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Preterm delivery is a stressful event for mothers, posing them at risk for post-traumatic stress reactions. This study examined the degree of depressive symptoms and post-traumatic stress in mothers of preterm infants born before 32 gestational weeks depending on whether the infant received music therapy in the neonatal intensive care unit (NICU) or not. We included 33 mothers of preterm infants enrolled in a previously described prospective randomized controlled trial, of whom 18 received music therapy (mean mothers’ age 34.1 ± 4.6 years) and 15 did not (mean mothers’ age 29.6 ± 4.2). The degree of depressive symptoms, anxiety and acute stress reactions of these mothers were measured by using the German version of the Center for Epidemiologic Studies Depression Scale (CES-D) and Impact of Events Scale-Revised (IES-R) one week after birth (T1) and at infants’ hospital discharge (T2). 605 music therapy sessions with a mean duration of 24.2 ± 8.6 min (range 10 to 50 min) were conducted two times a week from the second week of life (T1) until discharge (T2) to the infants from the intervention group. The infants from the control group received standard medical care without music therapy. The mean total CES-D score decreased from T1 (mean 34.7, 95% Confidence Interval (CI) 31.1–38.1) until T2 in all mothers (mean 16.3, 95% CI 12.6–20.1). Mothers whose infants received music therapy showed stronger declines of depressive and stress symptoms (with music therapy: CES-D mean difference of total score 25.7, 95% CI 20.0–31.3, IES-R mean difference of total score 1.7, 95% CI 0.9–2.5, IES-R mean difference of subcategory hyperarousal 10.2, 95% CI 6.2–14.3; without music therapy: CES-D mean difference of total score 9.5, 95% CI 3.8–15.3, IES-R mean difference of total score 0.1, 95% CI −1.0–1.2, IES-R mean difference of subcategory hyperarousal 1.6, 95% CI −4.7–7.9). Effect sizes were strong for CES-D, IES-R, and the hyperarousal subcategory, moderate for intrusion, and low for avoidance. These findings show that mothers of preterm infants are highly susceptible to supportive non-medical interventions such as music therapy to reduce psychological symptoms and distress during their infants’ NICU stay.

AimAmplitude-integrated electroencephalography (aEEG) is used to monitor electrocortical activity in critically ill children but age-specific reference values are lacking. We aimed to assess the impact of age and electrode position on aEEG amplitudes and derive normal values for pediatric aEEGs from neurologically healthy children.MethodsNormal EEGs from awake children aged 1 month to 17 years (213 female, 237 male) without neurological disease or neuroactive medication were retrospectively converted into aEEGs. Two observers manually measured the upper and lower amplitude borders of the C3 – P3, C4 – P4, C3 – C4, P3 – P4, and Fp1 – Fp2 channels of the 10–20 system. Percentiles (10th, 25th, 50th, 75th, 90th) were calculated for each age group (ResultsAmplitude heights and curves differed between channels without sex-specific differences. During the first 2 years of life, upper and lower amplitudes of all but the Fp1–Fp2 channel increased and then declined until 17 years. The decline of the upper Fp1–Fp2 amplitude began at 4 years, while the lower amplitude declined from the 1st year of life.ConclusionsaEEG interpretation must account for age and electrode positions but not for sex in infants and children.

BackgroundThe sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio serves as a clinical biomarker to predict the hypertensive, placenta-derived pregnancy disorder pre-eclampsia which is often associated with placental dysfunction and fetal growth restriction. Additionally elevated levels also indicate an increased risk for prematurity. However, its predictive value for subsequent neonatal neurological outcome has not been studied.ObjectiveThis study aimed to evaluate the correlation of maternal sFlt-1/PlGF ratio with early motor outcome of preterm infants. Design/Methods: 88 preterm infants (gestational age ≤ 34 + 0) born between February 2017 and August 2020 at the Department of Obstetrics and Gynecology, University Hospital Essen in Germany, were included, when the following variables were available: maternal sFlt-1/PlGF levels at parturition and general movement assessment of the infant at the corrected age of 3 to 5 months. The infants were stratified into high and low ratio groups according to maternal sFlt-1/PlGF cut-off values of 85. To investigate the early motor repertoire and quality of spontaneous movements of the infant, the Motor Optimality Score (MOS-R) based on antigravity movements and posture patterns, was applied. In the given age, special attention was paid to the presence of fidgety movements. Linear regressions were run to test differences in infants motor repertoire according to the maternal sFlt-1/PIGF ratio.ResultsLinear regression analysis showed that the sFlt-1/PlGF ratio does not predict the MOS-R score (β=≤0.001; p=0.282). However, children with birth weight below the 10th percentile scored significantly lower (mean 20.7 vs 22.7; p=0.035). These children were 91% in the group with an increased ratio, which in turn is a known predictor of low birth weight (β= -0.315; p <0.001). In the group with a high sFlt-1/PLGF ratio above 85 the mothers of female infants had a lower average sFlt-1/PlGF ratio compared to a male infant (median: 438 in female vs. 603 in male infant, p=0.145).ConclusionsIn our cohort, especially low birth weight, which correlated with an elevated sFlt-1/PlGF ratio, had a negative effect on the outcome in the MOS-R. A direct correlation between an increased ratio and a worse motor outcome was not demonstrated.

Genes 13(5), 893 (2022). doi:10.3390/genes13050893 special issue: "Special Issue "Genetics of Motor Neuron Diseases" / Special Issue Editor: Christopher Grunseich, Guest Editor", Published by MDPI, Basel

(1) Background: Postoperative infections are major contributors of morbidity and mortality after paediatric liver transplantation (pLTX). Evidence and recommendations regarding the most effective antimicrobial strategy are lacking. (2) Results: Of 39 pLTX centres, 20 responded. Aminopenicillins plus ß-lactamase inhibitors were used by six (30%) and third generation cephalosporins by three (15%), with the remaining centres reporting heterogenous regimens. Broad-spectrum regimens were the standard in 10 (50%) of centres and less frequent in the 16 (80%) centres with an infectious disease specialist. The duration ranged mainly between 24–48 h and 3–5 days in the absence and 3–5 days or 6–10 days in the presence of risk factors. Strategies regarding antifungal, antiviral, adjunctive antimicrobial, and surveillance strategies varied widely. (3) Methods: This international multicentre survey endorsed by the European Liver Transplant Registry queried all European pLTX centres from the registry on their current practice of perioperative antibiotic prophylaxis and antimicrobial strategies via an online questionnaire. (4) Conclusions: This survey found great heterogeneity regarding all aspects of postoperative antimicrobial treatment, surveillance, and prevention of infections in European pLTX centres. Evidence-based recommendations are urgently needed to optimise antimicrobial strategies and reduce the spectrum and duration of antimicrobial exposure.

