Dr. Uc Publishes in Pancreas

Congratulations to Dr. Uc (Gastroenterology) for her most recent publication in Pancreas.

Ferguson, Bassuk and Darbro Publish in Genetics Research

Congratulations to Drs. Ferguson, Bassuk, and Darbro for their collaborative paper in Genetics Research!

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.

New Publications for Dr. Strathearn

Congratulations to Dr. Strathearn on two publications recently. The first one is a reply in JAMA Pediatrics:

The second one is in the Journal of Neuroendocrinology about sex differences in parenting neurobiology and behavior:

Dr. McElroy’s Lab Publishes in Pediatric Research

Dr. Steve McElroy (Neonatology) and his lab team published a new article in Pediatric Research titled “A direct comparison of mouse and human intestinal development using epithelial gene expression patterns“. Current neonatology fellow, Dr. Amy Stanford, was also an author on the paper.

  • 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.

Dr. McElroy Publishes in Journal of Pediatrics

Congratulations to Dr. Steve McElroy (neonatology) for his recent article accepted for publication/published online in the Journal of Pediatrics on Necrotizing Enterocolitis (NEC).

Necrotizing Enterocolitis: Using Regulatory Science and Drug Development to Improve Outcomes.

Abstract portion:

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.

Dr. Uc Publishes on Pancreatitis in Children

Congratulations to Dr. Uc on her recent publication in the Journal of Pediatric Gastroenterology and Nutrition on Pancreatitis in children.

OBJECTIVE: The aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.

CONCLUSIONS: Children with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.

New Publication for Drs. Bassuk and Ferguson

Congratulations for Drs. Bassuk (Neurology) and Feguson (Rheumatology) on their recent publication in the Proceedings of the National Academy of Sciences.

Abstract: Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. Ali18 mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for Ali18 was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of Fgr, a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of Fgr were introduced in Ali18 mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of Fgr abolished the inflammatory phenotype in Ali18 mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that Fgr null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of FgrAli18 are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in FGR, including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in Fgr are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.

Dr. Widness Publishes on Erythropoietin in Premature Infants

Congratulations to Dr. Jack Widness (professor emeritus, Neonatology) and his research team on their recent publication in the Journal of Clinical Pharmacology.

D’Cunha R, Widness JA, Yan X, Schmidt RL, Veng-Pedersen P, An G. A Mechanism-Based Population Pharmacokinetics Model of Erythropoietin in Premature Infants and Healthy Adults Following Multiple Intravenous Doses. Journal of Clinical Pharmacology 2019, 59(6) 835–846.

Abstract: The objective of the current study was to develop a population pharmacokinetics (PK) model for erythropoietin (Epo) in premature infants and healthy adults to characterize the variation in PK, and to study the differences in Epo PK in these 2 populations. Thirteen very low-birth-weight premature infants (<1500 g at birth), and 10 healthy adults received up to 4 intravenous doses of Epo that ranged from 10 to 500 U/kg. The final model had a target-mediated saturable, nonlinear, elimination pathway that incorporated the mechanism of Epo binding to its receptors along with a parallel linear, central elimination pathway. Epo clearance was found to be significantly higher in preterm infants compared to adults. Epo clearance via the nonlinear pathway was found to be much higher in infants; they had an Epo receptor capacity of 133 pM vs 86.6 pM in adults, which is most likely due to the higher erythroid progenitor cell mass per kilogram of body weight in infants. The parallel linear elimination was found to be more dominant in adults, reaching 91% of the total clearance with a 500-U/kg dose compared to just 6.1% of the total clearance following the same dose in preterm infants. Thus, this mechanism-based population PK model revealed that receptor-based nonlinear elimination is the dominant Epo elimination pathway in premature infants, and parallel linear elimination is dominant in adults.

Dr. Ferguson Co-Authors Rheumatology Guidelines

Congratulations to Dr. Polly Ferguson, Division Director of the Division of Rheumatology, for being co-author on some recent guidelines published for the American College of Rheumatology/Arthritis Foundation. The guidelines are below:

2019 American College of Rheumatollgy/Arthritis Foundation Guidelines for Treatment of Juvenile Idipathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

Dr. O’Brien Publishes in Behavior Analysis in Practice

Congratulations to Matt O’Brien, PhD in the Division of Developmental and Behavioral Pediatrics on his recent article published in Behavior Analysis in Practice.

The Promise of Accountable Care Organizations: “The Code,” Reimbursement, and an Ethical No-Win Situation for Behavior Analysts. March 2019,12(1),247-254.

Abstract: Clinical ethics, with its emphasis on the actions of clinicians, risks overlooking the ways in which broader health-care structures influence the behavior of health-care providers. Analysis of a factual case study demonstrates that status quo reimbursement practices may place behavior analysts in a position where, no matter how they act, they risk acting unethically. By contrast, the reimbursement model set by accountable care organizations (ACOs), part of the Patient Protection and Affordable Care Act (also known as Obamacare), may offer a solution. However, making good on the promise of ACOs will require more resources than any individual behavior analyst possesses. In order to encourage institutional structures that facilitate ethical practice, behavior analysts’ professional organizations should engage in contemporary political discussions about the state of American health care.