant application is significantly associated with PPROM duration (p = 0.014). The other respiratory parameters including steroids and diuretics therapy, bronchopulmonary dysplasia, and the neurological parameters (intraventricular hemorrhage, Bayley II testing at a corrected age of 24 months) were not significantly associated with PPROM duration or gestational age at PPROM diagnosis. Conclusion: Latency duration of PPROM was not associated with adverse neonatal outcome in expectantly and carefully managed pregnancies, but respiratory distress syndrome was pronounced. The observed effect of pronounced respiratory distress syndrome can be treated with surfactant preparations and was not followed by increased rate of bronchopulmonary dysplasia.What is Known:• In case of preterm premature rupture of membranes, a decision between pregnancy prolongation with the risk of chorioamnionitis and early delivery with prematurity complications has to be made.• Chorioamnionitis is a dangerous situation for the pregnant woman and the fetus.• Impaired neurodevelopmental outcome is strongly correlated with pronounced prematurity due to the increased rate of serious complications.What is New:• Respiratory distress syndrome is significantly associated with gestational age at PPROM, and surfactant application is significantly associated with PPROM duration.• Latency duration of PPROM is not associated with adverse respiratory neonatal outcome (therapy with continuous positive airway pressure, therapy with diuretics and/or steroids, bronchopulmonary dysplasia) in expectantly and carefully managed pregnancies.• Intraventricular hemorrhage and Bayley II testing at a corrected age of 24 months are not associated with latency duration of PPROM when pregnancies are carefully observed.
CRIS-Team Scopus Importer:2021-10-15
Keywords: Chorioamnionitis; Neurological development; Preterm infant; Preterm premature rupture of membranes; Respiratory distress syndrome

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

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

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

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

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

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

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

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

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

Long-term positive and negative psychosocial outcomes in young childhood cancer survivors, type 1 diabetics and their healthy peers - Kremer, Anna-Lena; Schieber, Katharina; Metzler, Markus; Schuster, Sonja; Erim, Yesim (International Journal of Adolescent Medicine and Health, 2016)
EVALuna2:18942

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Medical care of adults with congenital heart diseases : Present and future - Neidenbach, R.; Achenbach, Stephan; Andonian, C.; Beckmann, J.; Biber, S.; Dittrich, Sven; Ewert, P.; Freilinger, S.; Huntgeburth, M.; Nagdyman, N.; Oberhoffer, R.; Pieper, L.; et al. (Herz, 2019)
Congenital heart diseases (CHD) are the most common types of congenital organ defects. Thanks to medical progress in congenital cardiology and heart surgery, most children with CHD reach adulthood. Despite primarily successful treatment residual and subsequent conditions as well as (non)cardiac comorbidities can influence the chronic course of the disease and lead to a higher morbidity and mortality. Adults with congenital heart disease (ACHD) in Germany are not tied to the healthcare structure despite the great need for aftercare. According to the results of the medical care of ACHD (MC-ACHD) study, ACHD centers and specialists in Germany are insufficiently perceived despite increased complication rates and the great need for specialist guidance. General practitioners and patients are not adequately informed about existing ACHD facilities. A better awareness of the ACHD problem should be created at the level of primary medical supply in order to optimize care and to reduce morbidity and mortality. Improved future-oriented patient care includes lifelong regular follow-up and the possibility of interdisciplinary, integrated medical care of CHD.
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Medication safety in children : What role do dosing and formulations play? - Neubert, Antje; Rascher, Wolfgang (Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz, 2018)
Medication errors are more common in children compared to adults due to often missing efficacy evidence and limited or missing regulatory approvals for paediatric drugs.Roots of errors are located at different levels. They result, for example, from missing clinical studies that particularly investigate efficacy and correct dosing in younger age groups, the lack of age-appropriate dosage forms, the use of harmful ingredients, as well as the complicated and high-risk prescribing process.Electronic systems may improve the quality of drug prescriptions and reduce medication errors. The basic assumption is valid, evidence-based data behind such a system. In contrast to other countries, such a database is not yet available in Germany. The Plan of Action for the improvement of medication safety in Germany 2016-2019 (Aktionsplan) contains an action point "Creation of a database for dosing of paediatric medicines". Initial funding for 2 years has been granted for its implementation.Through systematic literature searches and the availability and provision of up-to-date knowledge on paediatric medicines, medication safety for children and adolescents can be improved. A database with relevant information to support more correct prescriptions within the paediatric population appears productive. The Aktionsplan has paved the way for the dissemination of evidence-based drug information for the country's paediatric population.
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Medikamentenpriming am Beispiel der Therapie der Aufmerksamkeits-Defizit-Hyperaktivitäts-Störung (ADHS) - Rascher, Wolfgang (Drug Research, 2018)
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Medizinische Versorgung von Erwachsenen mit angeborenen Herzfehlern: Gegenwart und Zukunft - Neidenbach, R.; Achenbach, Stephan; Andonian, C.; Beckmann, J.; Biber, S.; Dittrich, Sven; Ewert, P.; Freilinger, S.; Huntgeburth, M.; Nagdyman, N.; Oberhoffer, R.; Pieper, L.; et al. (Herz, 2019)
Congenital heart diseases (CHD) are the most common types of congenital organ defects. Thanks to medical progress in congenital cardiology and heart surgery, most children with CHD reach adulthood. Despite primarily successful treatment residual and subsequent conditions as well as (non)cardiac comorbidities can influence the chronic course of the disease and lead to a higher morbidity and mortality. Adults with congenital heart disease (ACHD) in Germany are not tied to the healthcare structure despite the great need for aftercare. According to the results of the medical care of ACHD (MC-ACHD) study, ACHD centers and specialists in Germany are insufficiently perceived despite increased complication rates and the great need for specialist guidance. General practitioners and patients are not adequately informed about existing ACHD facilities. A better awareness of the ACHD problem should be created at the level of primary medical supply in order to optimize care and to reduce morbidity and mortality. Improved future-oriented patient care includes lifelong regular follow-up and the possibility of interdisciplinary, integrated medical care of CHD.
CRIS-Team Scopus Importer:2019-08-06
Keywords: ACHD; Cardiology; Comorbidities; Congenital heart defects; Prevention

