*The paper was led by Dr. Katie Harmony, one of our heme/onc fellowship graduates of 2018. She just completed a hospice and palliative care fellowship at Rochester in New York, and accepted a job in Columbia, MO, where she will be doing split time between heme/onc and palliative care.
Drs. Sarah Haskell (Critical Care) and Dianne Atkins (Cardiology, emeritus) were part of an author group on a recent scientific statement from the American Heart Association (AHA). Congratulations to both!
Topjian AA, de Caen A, Wainwright MS, Abella BS, Abend NS, Atkins DL, Bembea MM, Fink EL, Guerguerian AM, Haskell SE, Kilgannon JH, Lasa JJ, Hazinski MF; American Heart Association Emergency Cardiovascular Care Science Subcommittee; American Heart Association Emergency Cardiovascular Care Pediatric Emphasis Group; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; and Stroke Council. Pediatric Post-Cardiac Arrest Care: A Scientific Statement From the American Heart Association. Circulation 2019 June 27. Doi:10.1161/CIR.0000000000000697
Abstract: Compound heterozygotes occur when different variants at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of variants at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 Genomes Project participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or infantile spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 Genomes Project data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 Genomes Project participants using minor allele frequency (MAF) cutoffs of 0.5 and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous variants in six genes, including three involved in neuronal growth and development – PRTG (p = 0.00086, 1% MAF, combined ancestries), TNC (p = 0.022, 1% MAF, combined ancestries) and MACF1 (p = 0.0245, 0.5% MAF, EU ancestry). Due to the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous variants should be considered in sporadic epilepsy.
Background: Preterm infants are susceptible to unique pathology due to their immaturity. Mouse models are commonly used to study immature intestinal disease, including necrotizing enterocolitis (NEC). Current NEC models are performed at a variety of ages, but data directly comparing intestinal developmental stage equivalency between mice and humans are lacking.
Methods: Small intestines were harvested from C57BL/6 mice at 3–4 days intervals from birth to P28 (n = 8 at each age). Preterm human small intestine samples representing 17–23 weeks of completed gestation were obtained from the University of Pittsburgh Health Sciences Tissue Bank, and at term gestation during reanastamoses after resection for NEC (n = 4–7 at each age). Quantification of intestinal epithelial cell types and messenger RNA for marker genes were evaluated on both species.
Results: Overall, murine and human developmental trends over time are markedly similar. Murine intestine prior to P10 is most similar to human fetal intestine prior to viability. Murine intestine at P14 is most similar to human intestine at 22–23 weeks completed gestation, and P28 murine intestine is most similar to human term intestine.
Conclusion: Use of C57BL/6J mice to model the human immature intestine is reasonable, but the age of mouse chosen is a critical factor in model development.
In this review, the International Neonatal Consortium NEC working group addresses key issues that relate to the diagnosis, prevention, and treatment of NEC while suggesting a path forward to evaluate the safety and efficacy of each product. Despite years of clinical investigation, additional key data elements are needed to meet the requirements of regulatory agencies and evidence-based medicine.4 These include reliable diagnostic criteria, biomarkers predictive of risk and prognosis, and criteria for the design and conduct of clinical trials with consistent and clinically meaningful outcome measures for therapeutic trials.