Hintergrund: Die akute virale Bronchiolitis ist eine häufige Erkrankung im Säuglings- und Kleinkindalter. Trotz insgesamt guter Prognose bei adäquater Behandlung kann die Bronchiolitis zu einer respiratorischen Insuffizienz führen. Es existieren nur wenige Erkenntnisse über die Behandlung schwer erkrankter Kindermit Atemunzterstützung in unterschiedlichen europäischen Ländern. Patienten: Säuglinge (n = 146) mit Bronchiolitis und mechanischer Atemunterstützung in der Wintersaison 2015/2016, die in einer der zwei teilnehmenden Regionen behandelt wurden: Süden des Großraums Paris in Frankreich (Gruppe 1) oder erweitertes Ruhrgebiet in Deutschland (Gruppe 2). Methoden: Retrospektive Datenauswertung, primärer Outcomeparameter war die Dauer der Atemwegsunterstützung. Ergebnisse: Die Säuglinge in Gruppe 1 (n = 96) waren jünger, hatten seltener neurologische Grunderkrankungen und eine niedrigere Atemfrequenz als in Gruppe 2 (n = 50). Die erhobenen CO2-Werte und Dyspnoe-Score unterschieden sich nicht. Neunzig Prozent der Säuglinge in Gruppe 1 wurden mit nCPAP (nasal Continuous Airway Pressure) behandelt, während 80 % in Gruppe 2 HFNC (High Flow Nasal Cannula) erhielten. Die Dauer der Atemunterstützung war signifikant kürzer in Gruppe 1. Hingegen erhielten Säuglinge in Gruppe 2 häufiger Infusions- und Inhalationsherapien, sowie häufiger Antibiotika. Diskussion: Diese Ergebnisse zeigen ein besseres Outcome für Säuglinge, die in Frankreich behandelt wurden. Ein frappierender Unterschied zeigte sich in der Wahl der Atemunterstützung sowie in der Häufigkeit zusätzlicher Therapieformen. Auch der Einsatz von weniger potentiell Stress verursachende Therapien und eine zentralisierte Versorgung können Einflussfaktoren darstellen. Schlussfolgerung: Die Behandlung der schweren akuten viralen Bronchiolitis in Frankreich (Großraum Paris) unterscheidet sich deutlich von der in Deutschland (Ruhrgebiet)., Background: Acute viral bronchiolitis is a frequent disease in infancy. There is little knowledge on medical care of severely affected infants requiring respiratory support in different European countries. Patients: Infants (n = 146) with bronchiolitis needing respiratory support in winter season 2015/2016 treated in either one of two regions in Central Europe: South of greater Paris region in France (group 1) and Ruhr area in Germany (group 2). Methods: Retrospective chart review. Primary outcome parameter was duration of respiratory support. Results: Infants in group 1 (n = 96) were younger, suffered less frequently from neurologic disorders and had lower respiratory rates than in group 2 (n = 50). Measured CO2 levels and dyspnea score were similar. Ninety percent of infants in group 1 were treated by nasal Continuous Airway Pressure CPAP, while 80 % of infants in group 2 were treated by High Flow Nasal Cannula HFNC. Duration of respiratory support was significantly shorter in group 1. Infants in group 2 received more frequently infusion and inhalation therapy, and more antibiotics. Discussion: Our results show better outcome for infants with viral bronchiolitis treated in France. Striking differences were the practice of respiratory support (nasal CPAP vs. HFNC) and the prescription of supportive treatments. Conclusion: Treatment approaches in severe acute viral bronchiolitis differ widely between a French and a German urban region.

The pregnancy disorder preeclampsia (PE) is characterized by maternal hypertension, increased level of circulating antiangiogenic soluble fms-like tyrosine kinase-1 (sFLT1), and reduced placental perfusion, leading to foetal growth restriction (FGR) and preterm birth. All these adverse effects are associated with neurocognitive disorders in the offspring. However, the direct interplay between increased antiangiogenesis during PE and disturbed foetal brain development independent of prematurity has not been investigated yet. To examine foetal brain development in sFLT1-related PE, hsFLT1/rtTA-transgenic mice with systemic (maternal or maternal/fetoplacental) human sFLT1 (hsFLT1) overexpression since 10.5 days postconception (dpc) were used, and histological and molecular analyses of foetal brains were performed at 18.5 dpc. Consequences of elevated hsFLT1 on placental/foetal vascularization and hypoxia of placentas and foetal brains were analysed using the hypoxia markers pimonidazole and hemeoxygenase-1 (HO-1). Immunohistochemical analysis revealed increased hypoxia in placentas of PE-affected pregnancies. Moreover, an increase in HO-1 expression was observed upon elevated hsFLT1 in placentas and foetal brains. PE foetuses revealed asymmetrical FGR by increased brain/liver weight ratio. The brain volume was reduced combined with a reduction in the cortical/hippocampal area and an increase of the caudate putamen and its neuroepithelium, which was associated with a reduced cell density in the cortex and increased cell density in the caudate putamen upon hsFLT1 overexpression. Mild influences were observed on brain vasculature shown by free iron deposits and mRNA changes in Vegf signalling. Of note, both types of systemic hsFLT1 overexpression (indirect: maternal or direct: maternal/fetoplacental) revealed similar changes with increasing severity of impaired foetal brain development. Overall, circulating hsFLT1 in PE pregnancies impaired uteroplacental perfusion leading to disturbed foetal oxygenation and brain injury. This might be associated with a disturbed cell migration from the caudate putamen neuroepithelium to the cortex which could be due to disturbed cerebrovascular adaption. OA Förderung 2022

Children : open access pediatrics journal 9(3), 363 (2022). doi:10.3390/children9030363 special issue: "Special Issue "Pediatric Intensive Care – Practice and Research" / Special Issue Editors: Dr. Martin E.G. Blohm, Guest Editor; Prof. Dr. Dominique Singer, Guest Editor", Published by MDPI, Basel

OA Förderung 2022 Background: Infections, major surgeries, and hyperinflammatory syndromes are known to trigger Systemic Inflammatory Response Syndrome (SIRS). Discrimination between infectious and noninfectious inflammation often poses a challenge in chronically ill patients with multiple comorbidities. These patients are routinely treated with a variety of anti-infective medications before a pathogen is iden- tified. With the goal of improving pathogen detection rates and interventions, we evaluated Next Generation Sequencing (NGS) as a highly sensitive and fast means of detecting free microbial DNA in a small amount of serum samples from children with ongoing SIRS. Methods: We describe seven complex pediatric patients of SIRS or prolonged fever (>38.5 °C) >72 hours in which serum samples ana- lyzed by NGS had a major impact on therapy. One patient was analyzed twice. Results: In eight NGS there were six positive results (two bacterial, three viral, one fungal) which were subsequently confirmed by microbiological culture or polymerase chain reaction (PCR) in five of the six NGS. In five of the eight performed NGS, results led to a change of therapy: antibiotic therapy was discontinued in two, escalated in one, an initiated in another; in one an antiviral was administered. Conclusions: NGS may become a valuable addition to infectious disease diagnostics in cases of pediatric SIRS. However, NGS has not yet been validated as a diagnostic method in pediatric as a diagnostic method in pediatric patients and results should therefore be interpreted with caution. Multi-center NGS evaluation studies are currently being planned.

