A PrP EGFR signaling axis controls neural stem cell senescence through modulating cellular energy pathways.

Mis-folding of the prion protein (PrP) is known to cause neurodegenerative disease; however, the native function of this protein remains poorly defined. PrP has been linked with many cellular functions, including cellular proliferation and senescence. It is also known to influence epidermal growth factor receptor (EGFR) signaling, a pathway that is itself linked with both cell growth and senescence. Adult neural stem cells (NSCs) persist at low levels in the brain throughout life and retain the ability to proliferate and differentiate into new neural lineage cells. KO of PrP has previously been shown to reduce NSC proliferative capacity. We used PrP KO and WT NSCs from adult mouse brain to examine the influence of PrP on cellular senescence, EGFR signaling, and the downstream cellular processes. PrP KO NSCs showed decreased cell proliferation and increased senescence in in vitro cultures. Expression of EGFR was decreased in PrP KO NSCs compared with WT NSCs and additional supplementation of EGF was sufficient to reduce senescence. RNA-seq analysis confirmed that significant changes were occurring at the mRNA level within the EGFR signaling pathway and these were associated with reduced expression of mitochondrial components and correspondingly reduced mitochondrial function. Metabolomic analysis of cellular energy pathways showed that blockages were occurring at critical sites for production of energy and biomass, including catabolism of pyruvate. We conclude that, in the absence of PrP, NSC growth pathways are downregulated as a consequence of insufficient energy and growth intermediates.

Impact of Early Video Capsule Endoscopy on Hospitalization and Post-hospitalization Outcomes: A Propensity Score-Matching Analysis.

INTRODUCTION: Video capsule endoscopy (VCE) has become the accepted evaluation of choice for patients with suspected small bowel bleeding. Our aim was to evaluate the impact of early as compared to delayed inpatient VCE on post-index hospitalization readmission rates. METHODS: We performed a retrospective study using medical claims from the IBM® Marketscan® Commercial Database from January 1, 2004, through September 30, 2018, including adult patients that underwent an inpatient VCE. Early VCE was defined as occurring on days 0, 1, or 2 of the index hospitalizations, whereas delayed VCE was performed on days 3-7. Propensity matching was performed to create an analytic cohort, and outcomes were assessed using logistic regression. RESULTS: Following propensity score matching, 607 patients undergoing early VCE were matched 1:1 with 607 patients undergoing delayed VCE. The median patient age was 65 (IQR: 56-78) years, and 560 (37.9%) of the included patients were female. The mean time to VCE was 1.6 (± 0.6) days for the early VCE group and 4.0 (± 1.2) days from admission for delayed VCE. In unadjusted comparisons, we found no significant difference between early VCE and delayed VCE with respect to 90-day all-cause readmission (18.6% vs. 17.0%, P = 0.5) or 90-day rebleeding risk (10.5% vs. 8.7%, P = 0.331). Patients undergoing an early VCE had a shorter hospital LOS and less total hospitalization charges. CONCLUSION: Early as compared to delayed inpatient VCE was associated with a reduction in index hospitalization resource utilization. No differences were found with respect to reductions in readmissions or rebleeding events.

Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function.

Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is directly linked to PrP dysfunction. We differentiated cardiomyocyte cultures from donor human induced pluripotent stem cells and found a direct influence of the PRNP E200K mutation on cellular function. The PRNP E200K cardiomyocytes showed abnormal function evident in the irregularity of the rapid repolarization; a phenotype comparable with the dysfunction reported in Down Syndrome cardiomyocytes. PRNP E200K cardiomyocyte cultures also showed increased mitochondrial superoxide accompanied by increased mitochondrial membrane potential and dysfunction. To confirm that the changes were due to the E200K mutation, CRISPR-Cas9 engineering was used to correct the E200K carrier cells and insert the E200K mutation into control cells. The isotype matched cardiomyocytes showed that the lysine expressing allele does directly influence electrophysiology and mitochondrial function but some differences in severity were apparent between donor lines. Our results demonstrate that cardiomyopathy in hereditary prion disease may be directly linked to PrP dysfunction.