Elevated neuregulin-1ß levels correlate with plasma biomarkers of cerebral injury and high stroke risk in children with sickle cell anemia.

Stroke, or cerebral infarction, is one of the most serious complications of sickle cell anemia (SCA) in childhood, potentially leading to impaired development and life-long physical and cognitive disabilities. About one in ten children with SCA are at risk for developing overt stroke and an additional 25% may develop silent cerebral infarcts. This is largely due to underlying cerebral injury caused by chronic cerebral ischemia and vascular insult associated with SCA. We previously identified two elevated markers of cerebral injury, plasma brain-derived neurotropic factor (BDNF) and platelet-derived growth factor (PDGF)-AA, in children with SCA and high stroke risk. The objective of this study was to investigate whether neuregulin-1ß (NRG-1), an endogenous neuroprotective polypeptide may also be elevated in children with SCA. Neuregulin-1ß is involved in the preservation of blood brain barrier integrity and brain microvascular cell viability and is cytoprotective in conditions of heme-induced injury and ischemia. Since elevated plasma heme and ischemia are signature characteristics of SCA, we hypothesized that NRG-1 would be elevated in children with SCA, and that NRG-1 levels would also correlate with our biomarkers of cerebral injury. Plasma NRG-1, BDNF and PDGF-AA levels were measured in children with SCA and healthy Controls. Plasma NRG-1 was found to be nearly five-fold higher in those children with SCA compared to Controls. Neuregulin-1ß was also positively correlated with both BDNF and PDGF-AA concentrations, but was not associated with degree of anemia, suggesting that NRG-1 production may be an endogenous response to subclinical cerebral ischemia in SCA warranting further exploration.

Whole Blood Transcriptome Analysis in Children with Sickle Cell Anemia.

Whole transcriptome RNA-sequencing was performed to quantify RNA expression changes in whole blood samples collected from steady state sickle cell anemia (SCA) and control subjects. Pediatric SCA and control subjects were recruited from Atlanta (GA)-based hospital(s) systems and consented for RNA sequencing. RNA sequencing was performed on an Ion Torrent S5 sequencer, using the Ion Total RNA-seq v2 protocol. Data were aligned to the hg19 reference genome and analyzed in the Partek Genomics studio package (v7.0). 223 genes were differentially expressed between SCA and controls (± 1.5 fold change FDR p < 0.001) and 441 genes show differential transcript expression (± 1.5 fold FDR p < 0.001). Differentially expressed RNA are enriched for hemoglobin associated genes and ubiquitin-proteasome pathway genes. Further analysis shows higher gamma globin gene expression in SCA (33-fold HBG1 and 49-fold HBG2, both FDR p < 0.05), which did not correlate with hemoglobin F protein levels. eQTL analysis identified SNPs in novel non-coding RNA RYR2 gene as having a potential regulatory role in HBG1 and HBG2 expression levels. Gene expression correlation identified JHDM1D-AS1(KDM7A-DT), a non-coding RNA associated with angiogenesis, enhanced GATA1 and decreased JAK-STAT signaling to correlate with HBG1 and HBG2 mRNA levels. These data suggest novel regulatory mechanisms for fetal hemoglobin regulation, which may offer innovative therapeutic approaches for SCA.

A Multidisciplinary Educational Approach for Children With Chronic Illness: An Intervention Case Study.

Chronic illness requires frequent medical treatments and lifestyle restrictions that increase academic and socioemotional stressors for families. This paper presents academic intervention recommendations based on a hospital's approach to improving educational outcomes for children with chronic illness. A case study on an intervention for a girl with sickle cell disease (SCD) and a history of stroke. SCD is a relatively common chronic illness that has physical and psychosocial side effects that are central to other chronic illnesses (Platt, Eckman, & Hsu, 2016). A quality improvement approach resulted in five cycles of interventions that were assessed with both qualitative and quantitative measures. The initial strategy of improving academics through collaboration among the school, hospital, and family resulted in psychosocial, but not academic, improvements. Frequent tutoring, which was most achievable using online platforms, resulted in the greatest gains. The girl passed previously failed classes and advanced to the next grade. Recommendations for how to improve academic outcomes for children with chronic illness using the presented intervention strategies are discussed.