Recent research found evidence supporting music therapy for children with neurological diseases during their hospitalized neurological early rehabilitation to promote their development during physical therapy. We hypothesized that live music therapy might improve vital signs during a physical therapy session. Seventeen children received live music therapy during the physical therapy session twice a week. Two more physical therapy sessions per week were held without music therapy. Heart rate, respiratory rate and oxygen saturation were recorded from 15 min before to 15 min after the therapy sessions. Physical therapy interventions showed changes in heart rate, respiratory rate and oxygen saturation between, before and after the sessions with or without music ther-apy. Live music therapy was effective for the vital signs during the intervention. We observed sig-nificantly lower heart and respiratory rates and higher oxygen saturation during physical therapy intervention with live music therapy in general (mean differences −8.0 beats per min; −0.8 breaths per min and +0.6%). When physical therapy was applied without music therapy children’s heart rates increased by 8.5 beats per min and respiratory rates increased by 1.0 breaths per min. Live music therapy leads to a decrease in heart and respiratory rates and an increase in oxygen saturation in children with neurological diseases during physical therapy with live music therapy. Music therapy supports the children in physical therapy interventions during their hospitalization. OA Förderung 2022

IntroductionInterpretation of amplitude-integrated EEG (aEEG) is hindered by lacking knowledge on physiological background patterns in children. The aim of this study was to find out whether aEEG differs between wakefulness and sleep in children.MethodsForty continuous full-channel EEGs (cEEG) recorded during the afternoon and overnight in patients ResultsMedian age was 9.9 years (IQR 6.1–14.7). All patients displayed continuous background patterns. Amplitudes and BW differed between wakefulness and sleep with median amplitude values of the C3–C4 channel 35 μV (IQR: 27–49) for the upper and 13 μV (10–19) for the lower amplitude. The BW was 29 μV (21–34). During sleep, episodes with high amplitudes [upper: 99 μV (71–125), lower: 35 μV (25–44), BW 63 μV (44–81)] corresponded to sleep states N2–N3. High amplitude-sections were interrupted by low amplitude-sections, which became the longer toward the morning [upper amplitude: 39 μV (30–51), lower: 16 μV (11–20), BW 23 μV (19–31)]. Low amplitude-sections were associated with sleep states REM, N1, and N2. With increasing age, amplitudes and bandwidths declined.ConclusionaEEGs in non-critically ill children displayed a wide range of amplitudes and bandwidths. Amplitudes were low during wakefulness and light sleep and high during deep sleep. Interpretation of pediatric aEEG background patterns must take into account the state of wakefulness in in clinical practice and research.

Background During the COVID-19 pandemic, parents of infants born very preterm or at risk were exceptionally worried about being infected. The only means of protection during the onset of the pandemic was social distancing. Video consultations for neurodevelopmental follow-up care were offered as an alternative way to stay in contact with patients and their families, to provide expert support, and to monitor and assess children’s development. Objective To assess the feasibility of and family satisfaction with video consultations, interviews were conducted after video and in-person consultations. Methods An interview with 28 questions was created to evaluate parental satisfaction with the consultations (eg, their confidentiality and the children’s behavior). A total of 93 interviews with parents were conducted between March 2020 and February 2021 and compared (58 after video consultations and 35 after in-person consultations). The interviews were conducted at the end of the consultations by a trained professional. The video consultations were conducted using a certified platform created by Zava Sprechstunde Online, maintaining data protection with end-to-end encryption. Follow-up consultations (video or in-person) were performed at corrected ages of 3, 6, and 12 months as well as 2, 3, 4, and 5 years. The rate of total follow-up appointments attended during the survey period was evaluated and compared with the previous year. Results There were no significant differences between the video and in-person consultation groups in satisfaction, attitudes on the confidentiality of the consultation, or discussion of private and sensitive information. Following video consultations, parents were significantly more likely to report that they were avoiding contact with medical professionals during the pandemic (P=.045; Shapiro-Wilk W=1094.5, Cohen d=–0.1782146) than the in-person consultation group. Parents in the video-consultation group stated that performing a guided examination on their child was comfortable and helped them understand their child’s development. In fact, they agreed to take advantage of future video consultations. The rate of total follow-up appointments increased compared to the previous year. Between March 2019 and February 2020, 782 of 984 (79.5%) children born at Essen University Hospital attended a follow-up appointment. During the survey period, between March 2020 and February 2021, a total of 788 of 1086 children (73%) attended a follow-up appointment, of which 117 (14.9%) were video consultations. Conclusions The feasibility of attending video consultations for follow-up care of very preterm or at-risk infants and parental satisfaction with these consultations were as high as for in-person consultations. Parents rated video consultations as being as confidential as in-person appointments. Telemedicine can be offered as an equivalent alternative to in-person consultations and is particularly useful under certain circumstances, such as for very sick children who require assistive devices or respiratory support and oxygen or for those living a long distance away.

Cells : open access journal 10(12), 3481 (2021). doi:10.3390/cells10123481 special issue: "Special Issue "Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach" / Special Issue Editors: Dr. Anne Schänzer, Guest Editor; Dr. Tobias Ruck, Guest Editor; Prof. Dr. Andreas Hahn, Guest Editor; Dr. Corinna Preusse, Guest Editor", Published by MDPI, Basel

Premature birth places considerable demands on preterm infants and their families. Most of these infants are treated on a neonatal intensive care unit immediately after birth, leading to psychosocial stress for parents and making it more difficult to build a stable parent-child bond. We hypothesized that accompaniment with live music therapy by a music therapist supports the parents to get in contact with their child and to promote the parents’ wellbeing. Preterm infants born at less than 32 gestational weeks received creative music therapy twice a week until discharge. At the time of discharge, the parents were asked to complete a Likert-style questionnaire to evaluate the music therapy. Six items related to socio-demographic characteristics, 4 items to observations on the infant and 10 items to personal perception. Of 40 preterm infants receiving music therapy, 32 (80%) parents completed the questionnaires. Thirty (94%) of these parents were able to relax during the music therapy session. Relaxation in their infants was observed by 29 (91%) during and by 28 (88%) after music therapy. Parents perceived music therapy as a positive change and enrichment during their infant’s hospital stay. All parents were thankful for the music therapy they received. Music therapy supports the parents of preterm infants in the first time after birth until discharge from the hospital. OA Förderung 2021

Background Neonatal encephalopathy due to hypoxia–ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice. Methods Nine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry. Results Immediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT. Conclusion Our data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.

