Elimination of 15 N-thymidine after oral administration in human infants

• Published in: PloS one 2024-01, Vol.19 (1)
• Main Authors: Ammanamanchi, Niyatie, Yester, Jessie, Bargaje, Anita, Thomas, Dawn, Little, Kathryn, Janzef, Shannon, Francis, Kimberly, Weinberg, Jacqueline, Johnson, Jennifer, Seery, Thomas, Tyler Hutchinson Harris, Funari, Bryan, Rose-Felker, Kirsten, Matthew Zinn, Miller, Susan, West, Shawn, Feingold, Brian, Zhou, Hairu, Matthew L. Steinhauser, Csernica, Timothy, Michener, Robert, Kühn, Bernhard
• Format: Article
• Language: English
• Subjects: Body weight; Cardiomyocytes; Cardiovascular diseases; Caregivers; Cell cycle; Clinical trials; Comparative analysis; Congestive heart failure; Consent; Enrichment; Heart diseases; Heart failure; Hospitals; Infants; Isotope ratios; Isotopes; Labels; Mass spectrometry; Mass spectroscopy; Nitrogen; Nitrogen isotopes; Observational studies; Oral administration; Patients; Pediatrics; Pilot projects; Scientific imaging; Tetralogy of Fallot; Thymidine; Urine
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0295651

Background We have developed a new clinical research approach for the quantification of cellular proliferation in human infants to address unanswered questions about tissue renewal and regeneration. The approach consists of oral 15 N-thymidine administration to label cells in S-phase, followed by Multi-isotope Imaging Mass Spectrometry for detection of the incorporated label in cell nuclei. To establish the approach, we performed an observational study to examine uptake and elimination of 15 N-thymidine. We compared at-home label administration with in-hospital administration in infants with tetralogy of Fallot, a form of congenital heart disease, and infants with heart failure. Methods We examined urine samples from 18 infants who received 15 N-thymidine (50 mg/kg body weight) by mouth for five consecutive days. We used Isotope Ratio Mass Spectrometry to determine enrichment of 15 N relative to 14 N (%) in urine. Results/findings 15 N-thymidine dose administration produced periodic rises of 15 N enrichment in urine. Infants with tetralogy of Fallot had a 3.2-fold increase and infants with heart failure had a 4.3-fold increase in mean peak 15 N enrichment over baseline. The mean 15 N enrichment was not statistically different between the two patient populations (p = 0.103). The time to peak 15 N enrichment in tetralogy of Fallot infants was 6.3 ± 1 hr and in infants with heart failure 7.5 ± 2 hr (mean ± SEM). The duration of significant 15 N enrichment after a dose was 18.5 ± 1.7 hr in tetralogy of Fallot and in heart failure 18.2 ± 1.8 hr (mean ± SEM). The time to peak enrichment and duration of enrichment were also not statistically different (p = 0.617 and p = 0.887). Conclusions The presented results support two conclusions of significance for future applications: (1) Demonstration that 15 N-thymidine label administration at home is equivalent to in-hospital administration. (2) Two different types of heart disease show no differences in 15 N-thymidine absorption and elimination. This enables the comparative analysis of cellular proliferation between different types of heart disease.