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

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

Memorandum on the use of information technology to improve medication safety - Ammenwerth, E.; Aly, A. -F.; Bürkle, Thomas; Christ, P.; Dormann, H.; Friesdorf, W.; Haas, C.; Haefeli, W. E.; Jeske, M.; Kaltschmidt, J.; Menges, K.; Moeller, H.; et al. (Methods of Information in Medicine, 2014)
Information technology in health care has a clear potential to improve the quality and efficiency of health care, especially in the area of medication processes. On the other hand, existing studies show possible adverse effects on patient safety when IT for medication-related processes is developed, introduced or used inappropriately.To summarize definitions and observations on IT usage in pharmacotherapy and to derive recommendations and future research priorities for decision makers and domain experts.This memorandum was developed in a consensus-based iterative process that included workshops and e-mail discussions among 21 experts coordinated by the Drug Information Systems Working Group of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS).The recommendations address, among other things, a stepwise and comprehensive strategy for IT usage in medication processes, the integration of contextual information for alert generation, the involvement of patients, the semantic integration of information resources, usability and adaptability of IT solutions, and the need for their continuous evaluation.Information technology can help to improve medication safety. However, challenges remain regarding access to information, quality of information, and measurable benefits.
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Metabolic and molecular imaging in inflammatory arthritis - de Sousa, Rita Noversa; Tascilar, Koray; Corte, Giulia; Atzinger, Armin; Minopoulou, Ioanna; Ohrndorf, Sarah; Waldner, Maximilian; Schmidkonz, Christian; Kuwert, Torsten; Knieling, Ferdinand; Kleyer, Arnd; Ramming, Andreas; et al. (RMD Open, 2024)
It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively. Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation. Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.
CRIS-Team Scopus Importer:2024-02-23

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

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

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

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

Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system - Man, K. K. C.; Coghill, D.; Chan, E. W.; Lau, W. C. Y.; Hollis, Chris; Liddle, Elizabeth; Banaschewski, T.; Mccarthy, S.; Neubert, Antje; Sayal, Kapil; Ip, P.; Wong, I. C. K. (Translational Psychiatry, 2016)
Previous studies have suggested that risk of psychotic events may be increased in children exposed to methylphenidate (MPH). However, this risk has not been fully examined, and the possibility of confounding factors has not been excluded. Patients aged 6-19 years who received at least one MPH prescription were identified using Hong Kong population-based electronic medical records on the Clinical Data Analysis and Reporting System (2001-2014). Using the self-controlled case series design, relative incidence of psychotic events was calculated comparing periods when patients were exposed to MPH with non-exposed periods. Of 20,586 patients prescribed MPH, 103 had an incident psychotic event; 72 (69.9%) were male and 31 (30.1%) female. The mean age at commencement of observation was 6.95 years and the mean follow-up per participant was 10.16 years. On average, each participant was exposed to MPH for 2.17 years. The overall incidence of psychotic events during the MPH exposure period was 6.14 per 10,000 patient-years. No increased risk was found during MPH-exposed compared with non-exposed periods (incidence rate ratio (IRR) 1.02 (0.53-1.97)). However, an increased risk was found during the pre-exposure period (IRR 4.64 (2.17-9.92)). Results were consistent across all sensitivity analyses. This study does not support the hypothesis that MPH increases risk of incident psychotic events. It does indicate an increased risk of psychotic events before the first prescription of MPH, which may be because of an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment.
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Microbiota-Derived Propionate Modulates Megakaryopoiesis and Platelet Function - Dürholz, Kerstin; Schmid, Eva; Frech, Michael; Azizov, Vugar; Otterbein, Nadine; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (Frontiers in Immunology, 2022)
Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular events driven by abnormal platelet clotting effects. Platelets are produced by megakaryocytes, deriving from megakaryocyte erythrocyte progenitors (MEP) in the bone marrow. Increased megakaryocyte expansion across common autoimmune diseases was shown for RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS). In this context, we evaluated the role of the microbial-derived short chain fatty acid (SCFA) propionate on hematopoietic progenitors in the collagen induced inflammatory arthritis model (CIA) as we recently showed attenuating effects of preventive propionate treatment on CIA severity. In vivo, propionate treatment starting 21 days post immunization (dpi) reduced the frequency of MEPs in the bone marrow of CIA and naïve mice. Megakaryocytes numbers were reduced but increased the expression of the maturation marker CD61. Consistent with this, functional analysis of platelets showed an upregulated reactivity state following propionate-treatment. This was confirmed by elevated histone 3 acetylation and propionylation as well as by RNAseq analysis in Meg-01 cells. Taken together, we identified a novel nutritional axis that skews platelet formation and function.
CRIS-Team Scopus Importer:2022-08-05
Keywords: hematopoietic progenitors; megakaryocytes; microbiota; platelets; rheumatoid arthritis; short-chain fatty acids

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

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