OA Förderung 2021 Background: Rituximab (RTX) is used in cancer therapy as well as in the treatment of autoimmune diseases and alloimmune responses after transplantation. It depletes the disease-causing B cells by binding to the CD (cluster of differentiation) 20 antigen. We evaluate different pediatric treatment protocols (via fixed treatment schedule, B cell- or symptom-controlled) and their therapeutic effects. Methods: Demographic information, clinical and laboratory characteristics, and special laboratory values such as immunoglobulin G (IgG), CD19 positive B cells and Epstein-Barr viral load were retrospectively analyzed in children treated with RTX between 2008 and 2016. Results: Seventy-six patients aged 1 to 19 (median 13) years were treated with 259 RTX infusions. The spectrum of diseases was very heterogeneous. RTX led to a complete depletion of the B cells. The reconstitution time varied between patients and was dependent on the application schedule (median 11.8 months). Fourteen out of 27 (52%) patients developed hypogammaglobulinaemia. The risk of IgG deficiency was 2.6 times higher in children under 4 years of age than in olderones. In the last group IgG deficiency developed in only 38% of the cases (n = 8). Recurrent and severe infections were observed each in 11/72 (15%) patients. Treatment-related reactions occurred in 24/76 (32%) cases; however, treatment had to be discontinued in only 1 case. In 16/25 (76%), the Epstein-Barr viral load dropped below the detection limit after the first RTX infusion. Conclusion: RTX is an effective and well-tolerated drug for the treatment of oncological diseases as well as autoimmune and alloimmune conditions in children. B cell depletion and reconstitution varies both intra- und interindividually, suggesting that symptom-oriented and B cell-controlled therapy may be favorable. Treatment-related reactions, IgG deficiency and infections must be taken into account.

The normative transition to formal schooling confronts children with social challenges but also opportunities. Longitudinal research on how school entry impacts children’s family and friend-ship relationships is scarce. This study investigated social relationship qualities with parents, siblings, and friends among 1110 children (49.9% female) from the prospective, population-based Bavarian Longitudinal Study at 6 years (before school entry) and 8 years using a forced-choice card-sorting task. Multivariate analyses of variance revealed significant effects of age (i.e., school entry) on social relationship qualities with mothers (Pillai’s Trace (PT) = 0.28, F(9, 1101) = 47.73, p &lt, 0.001), fathers (PT = 0.14, F(9, 1101) = 19.47, p &lt, 0.001), siblings (PT = 0.27, F(9, 1101) = 46.14, p &lt, 0.001), and friends (PT = 0.21, F(9, 1101) = 32.57, p &lt, 0.001). On average, children reported higher levels of parental comfort after school entry. Companionable qualities increased in relationships with friends, whereas sibling relationships became more conflictual from preschool to early school age. Findings provide unique insights into how social relationships develop from preschool to early school age, supporting evidence of the growing importance of friends. Conflict was predominant and increasing in sibling relationships and should be considered more in future research.

Introduction: High oxygen concentrations have been identified as one factor contributing to the pathogenesis of the retinopathia of prematurity, chronic lung disease of the preterm infant and preterm brain injury. Preterm infants also show short- and long-term alterations of the endocrine system. If hyperoxia is one pathogenetic factor has not been investigated yet. With regard to the high prevalence of neurodevelopmental impairments in preterm infants, the hypothalamus-pituitary-thyroid (HPT) axis, the hypothalamus-pituitary-adrenal (HPA) axis and the hypothalamus-pituitary-somatotropic (HPS) axis are of special interest due to their important role in neurodevelopment. Objective: The aim of this study was to investigate the effect of hyperoxia on the endocrine system in the neonatal rat by analyzing the activities of the HPT, HPA and HPS axes, respectively. Methods: Three-days old Wistar rats were exposed to hyperoxia (oxygen 80%, 48 h). On postnatal day 5 (P5) and P11, transcript levels of thyroid-stimulating hormone (TSH), proopiomelanocortin and growth hormone (GH) were analyzed in pituitary sections by in situ hybridization. Serologic quantification of TSH and thyroxine (T4), adrenocorticotropic hormone and GH were performed by Multiplex analysis and Enzyme-linked Immunosorbent Assay. Results: At P5, significantly lower GH levels were observed in pituitaries (mRNA) and in sera of rats exposed to hyperoxia. Serum TSH was significantly elevated without changes in T4. Conclusion: This is the first study demonstrating transient endocrine alterations following hyperoxia in the neonatal rat making oxygen a possible contributor to the pathogenesis of endocrine alterations seen in preterm infants. Considering the detrimental multi-organ effects of hyperoxia on the immature organism, a rational use of therapeutic oxygen in the treatrnent of preterm infants is of utmost importance.

Background: Even though traumatic brain injury (TBI) is a major cause of morbidity and mortality in children around the globe, population-based and nation-wide data to assess the burden of TBI is scarce. Methods:Based on diagnosis related groups from nation-wide hospital data, we extracted data on all TBI-related hospitalizations in children

(1) Background: Immune–mediated necrotizing myopathy (IMNM) is a rare form of inflammatory muscle disease which is even more rare in pediatric patients. To increase the knowledge of juvenile IMNM, we here present the clinical findings on long-term follow-up, myopathological changes, and therapeutic strategies in two juvenile patients. (2) Methods: Investigations included phenotyping, determination of antibody status, microscopy on muscle biopsies, MRI, and response to therapeutic interventions. (3) Results: Anti-signal recognition particle (anti-SRP54) and anti-3-hydroxy-3-methylglutarly coenzyme A reductase (anti-HMGCR) antibodies (Ab) were detected in the patients. Limb girdle presentation, very high CK-levels, and a lack of skin rash at disease-manifestation and an absence of prominent inflammatory signs accompanied by an abnormal distribution of α-dystroglycan in muscle biopsies initially hinted toward a genetically caused muscle dystrophy. Further immunostaining studies revealed an increase of proteins involved in chaperone-assisted autophagy (CASA), a finding already described in adult IMNM-patients. Asymmetrical muscular weakness was present in the anti-SRP54 positive Ab patient. After initial stabilization under therapy with intravenous immunoglobulins and methotrexate, both patients experienced a worsening of their symptoms and despite further therapy escalation, developed a permanent reduction of their muscle strength and muscular atrophy. (4) Conclusions: Diagnosis of juvenile IMNM might be complicated by asymmetric muscle weakness, lack of cutaneous features, absence of prominent inflammatory changes in the biopsy, and altered α-dystroglycan. OA Förderung 2021

