THE ROLE OF OXIDATIVE STRESS IN THE NECROTIZING ENTEROCOLITIS OF PRETERM

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Early biomarkers of brain development in preterm infants

The general aim of this thesis was to describe the use of early clinical and biochemical biomarkers, and its interpretation for understanding and prediction of brain development and brain injury in preterm infants. The clinical use of early biomarkers and the possible effect of confounders, such as medications was evaluated. Secondly, the relation between single and combined clinical and biochemical biomarkers and their association with brain development were discussed. In Chapter 2, the effect of morphine on aEEG/EEG was evaluated. Morphine administration had a significant effect on quantitative aEEG/EEG measures, causing depression of early brain activity. Furthermore, results suggest that sedatives should always be considered when interpreting aEEG/EEG. In Chapter 3 the role of oxidative stress was investigated. Oxygen, while essential for life, may also generate toxic free radicals species and, in preterm infants, has the potential to cause the “Free Radicals Disease” (FRD). Preterm infants were randomized at birth to receive either 100% oxygen or room air. Significantly higher levels of free radicals were found in the 100% oxygen group. Results from Chapter 3 should alert clinicians that the use of 100% oxygen in the delivery room, may cause lipid as well as protein damage. In Chapter 4, cord blood biomarkers of placental disease were evaluated. OS biomarkers were significantly increased in the histological chorioamnionitis group compared to controls. Significant associations were also found between vascular underperfusion and oxidative injury to proteins. In Chapter 5 the relationship between NIRS and quantitative EEG parameters was investigated in the first few hours after birth in babies < 28 weeks of GA. Oxygen utilization and delivery were associated with quantitative EEG metrics. These results clearly underline that oxygen delivery and utilization are directly related to functional brain activity during the first hours after birth. The results shown in Chapter 5 suggest that the simultaneous monitoring of NIRS and aEEG may be a noninvasive useful biomarker of brain function in high-risk, preterm infants. Chapter 6 we evaluated the changes in brain morphology and microstructure, detected using serial MRI, in relation to early brain activity, monitored with aEEG/EEG in extremely preterm infants. Results showed that increased early brain activity was associated with cerebellar and cortical growth, and with higher microstrusctural growth in the corpus callosum. These results underline the importance of early neuromonitoring in extremely preterm neonates to identify those at risk of altered brain development. In Chapter 7 we tested the hypothesis that early urinary metabolic profile in preterm neonates could predict abnormal MRI score at TEA. ROC curves about urinary metabolic profile could distinguish neonates who later developed a markedly abnormal cortical grey matter and white matter score from the others. Results of Chapter 7 suggest that urine metabolomics is a promising tool for early identification of neonates at high risk of brain damage. The present thesis describes the use and potentialities of biomarkers, their combination and possible use in a clinical setting, which can help clinicians to have more insight into brain development and injury and, thus, to predict outcome

Early biomarkers of brain development in preterm infants

The general aim of this thesis was to describe the use of early clinical and biochemical biomarkers, and its interpretation for understanding and prediction of brain development and brain injury in preterm infants. The clinical use of early biomarkers and the possible effect of confounders, such as medications was evaluated. Secondly, the relation between single and combined clinical and biochemical biomarkers and their association with brain development were discussed. In Chapter 2, the effect of morphine on aEEG/EEG was evaluated. Morphine administration had a significant effect on quantitative aEEG/EEG measures, causing depression of early brain activity. Furthermore, results suggest that sedatives should always be considered when interpreting aEEG/EEG. In Chapter 3 the role of oxidative stress was investigated. Oxygen, while essential for life, may also generate toxic free radicals species and, in preterm infants, has the potential to cause the “Free Radicals Disease” (FRD). Preterm infants were randomized at birth to receive either 100% oxygen or room air. Significantly higher levels of free radicals were found in the 100% oxygen group. Results from Chapter 3 should alert clinicians that the use of 100% oxygen in the delivery room, may cause lipid as well as protein damage. In Chapter 4, cord blood biomarkers of placental disease were evaluated. OS biomarkers were significantly increased in the histological chorioamnionitis group compared to controls. Significant associations were also found between vascular underperfusion and oxidative injury to proteins. In Chapter 5 the relationship between NIRS and quantitative EEG parameters was investigated in the first few hours after birth in babies < 28 weeks of GA. Oxygen utilization and delivery were associated with quantitative EEG metrics. These results clearly underline that oxygen delivery and utilization are directly related to functional brain activity during the first hours after birth. The results shown in Chapter 5 suggest that the simultaneous monitoring of NIRS and aEEG may be a noninvasive useful biomarker of brain function in high-risk, preterm infants. Chapter 6 we evaluated the changes in brain morphology and microstructure, detected using serial MRI, in relation to early brain activity, monitored with aEEG/EEG in extremely preterm infants. Results showed that increased early brain activity was associated with cerebellar and cortical growth, and with higher microstrusctural growth in the corpus callosum. These results underline the importance of early neuromonitoring in extremely preterm neonates to identify those at risk of altered brain development. In Chapter 7 we tested the hypothesis that early urinary metabolic profile in preterm neonates could predict abnormal MRI score at TEA. ROC curves about urinary metabolic profile could distinguish neonates who later developed a markedly abnormal cortical grey matter and white matter score from the others. Results of Chapter 7 suggest that urine metabolomics is a promising tool for early identification of neonates at high risk of brain damage. The present thesis describes the use and potentialities of biomarkers, their combination and possible use in a clinical setting, which can help clinicians to have more insight into brain development and injury and, thus, to predict outcome

Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study

Background: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates. Methods: In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (>= 36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45-50 x 10(6) bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821. Findings: Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38 degrees C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus postadministration and, although thrombocyte levels increased (p=0.011), all were within the physiological range. Followup MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants. Interpretation: This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.</p