Neonatal mouse hippocampus: phlebotomy-induced anemia diminishes and treatment with erythropoietin partially rescues mammalian target of rapamycin signaling.

BackgroundPhlebotomy-induced anemia (PIA) is common in premature infants and affects neurodevelopment. PIA alters hippocampal metabolism in neonatal mice through tissue hypoxia and iron deficiency. The mammalian target of rapamycin (mTOR) pathway senses the status of critical metabolites (e.g., oxygen, iron), thereby regulating hippocampal growth and function. We determined the effect of PIA and recombinant human erythropoietin (rHuEpo) treatment on mTOR signaling and expression of genes related to mTOR pathway functions.MethodsMice receiving an iron-supplemented diet were phlebotomized from postnatal day (P)3 to a target hematocrit of <25% by P7. Half were maintained at <25% until P14; half received rHuEpo from P7 to increase the hematocrit to 25-28%. Hippocampal phosphorylated to total protein ratios of four key mTOR pathway proteins were measured by western blotting at P14 and compared with non-phlebotomized, non-anemic control mice. mRNA levels of genes regulated by mTOR were measured by quantitative PCR.ResultsPIA suppressed phosphorylation of all mTOR proteins. rHuEpo restored AMP-activated protein kinase (AMPK) and AKT status, and partially rescued the mTOR output protein S6K. PIA and rHuEpo treatment also altered the expression of genes regulated by S6K.ConclusionPIA compromises and rHuEpo treatment partially rescues a pathway regulating neuronal DNA transcription, protein translation, and structural complexity.

Burden of severe neonatal jaundice: a systematic review and meta-analysis.

CONTEXT: To assess the global burden of late and/or poor management of severe neonatal jaundice (SNJ), a common problem worldwide, which may result in death or irreversible brain damage with disabilities in survivors. Population-based data establishing the global burden of SNJ has not been previously reported. OBJECTIVE: Determine the burden of SNJ in all WHO regions, as defined by clinical jaundice associated with clinical outcomes including acute bilirubin encephalopathy/kernicterus and/or exchange transfusion (ET) and/or jaundice-related death. DATA SOURCES: PubMed, Scopus and other health databases were searched, without language restrictions, from 1990 to 2017 for studies reporting the incidence of SNJ. STUDY SELECTION/DATA EXTRACTION: Stratification was performed for WHO regions and results were pooled using random effects model and meta-regression. RESULTS: Of 416 articles including at least one marker of SNJ, only 21 reported estimates from population-based studies, with 76% (16/21) of them conducted in high-income countries. The African region has the highest incidence of SNJ per 10 000 live births at 667.8 (95% CI 603.4 to 738.5), followed by Southeast Asian, Eastern Mediterranean, Western Pacific, Americas and European regions at 251.3 (132.0 to 473.2), 165.7 (114.6 to 238.9), 9.4 (0.1 to 755.9), 4.4 (1.8 to 10.5) and 3.7 (1.7 to 8.0), respectively. The incidence of ET per 10 000 live births was significantly higher for Africa and Southeast Asian regions at 186.5 (153.2 to 226.8) and 107.1 (102.0 to 112.5) and lower in Eastern Mediterranean (17.8 (5.7 to 54.9)), Americas (0.38 (0.21 to 0.67)), European (0.35 (0.20 to 0.60)) and Western Pacific regions (0.19 (0.12 to 0.31). Only 2 studies provided estimates of clear jaundice-related deaths in infants with significant jaundice [UK (2.8%) and India (30.8%). CONCLUSIONS: Limited but compelling evidence demonstrates that SNJ is associated with a significant health burden especially in low-income and middle-income countries.

Iron is prioritized to red blood cells over the brain in phlebotomized anemic newborn lambs.

BACKGROUND: Critically ill preterm and term neonates are at high risk for negative iron balance due to phlebotomy that occurs with frequent laboratory monitoring, and the high iron demand of rapid growth. Understanding the prioritization of iron between red blood cells (RBCs) and brain is important given iron's role in neurodevelopment. METHODS: Ten neonatal twin lamb pairs (n = 20) underwent regular phlebotomy for 11 d. Lambs were randomized to receive no iron or i.v. daily iron supplementation from 1 to 5 mg/kg. Serum hemoglobin concentration and reticulocyte count were assayed, iron balance calculated, and iron content of RBCs, liver, brain, muscle, and heart measured at autopsy. RESULTS: Among phlebotomized lambs: (i) liver iron concentration was directly related to net iron balance (r = 0.87; P < 0.001) and (ii) brain iron concentration was reduced as a function of net iron balance (r = 0.63) only after liver iron was depleted. In animals with negative iron balance, total RBC iron was maintained while brain iron concentration decreased as a percentage of the iron present in RBCs (r = -0.70; P < 0.01) and as a function of reticulocyte count (r = -0.63; P < 0.05). CONCLUSION: Phlebotomy-induced negative iron balance limits iron availability to the developing brain.

Addressing the burden of neonatal hyperbilirubinaemia in countries with significant glucose-6-phosphate dehydrogenase deficiency.

UNLABELLED: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an established worldwide risk factor for severe hyperbilirubinaemia. This literature review examined the pattern and management of severe hyperbilirubinaemia in low- and middle-income countries (LMICs) where G6PD deficiency was 10% or more and found that it was frequently associated with neonatal mortality and, or, neurodevelopmental disorders. CONCLUSION: Low- and middle-income countries need to pay urgent attention to G6PD deficiency to curtail the preventable burden of jaundice-related morbidity, mortality and disability.

Four-year follow-up of megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephalus (MPPH) syndrome.

A male infant was born by emergent caesarean section at 39 weeks gestational age secondary to maternal and fetal distress. Initial physical examination was notable for macrocephaly (greater than+2SD), postaxial polydactyly of the hands and facial dysmorphism. Head imaging demonstrated diffuse polymicrogyria without hydrocephalus. All findings were consistent with a diagnosis of megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephalus (MPPH) syndrome. At the 4-year follow-up, megalencephaly persisted without evidence of hydrocephalus. The child was severely delayed with a stable seizure disorder controlled with dual antiepileptic therapy. This case meets the classic criteria for MPPH syndrome, adding to the limited experience with this disease. The 4-year follow-up and absence of hydrocephalus, once thought to be a key diagnostic criterion, adds to our understanding of the long-term sequelae.