Recent research found evidence supporting music therapy for preterm infants to stabilize vital signs and possibly promote neurodevelopment. Even though preterm infants spend a considerable amount of time sleeping, the effectiveness of music therapy during sleep has not been studied. The aim of this study was to investigate the effect of music therapy on preterm infants’ vital signs with respect to the state of wakefulness. The first 20 consecutive infants born with &lt, 32 weeks’ gestational age (GA) from the intervention group of an ongoing randomized controlled trial received live music therapy twice a week until hospital discharge. The heart rate, respiratory rate, oxygen saturation, and state of wakefulness were recorded before and after therapy. We observed significantly lower heart and respiratory rates and higher oxygen saturation after live music therapy sessions in general (mean differences −4.9 beats per min, −7.0 breaths per min and +1.5%, respectively). When music therapy was applied during sleep, respiratory rates significantly lowered by 8.8 breaths per min and oxygen saturation increased by 1.6%, whereas in the awake state the vital parameters did not significantly change (heart rate −5.2 beats per min, respiratory rate +0.6 breaths per min and oxygen saturation +1.0%). Music therapy stabilized the respiratory rates and oxygen saturations in sleeping preterm infants.

Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.

Background: Hashimoto's thyroiditis is frequently associated with other autoimmune diseases and may include renal involvement. Case description: A 17-year-old female with previously diagnosed Hashimoto's thyroiditis and vitiligo was admitted to a pediatric intensive care unit with hypokalemic paralysis and acidosis, after having suffered from recurrent muscular weakness for approximately one year. A few days later she developed central pontine myelinolysis. After initial stabilization she was also diagnosed with distal renal tubular acidosis (dRTA) and tubular proteinuria which can occur in Sjögren's syndrome. Extended screening for autoimmune diseases additionally revealed celiac disease. Treatment with Prednisone and substitution of potassium quickly lead to the resolution of proteinuria and dRTA, but unilateral paralysis of the sixth nerve as a result of central pontine myelinolysis was irreversible. Conclusions: This is the rare case of polyautoimmunity including autoimmune thyroiditis, Sjögren's syndrome, vitiligo and celiac disease in an adolescent with few disease-specific symptoms. The diagnoses were made via a complicating nephritis causing dRTA and proteinuria. Delay in diagnosis lead to permanent neurological damage. This case highlights the need for pediatricians to be aware of rare accompanying diseases and their complications in “common” pediatric autoimmune diseases like Hashimoto's thyroiditis and celiac disease. OA Förderung 2020

Introduction: Preterm infants born before 28 weeks of gestation are at high risk of neurodevelopmental impairment in later life. Cerebral white and gray matter injury is associated with adverse outcomes. High oxygen levels, often unavoidable in neonatal intensive care, have been identified as one of the main contributing factors to preterm brain injury. Thus, preventive and therapeutic strategies against hyperoxia-induced brain injury are needed. Erythropoietin (Epo) is a promising and also neuroprotective candidate due to its clinical use in infants as erythropoiesis-stimulating agent. Objective: The objective of this study was to investigate the effects of repetitive Epo treatment on the cerebral white matter and long-term motor-cognitive outcome in a neonatal rodent model of hyperoxia-induced brain injury. Methods: Three-day old Wistar rats were exposed to hyperoxia (48 h, 80% oxygen). Four doses of Epo (5,000 IU/kg body weight per day) were applied intraperitoneally from P3-P6 with the first dose at the onset of hyperoxia. Oligodendrocyte maturation and myelination were evaluated via immunohistochemistry and Western blot on P11. Motor-cognitive deficits were assessed in a battery of complex behavior tests (Open Field, Novel Object Recognition, Barnes maze) in adolescent and fully adult animals. Following behavior tests animals underwent post-mortem diffusion tensor imaging to investigate long-lasting microstructural alterations of the white matter. Results: Repetitive treatment with Epo significantly improved myelination deficits following neonatal hyperoxia at P11. Behavioral testing revealed attenuated hyperoxia-induced cognitive deficits in Epo-treated adolescent and adult rats. Conclusion: A multiple Epo dosage regimen protects the developing brain against hyperoxia-induced brain injury by improving myelination and long-term cognitive outcome. Though current clinical studies on short-term outcome of Epo-treated prematurely born children contradict our findings, long-term effects up to adulthood are still lacking. Our data support the essential need for long-term follow-up of preterm infants in current clinical trials. OA Förderung 2020

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

Very preterm children (&lt, 32 weeks gestation at birth, VP) are at risk of developmental difficulties. Specific functional difficulties and delays in visual perception, fine motor, and visual-motor skills have received little research attention, although they are critical for daily life and school readiness. Our aim was to assess these skills in a contemporary cohort of 60 VP and 60 matched term-born children before school entry. We administered the Movement Assessment Battery for Children (M-ABC-2) and the Developmental Test of Visual Perception (DTVP-2). Linear and logistic regressions were run to test group differences in performance and rates of developmental delay in visual perception, fine motor, and visual-motor skills. Very preterm children had lower scores than term-born children in visual perception (&beta, = &minus, 0.25, p = 0.006), fine motor (&beta, 0.44, p &lt, 0.001), and visual-motor tasks (&beta, 0.46, 0.001). The rate of developmental delay (&lt, &minus, 1 SD) was higher among VP in visual perception (odds ratio (OR) = 3.4, 95% confidence interval (CI 1.1&ndash, 10.6)), fine motor (OR = 6.2 (2.4&ndash, 16.0)), and visual-motor skills (OR = 13.4 (4.1&ndash, 43.9)) than in term-born controls. VP children are at increased risk for clinically relevant developmental delays in visual perception, fine motor, and visual-motor skills. Following up VP children until preschool age may facilitate early identification and timely intervention.

