Neurologic Consequences of Neonatal Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant with high mortality and morbidity. Children who survive NEC have been shown to demonstrate neurodevelopmental delay, with significantly worse outcomes than from prematurity alone. The pathways leading to NEC-associated neurological impairments remain unclear, limiting the development of preventative and protective strategies. This review aims to summarize the existing clinical and experimental studies related to NEC-associated brain injury. We describe the current epidemiology of NEC, reported long-term neurodevelopmental outcomes among survivors, and proposed pathogenesis of brain injury in NEC. Highlighted are the potential connections between hypoxia-ischemia, nutrition, infection, gut inflammation, and the developing brain in NEC.

Supplemental Oxygen in the Newborn: Historical Perspective and Current Trends.

Oxygen is the final electron acceptor in aerobic respiration, and a lack of oxygen can result in bioenergetic failure and cell death. Thus, administration of supplemental concentrations of oxygen to overcome barriers to tissue oxygen delivery (e.g., heart failure, lung disease, ischemia), can rescue dying cells where cellular oxygen content is low. However, the balance of oxygen delivery and oxygen consumption relies on tightly controlled oxygen gradients and compartmentalized redox potential. While therapeutic oxygen delivery can be life-saving, it can disrupt growth and development, impair bioenergetic function, and induce inflammation. Newborns, and premature newborns especially, have features that confer particular susceptibility to hyperoxic injury due to oxidative stress. In this review, we will describe the unique features of newborn redox physiology and antioxidant defenses, the history of therapeutic oxygen use in this population and its role in disease, and clinical trends in the use of therapeutic oxygen and mitigation of neonatal oxidative injury.

Intrauterine Growth Restriction Causes Abnormal Embryonic Dentate Gyrus Neurogenesis in Mouse Offspring That Leads to Adult Learning and Memory Deficits.

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR offspring of both sexes had short-term adult learning and memory deficits. Prenatally, we found that IUGR caused accelerated embryonic DG neurogenesis and Sox2+ neural stem cell depletion. IUGR mice were marked by decreased hippocampal volumes and decreased doublecortin+ neuronal progenitors with increased mean dendritic lengths at postnatal day 18. Consistent with its known molecular role in embryonic DG neurogenesis, we also found evidence for decreased Wnt pathway activity during IUGR. In conclusion, we have discovered that postnatal memory deficits are associated with accelerated NSC differentiation and maturation into glutamatergic granule neurons following IUGR, a phenotype that could be explained by decreased embryonic Wnt signaling.

Intrauterine growth restriction followed by oxygen support uniquely interferes with genetic regulators of myelination.

Intrauterine growth restriction (IUGR) and oxygen exposure in isolation and combination adversely affect the developing brain, putting infants at risk for neurodevelopmental disability including cerebral palsy. Rodent models of IUGR and postnatal hyperoxia have demonstrated oligodendroglial injury with subsequent white matter injury (WMI) and motor dysfunction. Here we investigate transcriptomic dysregulation in IUGR with and without hyperoxia exposure to account for the abnormal brain structure and function previously documented. We performed RNA sequencing and analysis using a mouse model of IUGR and found that IUGR, hyperoxia, and the combination of IUGR with hyperoxia (IUGR/hyperoxia) produced distinct changes in gene expression. IUGR in isolation demonstrated the fewest differentially expressed genes compared to control. In contrast, we detected several gene alterations in IUGR/hyperoxia; genes involved in myelination were strikingly downregulated. We also identified changes to specific regulators including TCF7L2, BDNF, SOX2, and DGCR8, through Ingenuity Pathway Analysis, that may contribute to impaired myelination in IUGR/hyperoxia. Our findings show that IUGR with hyperoxia induces unique transcriptional changes in the developing brain. These indicate mechanisms for increased risk for WMI in IUGR infants exposed to oxygen and suggest potential therapeutic targets to improve motor outcomes.Significance StatementThis study demonstrates that perinatal exposures of IUGR and/or postnatal hyperoxia result in distinct transcriptomic changes in the developing brain. In particular, we found that genes involved in normal developmental myelination, myelin maintenance, and remyelination were most dysregulated when IUGR was combined with hyperoxia. Understanding how multiple risk factors lead to WMI is the first step in developing future therapeutic interventions. Additionally, because oxygen exposure is often unavoidable after birth, an understanding of gene perturbations in this setting will increase our awareness of the need for tight control of oxygen use to minimize future motor disability.

Intrauterine Growth Restriction and Hyperoxia as a Cause of White Matter Injury.

Intrauterine growth restriction (IUGR) is estimated to occur in 5% of pregnancies, with placental insufficiency being the most common cause in developed countries. While it is known that white matter injury occurs in premature infants, the extent of IUGR on white matter injury is less defined in term infants. We used a novel murine model that utilizes a thromboxane A2 (TXA2) analog (U46619), a potent vasoconstrictor, to induce maternal hypertension and mimic human placental insufficiency-induced IUGR to study the white matter. We also investigated the role of hyperoxia as an additional risk factor for white matter injury, as IUGR infants are at increased risk of respiratory comorbidities leading to increased oxygen exposure. We found that TXA2 analog-induced IUGR results in white matter injury as demonstrated by altered myelin structure and changes in the oligodendroglial cell/oligodendrocyte population. In addition, our study demonstrates that hyperoxia exposure independently results in white matter perturbation. To our knowledge, this is the first study to report single and combined effects of IUGR with hyperoxia impacting the white matter and motor function. These results draw attention to the need for close monitoring of motor development in IUGR babies following hospital discharge as well as highlighting the importance of limiting, as clinically feasible, the degree of oxygen overexposure to potentially improve motor outcomes in this population of infants.

Late hematogenous bacterial infections of breast implants: two case reports of unique bacterial infections.

Late infections of breast implants are rare occurrences. We present 2 cases of late infections of breast implants, resulting from hematogenous spread from bacterial infection from distant sites. The first case involves a late implant infection following development of a chronic foot sore, caused by Achromobacter xylosoxidans, an aerobic pathogen. The second case describes a late infection, after extensive dental treatment, caused by Streptococcus viridans, a bacterium that normally lives in close association with the teeth and gingiva. On the basis of these 2 cases and others in the literature, systemic antibiotic therapy should be considered in breast implant patients who are exposed to potential bacterial inoculation and bacteremia to prevent late breast infections and subsequent capsular contractures.