TY  - JOUR
AB  - OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic®, Olink-Proteomics®) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD.
AU  - Kindt, A.
AU  - Förster, K.
AU  - Cochius-den Otter, S.C.M.*
AU  - Flemmer, A.W.
AU  - Hauck, S.M.
AU  - Flatley, A.
AU  - Kamphuis, J.*
AU  - Karrasch, S.
AU  - Behr, J.*
AU  - Franz, A.*
AU  - Härtel, C.*
AU  - Krumsiek, J.
AU  - Tibboel, D.*
AU  - Hilgendorff, A.
C1  - 65077
C2  - 52662
SP  - 625-632
TI  - Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia.
JO  - Pediatr. Res.
VL  - 93
IS  - 3
PY  - 2023
SN  - 0031-3998
ER  - 

TY  - JOUR
AU  - de Paepe, B.*
AU  - Smet, J.*
AU  - Kopajtich, R.*
AU  - Prokisch, H.
AU  - van Coster, R.*
AU  - Vanlander, A.*
C1  - 65523
C2  - 52716
TI  - Neonatal lactic acidosis explained by LARS2 defect.
JO  - Pediatr. Res.
PY  - 2022
SN  - 0031-3998
ER  - 

TY  - JOUR
AB  - Background:Few human studies have explored the role of adiponectin in early life on growth and adipose tissue development.Methods:High molecular weight (HMW) and total adiponectin levels from 141 cord blood samples and plasma blood samples from 40 3-y-old children were analyzed. Associations between adiponectin levels in cord blood and child plasma, and infant/child growth and fat mass measurements up to the age of 5 y were assessed using linear regression models.Results:HMW cord blood adiponectin was positively associated with weight, BMI percentiles, and lean body mass at birth only. At 3 and 4 y, positive associations were found with cord blood adiponectin and sum of four skinfold thickness measures and percentage of body fat following adjustment for maternal and child covariates, but did not persist at 5 y. There was no significant evidence of an association between child plasma HMW adiponectin and growth or body composition characteristics at 3-5 y.Conclusion:Our results do not support the hypothesis that HMW cord blood adiponectin is a useful biomarker for the prediction of adiposity at the age of 5 y. Additionally, there is no evidence that plasma HMW adiponectin levels predict body fat distribution between 3-5 y.
AU  - Meyer, D.M.*
AU  - Brei, C.*
AU  - Stecher, L.*
AU  - Much, D.
AU  - Brunner, S.*
AU  - Hauner, H.*
C1  - 51542
C2  - 43300
SP  - 745-751
TI  - Cord blood and child plasma adiponectin levels in relation to childhood obesity risk and fat distribution up to 5 y.
JO  - Pediatr. Res.
VL  - 81
IS  - 5
PY  - 2017
SN  - 0031-3998
ER  - 

TY  - JOUR
AB  - BackgroundOsteogenesis imperfecta (OI) is a heritable bone fragility disorder usually caused by dominant variants in COL1A1 or COL1A2 gen es. Over the last few years, 17 genes including 12 autosomal recessive and five autosomal dominant forms of OI, involved in various aspects of bone formation, have been identified.MethodsWhole-exome sequencing followed by conventional Sanger sequencing was performed in a single affected individual (IV-3) in a family.ResultsHere, we report the clinical and genetic characterization of OI type 3 in a consanguineous family with four affected members. Clinical examinations revealed low bone density, short stature, severe vertebral compression fractures, and multiple long bone fractures in the affected members. Exome sequencing revealed a biallelic pathogenic splice acceptor site variant (c.359-3C > G) in a wingless-type mouse mammary tumor virus integration site family 1 (WNT1) gene located on chromosome 12q13.12.ConclusionWe report a biallelic splice site variant underlying OI type 3 and the first case from the Pakistani population.
AU  - Umair, M.*
AU  - Alhaddad, B.*
AU  - Rafique, A.*
AU  - Jan, A.*
AU  - Haack, T.B.*
AU  - Graf, E.
AU  - Ullah, A.*
AU  - Ahmad, F.*
AU  - Strom, T.M.*
AU  - Meitinger, T.*
AU  - Ahmad, W.*
C1  - 52213
C2  - 43811
SP  - 753-758
TI  - Exome sequencing reveals a novel homozygous splice site variant in the WNT1 gene underlying osteogenesis imperfecta type 3.
JO  - Pediatr. Res.
VL  - 82
IS  - 5
PY  - 2017
SN  - 0031-3998
ER  - 

TY  - JOUR
AB  - Background:Heterozygous ABCA3 (ATP-binding-cassette sub-family A member3) mutations are associated with neonatal respiratory complications. We investigated in an adult murine model whether Abca3 haploinsufficiency is a predisposing factor for lung injury induced by hyperoxia or mechanical ventilation.Methods:Abca3 haploinsufficient (Abca3+/-) and wild-type (WT) mice were prospectively randomized to 25 min of ventilation or 72 hours of hyperoxia or left unchallenged in air.Results:As compared to WT, unchallenged Abca3+/- mice had significantly decreased lung phosphatidylcholine (PC) and phosphatidylglycerol (PG) levels (p<0.02) and decreased lung compliance (p<0.05). When ventilated for 25 min, Abca3+/- mice demonstrated a significantly greater increase in bronchoalveolar lavage (BAL) interleukins (p<0.01) and lung wet to dry ratio (p<0.005). Hyperoxia resulted in increased compliance (p<0.05) and total lung capacity (TLC) (p=0.01) only in the Abca3+/- mice consistent with enlarged alveolar spaces. The ratio of PC to PG in BAL - relevant for surfactant dysfunction - was significantly elevated by oxygen exposure with the greatest increase in Abca3+/- mice.Conclusions:In a murine model, Abca3 haploinsufficiency results in an altered biochemical and lung mechanical phenotype as well as a greater lung injury induced by hyperoxia or mechanical ventilation. The inability to maintain a normal PC/PG ratio appears to play a key role.
AU  - Herber-Jonat, S.*
AU  - Mittal, R.*
AU  - Huppmann, M.*
AU  - Hammel, M.*
AU  - Liebisch, G.*
AU  - Yildirim, A.Ö.
AU  - Eickelberg, O.
AU  - Schmitz, G.*
AU  - Hrabě de Angelis, M.
AU  - Flemmer, A.W.*
AU  - Holzinger, A.*
C1  - 27236
C2  - 32582
SP  - 384-392
TI  - Abca3 haploinsufficiency is a risk factor for lung injury induced by hyperoxia or mechanical ventilation in a murine model.
JO  - Pediatr. Res.
VL  - 74
IS  - 4
PB  - Nature Publishing
PY  - 2013
SN  - 0031-3998
ER  -