The consumption of energy drinks is continuously rising, particularly in children and adolescents. While risks for adverse health effects, like arrhythmia, have been described, effects on neural cells remain elusive. Considering that neurodevelopmental processes like myelination and neuronal network formation peak in childhood and adolescence we hypothesized that developing oligodendrocytes and neurons are particularly vulnerable to main energy drink components. Immature oligodendrocytes and hippocampal neurons were isolated from P0-P1 Wistar rats and were incubated with 0.3 mg/mL caffeine and 4 mg/mL taurine alone or in combination for 24 h. Analysis was performed immediately after treatment or after additional three days under differentiating conditions for oligodendrocytes and standard culture for neurons. Oligodendrocyte degeneration, proliferation, and differentiation were assessed via immunocytochemistry and immunoblotting. Neuronal integrity was investigated following immunocytochemistry by analysis of dendrite outgrowth and axonal morphology. Caffeine and taurine induced an increased degeneration and inhibited proliferation of immature oligodendrocytes accompanied by a decreased differentiation capacity. Moreover, dendritic branching and axonal integrity of hippocampal neurons were negatively affected by caffeine and taurine treatment. The negative impact of caffeine and taurine on developing oligodendrocytes and disturbed neuronal morphology indicates a high risk for disturbed neurodevelopment in children and adolescents by excessive energy drink consumption. OA Förderung 2019

Objective: The aim of our study was to assess the use of aEEG in our pediatric intensive care unit (PICU), indications for neuromonitoring and its findings, utility for seizure detection, and associations with outcome. Design: We retrospectively analyzed non-neonates who were treated in our PICU and received amplitude-integrated EEG (aEEG). Patients: 27 patients aged between 29 days and 10 0/12 years (median 7.3 months) were included, who received a total of 35 aEEGS. Measurements: aEEG tracings were assessed for background (BG) pattern and its evolution, seizures, and side differences using a visual classification (Hellström-Westas). Clinical data were collected from patients’ histories and analyzed for correlation with aEEG findings. Main results: While rare in early years, there was an increase in use over time. Most aEEGs were conducted because of (suspected) seizures or for management of antiepileptic treatment. aEEG had low sensitivity but high specificity for recognition of pathological BG pattern with reference to conventional EEG. Worsening of BG pattern or failure to improve was associated with death. Seizure detection rates by aEEG were higher than by clinical observation, especially for identification of non-convulsive epileptic state (ES). Side differences in aEEG were rare, but if present, they were associated with unilateral brain injury. Conclusions: aEEG is useful for the detection of seizures and ES in pediatric intensive care patients. Abnormal BG pattern and poor evolution of BG are negatively associated with survival. aEEG is a potential supplement to conventional EEG, facilitating long-term surveillance of cerebral function when continuous full-channel EEG is not available. Further investigation is needed. OA Förderung 2019

Introduction: Inflammation is an important factor contributing to developmental brain injury in preterm infants. Although tumor necrosis factor-inducible gene 6 protein (TSG-6) has immunomodulatory effects in several inflammatory conditions in adult animals, the role of TSG-6 in the developing brain, its impact on perinatal inflammation and its therapeutic potential is currently unknown. The aim of the current work was 1) to characterise the developmental expression of TSG-6 in the newborn rat brain, 2) to evaluate the impact of lipopolysaccharide (LPS) exposure on TSG-6 expression and 3) to assess the therapeutic potential of exogenous TSG-6 administration. Methods: Brain hemispheres of healthy Wistar rats (postnatal day 1-postnatal day 15 (P1-P15)) were evaluated with regard to the physiological expression of TSG-6. LPS-treated rats (0.25 mg/kg LPS intraperitoneally (i.p.) on P3) were analysed for inflammation-induced changes in TSG-6 and cytokine expression. To evaluate whether exogenous recombinant human (rh)TSG-6 affects inflammation-induced brain injury, Wistar rats exposed to LPS on P3 were treated with rhTSG-6 i.p. (4 repetitive doses of 2.25 mg/kg every 12 h, first dose 3 h before LPS injection). Results: TSG-6 is physiologically expressed in the developing brain with a linear increase in expression from P1 to P15 at the messenger ribonucleic acid (mRNA) level. At P6, regional differences in TSG-6 expression in the cortex, thalamus and striatum were detected at mRNA and protein level. Furthermore, TSG-6 gene expression was significantly increased by inflammation (induced by LPS treatment). Combined treatment with LPS and TSG-6 vs. LPS exposure alone resulted in significant down-regulation of cleaved caspase-3, a marker of apoptosis and neuronal plasticity. In addition, several inflammatory serum markers were decreased after TSG-6 treatment. Conclusion: TSG-6 is physiologically expressed in the developing brain. Changes of TSG-6 expression associated with inflammation suggest a role of TSG-6 in neuroinflammation. Reduction of cleaved caspase-3 by TSG-6 treatment demonstrates the putative neuroprotective potential of exogenous TSG-6 administration in inflammation-induced developmental brain injury. Einleitung: Inflammation spielt eine entscheidende Rolle bei der Entwicklung von Hirnschädigungen bei Frühgeborenen. Obwohl Tumor necrosis factor-inducible gene 6 protein (TSG-6) immun-modulatorische Eigenschaften unter unterschiedlichen inflammatorischen Bedingungen in erwachsenen Tieren zeigte, sind eine Rolle von TSG-6 im sich entwickelnden Gehirn, ein Einfluss während einer perinatalen Inflammation und ein therapeutisches Potential noch unerforscht. Das Ziel dieser Arbeit war 1) die entwicklungsabhängige Expression von TSG-6 im Rattenhirn zu charakterisieren 2) den Einfluss von Lipopolysaccharide (LPS) auf die TSG-6 Expression zu evaluieren 3) das therapeutische Potential einer externen TSG-6 Gabe zu beurteilen. Methoden: Hirnhälften von gesunden Wistar Ratten (postnatal Tag 1-postnatal Tag 15 (P1-P15)) wurden hinsichtlich der physiologischen Expression von TSG-6 untersucht. Die Expression von Cytokinen und TSG-6 unter inflammatorischen Bedingungen wurde bei LPS-behandelten Ratten untersucht (0,25 mg/kg LPS intraperitoneal (i.p.) an P3). Um zu evaluieren, ob rekombinantes, humanes (rh)TSG-6 einen Einfluss auf inflammatorische Schädigungen während der Hirnentwicklung hat, wurden Wistar Ratten mit LPS an P3 und zusätzlichem rhTSG-6 i.p. behandelt (4 repetitive Dosen von 2,25 mg/kg alle 12 h, erste Dosis 3 h bevor LPS Behandlung). Resultate: TSG-6 messenger Ribonukleinsäure (mRNA) wird physiologisch im sich entwickelnden Gehirn exprimiert mit linearem Anstieg von P1 zu P15. An P6 wurden regionale Unterschiede in der TSG-6 Expression zwischen Cortex, Thalamus und Striatum auf Gen- und Proteinebene nachgewiesen. Zudem wird die TSG-6 Gen-expression durch LPS-induzierte Inflammation signifikant erhöht. Zusätzliche Therapie mit TSG-6 im Vergleich zu alleiniger Gabe von LPS zeigte eine signifikante Verringerung der cleaved caspase-3 Menge, einem Marker für Apoptose und neuronaler Plastizität. Außerdem zeigte sich eine verringerte Expression einiger inflammatorischer Moleküle im Serum nach TSG-6 Therapie. Schlussfolgerung: TSG-6 wird physiologisch exprimiert im sich entwickelnden Gehirn. Änderungen der TSG-6 Expression im Rahmen einer Inflammation deuten auf eine Rolle von TSG-6 während einer Neuroinflammation hin. Die Reduktion der cleaved caspase-3 Menge durch TSG-6 demonstriert ein mögliches neuroprotektives Potential von exogenem TSG-6 bei inflammatorischen Schädigungen während der Hirnentwicklung. Dissertation, Universität Duisburg-Essen, 2017

Perinatal infections have a negative impact on brain development. However, the underlying mechanisms leading to neurological impairment are not completely understood and reliable models of inflammation are urgently needed. Using phorbol-myristate-acetate as an activator of inflammation, we investigated the effect on the developing rodent brain. Neonatal rats and mice deficient in IL-18 or IRAK-4 were exposed to PMA. Brains were assessed for regulation of pro- and anti-inflammatory cytokines and cell death 24 hrs, 7 and 14 days after treatment. PMA induced an inflammatory response and caused widespread neurodegeneration in the brains of 3- and 7-day-old rats. In contrast, 14-day-old rats were resistant to the neurotoxic effect of PMA. Histological evaluation at the age of 14 and 21 days revealed a destruction of the cortical microstructure with decreased numerical density of neuronal cells. Mice deficient in IL-18 or IRAK-4 were protected against PMA induced brain injury. PMA treatment during a vulnerable period can alter brain development. IL-18 and IRAK-4 appear to be important for the development of PMA induced injury.

We present the case of a 38-year-old woman diagnosed with metastatic adenocarcinoma of the biliary tract in the 18th week of pregnancy. Chemotherapy based on cisplatin and gemcitabine was administered, reaching disease stabilization until late-preterm delivery at 35 + 0 weeks of gestation. The infant was healthy and showed no malformations. Her head circumference was small, yet no neurological and behavioral defects have been detected. Development was normal during 14 months of follow-up. We discuss the implications of metastatic cancer in pregnancy with focus on therapeutic options for metastatic adenocarcinoma of the biliary tract. In this context, available data for the active regimens in biliary tract cancers-platinum compounds and gemcitabine-are discussed. This report is the fourth in the literature detailing the application of gemcitabine during pregnancy and the first presenting longer term follow-up, complementing available evidence that gemcitabine-based regimens are feasible in this situation. OA Förderung 2014

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. OA Förderung 2014

Background Propofol is commonly used as sedative in newborns and children. Recent experimental studies led to contradictory results, revealing neurodegenerative or neuroprotective properties of propofol on the developing brain. We investigated neurodevelopmental short- and long-term effects of neonatal propofol treatment. Methods 6-day-old Wistar rats (P6), randomised in two groups, received repeated intraperitoneal injections (0, 90, 180 min) of 30 mg/kg propofol or normal saline and sacrificed 6, 12 and 24 hrs following the first injection. Cortical and thalamic areas were analysed by Western blot and quantitative real-time PCR (qRT-PCR) for expression of apoptotic and neurotrophin-dependent signalling pathways. Long-term effects were assessed by Open-field and Novel-Object-Recognition at P30 and P120. Results Western blot analyses revealed a transient increase of activated caspase-3 in cortical, and a reduction of active mitogen-activated protein kinases (ERK1/2, AKT) in cortical and thalamic areas. qRT-PCR analyses showed a down-regulation of neurotrophic factors (BDNF, NGF, NT-3) in cortical and thalamic regions. Minor impairment in locomotive activity was observed in propofol treated adolescent animals at P30. Memory or anxiety were not impaired at any time point. Conclusion Exposing the neonatal rat brain to propofol induces acute neurotrophic imbalance and neuroapoptosis in a region- and time-specific manner and minor behavioural changes in adolescent animals. OA Förderung 2013

Autophagy is a self-degradative process that involves turnover and recycling of cytoplasmic components in healthy and diseased tissue. Autophagy has been shown to be protective at the early stages of programmed cell death but it can also promote apoptosis under certain conditions. Earlier we demonstrated that oxygen contributes to the pathogenesis of neonatal brain damage, which can be ameliorated by intervention with recombinant human erythropoietin (rhEpo). Extrinsic- and intrinsic apoptotic pathways are involved in oxygen induced neurotoxicity but the role of autophagy in this model is unclear. We analyzed the expression of autophagy activity markers in the immature rodent brain after exposure to elevated oxygen concentrations. We observed a hyperoxia-exposure dependent regulation of autophagy-related gene (Atg) proteins Atg3, 5, 12, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), LC3A-II, and LC3B-II which are all key autophagy activity proteins. Interestingly, a single injection with rhEpo at the onset of hyperoxia counteracted these oxygen-mediated effects. Our results indicate that rhEpo generates its protective effect by modifying the key autophagy activity proteins. OA Förderung 2012

Intrauterine infection and inflammation are major reasons for preterm birth. The switch from placenta-mediated to lung-mediated oxygen supply during birth is associated with a sudden rise of tissue oxygen tension that amounts to relative hyperoxia in preterm infants. Both infection/inflammation and hyperoxia have been shown to be involved in brain injury of preterm infants. Hypothesizing that they might be additive or synergistic, we investigated the influence of a systemic lipopolysaccharide (LPS) application on hyperoxia-induced white matter damage (WMD) in newborn rats. Three-day-old Wistar rat pups received 0.25 mg/kg LPS i.p. and were subjected to 80% oxygen on P6 for 24 h. The extent of WMD was assessed by immunohistochemistry, western blots, and diffusion tensor (DT) magnetic resonance imaging (MRI). In addition, the effects of LPS and hyperoxia were studied in an in vitro co-culture system of primary rat oligodendrocytes and microglia cells. Both noxious stimuli, hyperoxia, and LPS caused hypomyelination as revealed by western blot, immunohistochemistry, and altered WM microstructure on DT-MRI. Even so, cellular changes resulting in hypomyelination seem to be different. While hyperoxia induces cell death, LPS induces oligodendrocyte maturity arrest without cell death as revealed by TUNEL-staining and immunohistological maturation analysis. In the two-hit scenario cell death is reduced compared with hyperoxia treated animals, nevertheless white matter alterations persist. Concordantly with these in vivo findings we demonstrate that LPS pre-incubation reduced premyelinating-oligodendrocyte susceptibility towards hyperoxia in vitro. This protective effect might be caused by upregulation of interleukin-10 and superoxide dismutase expression after LPS stimulation. Reduced expression of transcription factors controlling oligodendrocyte development and maturation further indicates oligodendrocyte maturity arrest. The knowledge about mechanisms that triggered hypomyelination contributes to a better understanding of WMD in premature born infants. OA Förderung 2012

Duisburg, Essen, Univ., Diss., 2006 Exspiratorisches Stickstoffmonoxid (FENO) gilt als Marker von Entzündungsprozessen der unteren Atemwege bei Kindern und Erwachsenen. Die Messung von FENO ist im Rahmen der Diagnostik und Verlaufsbeurteilung entzündlicher Atem­wegs­erkrankungen, wie dem Asthma bronchiale, sinnvoll einzusetzen. Allerdings sind die verschiedenen Einflussfaktoren auf die NO-Messungen bei Säuglingen nicht ausreichend untersucht, so dass, anders als bei Kindern und Erwachsenen, keine allgemein gültigen Empfehlungen zur FENO-Messung in dieser Altersgruppe vorliegen. In dieser Studie wurde der Einfluss der bekannten Störfaktoren bei Säuglingen untersucht. Dazu wurden vier verschiedene Methoden zur Messung von FENO von insgesamt 43 schlafen­den, nicht sedierten Säuglingen während ruhiger Spontan­atmung durchgeführt und ver­glichen: eine nasale NO-Mes­sung mit Hilfe einer Kunst­stoff­olive (n1 = 20), jeweils im rechten und im linken Nasen­loch, eine gemischt-exspiratorische2 NO-Messung mit Hilfe einer Maske über Mund und Nase bei Ein­atmung von Raumluft (n = 33) versus Einatmung NO-freier Luft (n = 25) und eine NO-Messung über eine Mundmaske bei Okklusion der Nase (n = 29). Die Ergebnisse dieser Studie zeigen, dass die nasale NO-Messung über eine Kunststoff-Olive bei Säuglingen relativ unproblema­tisch durchzuführen war. Hierbei wurden er­heb­lich höhere NO-Konzentrationen als bei den gemischt­­­exspiratorischen Messungen festgestellt. Die gemischt­­-­exspiratorischen Messungen waren signifikant von NO in der Einatemluft beeinflusst. Daher ist bei dieser Messung ab einer Raum-NO-Konzentration von 3 ppb eine Ein­at­mung von NO-freier Luft notwendig. Erhebliche Schwierigkeiten bereitete es, Säug­linge, die vorwiegende Nasenatmer sind, durch eine Okklusion der Nase zur Mundatmung zu bringen. Demzufolge war eine Trennung von oberen und unteren Atemwegen nicht möglich und somit eine Kontamination des FENO durch nasales NO nicht zu verhindern. Die Messung von gemischt-exspiratorischem NO bei Säuglingen mit Hilfe einer Maske über Mund und Nase bei Einatmung NO-freier Luft ist daher diejenige, die von den hier untersuchten vier nicht-invasiven Methoden am besten geeignet ist. Eine genaue Aussage über die NO-Konzentrationen der unteren Atemwege kann jedoch nicht getroffen werden. Da sich aber das FENO aus den unteren Atemwegen als Marker von Entzündungs­prozessen in den Atemwegen erwiesen hat, müssen weitere Untersuchungen zeigen, inwieweit die gemischt-exspiratorischen NO-Werte in der untersuchten Altersgruppe von diagnostischem Wert sind.

Zerebrale Läsionen wie intraventrikuläre und periventrikuläre Blutungen und die periventrikuläre Leukomalazie sind wesentlich für spätere motorische und intellektuelle Entwicklungsstörungen Frühgeborener verantwortlich. In ihrer Genese spielt eine Instabilität der zerebralen Hämodynamik in den ersten Lebenstagen eine wichtige Rolle. Maßnahmen, die zu akuten Veränderungen der zerebralen Hämodynamik führen, sollten daher vermieden werden. Ziel dieser Arbeit war es, die Frage zu klären, ob eine Blutentnahme aus einem Nabelarterienkatheter (NAK) bei sehr kleinen Frühgeborenen zu Veränder-ungen der zerebralen Hämodynamik führt. Zur Messung von Veränderungen des zerebralen Blutvolumens und der zerebralen Oxygenierung wurde die Nahinfrarotspektroskopie (NIRS) eingesetzt. Sie nutzt die Transparenz biolo-gischer Gewebe für nahinfrarotes Licht und die Tatsache, dass im Hirngewebe nur wenige Chromophore in sich ändernden Konzentrationen vorliegen: oxygeniertes Hämoglobin (O2Hb), desoxygeniertes Hämoglobin (HHb) und die Cytochromoxydase. Durch Einsatz von Laserlicht 4 verschiedener Wellen-längen können Konzentrationsveränderungen dieser Chromophore gemessen und Veränderungen des zerebralen Blutvolumens und der zerebralen Oxygenierung (HbD) berechnet werden. Die Vorteile der NIRS liegen in der Nicht-Invasivität und der Möglichkeit der kontinuierlichen, bettseitigen Erhebung von Daten. 20 Frühgeborene (530-1500 g) wurden während einer diagnostischen Blut-entnahme aus einem NAK mit der NIRS und zeitgleicher Aufzeichnung der Vitalparameter untersucht. Die Messergebnisse zeigen, dass die Blutentnahme aus dem NAK einen signifikanten Abfall des O2Hb induzierte, während das HHb konstant blieb. Es resultierte ein signifikanter Abfall des CBV und des HbD. Das bedeutet, dass es durch die Blutentnahme zu einer akuten Reduktion der globalen Oxygenierung des Hirngewebes und somit zu einer Reduktion der zerebralen Sauerstoffversorgung kommt. Die Tatsache, dass Blutentnahmen in der besonders vulnerablen Phase der ersten Lebenstage bei sehr kranken Frühgeborenen häufig durchgeführt werden müssen, sollte Anlass geben, jede Blutentnahme kritisch auf ihre Notwendigkeit zu hinterfragen und kleinste Probemengen zu entnehmen, um ein mögliches Risiko für das Kind zu minimieren. Folgestudien sind notwendig, um die optimale Form der Blutentnahme zu finden.