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Browsing by Author "Hunter, Chelsea E."
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Item A hydrogen-sulfide derivative of mesalamine reduces the severity of intestinal and lung injury in necrotizing enterocolitis through endothelial nitric oxide synthase(American Physiological Society, 2022-10-01) Hosfield, Brian D.; Hunter, Chelsea E.; Li, Hongge; Drucker, Natalie A.; Pecoraro, Anthony R.; Manohar, Krishna; Shelley, W. Christopher; Markel, Troy A.; Surgery, School of MedicineNecrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and 4) NEC + 130 mg/kg ATB-429. Mesalamine and ATB-429 doses were equimolar. Pups were monitored for sickness scores and perfusion to the gut was measured by Laser Doppler Imaging (LDI). After euthanasia of the pups, intestine and lung were hematoxylin and eosin-stained and scored for injury in a blind fashion. TLR4 expression was quantified by Western blot and IL-6 expression by ELISA. P < 0.05 was significant. Both WT and eNOSKO breastfed controls underwent normal development and demonstrated milder intestinal and pulmonary injury compared with NEC groups. For the WT groups, ATB-429 significantly improved weight gain, reduced clinical sickness score, and improved perfusion compared with the NEC group. In addition, WT ATB-429 pups had a significantly milder intestinal and pulmonary histologic injury when compared with NEC. ATB-429 attenuated the increase in TLR4 and IL-6 expression in the intestine. When the experiment was repeated in eNOSKO pups, ATB-429 offered no benefit in weight gain, sickness scores, perfusion, intestinal injury, pulmonary injury, or decreasing intestinal inflammatory markers. An H2S derivative of mesalamine improves outcomes in experimental NEC. Protective effects appear to be mediated through eNOS. Further research is warranted to explore whether ATB-429 may be an effective oral therapy to combat NEC.Item Inter- and Intra-rater Reliability of A Grading System for Congenital Diaphragmatic Hernia Defect Size(Elsevier, 2019-01) Hunter, Chelsea E.; Saenz, Zoe M.; Nunez, Daisy; Timsina, Lava; Gray, Brian W.; Surgery, School of MedicineBackground The Congenital Diaphragmatic Hernia Study Group (CDHSG) registry is a multi-institutional tool to track outcomes of patients with CDH. The CDHSG asks surgeons to categorize diaphragmatic defect sizes as type A-D based on published guidelines. The reported size of the defect has been correlated with patient outcomes, but the reliability of this system has never been studied. Our goal was to evaluate the inter- and intra-rater reliability of the CDHSG grading system. Materials and methods Forty-six operative notes from CDH patients that underwent surgical repair at a single institution were collected and cropped to include only the information necessary to grade the hernia defect based on the CDHSG guidelines. The defects were graded by nine pediatric surgeons on two separate occasions (18 wk apart). Inter-rater reliability was calculated using a Cohen's kappa (κ). Intra-rater reliability was calculated using an intraclass correlation coefficient. Results Inter-rater reliability was minimal to weak (κ round1 = 0.395, κ round2 = 0.424). Agreement ranged from 19.57% (κ = −0.0745) to 82.61% (κ = 0.7543). Inter-rater agreement was similar despite operative findings and outcomes: survival yes/no (κ = 0.3690, κ = 0.3518), need for ECMO yes/no (κ = 0.3323, κ = 0.3362), patch repair yes/no (κ = 0.2050, κ = 0.1916), and liver up/down (κ = 0.2941, κ = 0.4404). Intra-rater reliability was good to excellent (intraclass correlation coefficient = 0.88, 95% CI [0.83-0.92]). Agreement with oneself ranged from 71.74% to 93.48%. Conclusions The demonstrated weak inter-rater reliability of the current CDHSG grading system shows the need for improvement in how the grading system is applied by surgeons when reporting CDH defect size.Item Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter(MDPI, 2022-09-10) Liu, Jianyun; Mesfin, Fikir M.; Hunter, Chelsea E.; Olson, Kenneth R.; Shelley, W. Christopher; Brokaw, John P.; Manohar, Krishna; Markel, Troy A.; Surgery, School of MedicineHydrogen sulfide has been recently identified as the third biological gasotransmitter, along with the more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential as a therapeutic agent for cardiovascular, inflammatory, infectious and neuropathological diseases have been undertaken. Here we review the possible direct targets of H2S in mammals. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling. H2S also reacts with hemeproteins and modulates metal-containing complexes. Once being oxidized, H2S can persulfidate proteins by adding -SSH to the amino acid cysteine. These direct modifications by H2S have significant impact on cell structure and many cellular functions, such as tight junctions, autophagy, apoptosis, vesicle trafficking, cell signaling, epigenetics and inflammasomes. Therefore, we conclude that H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases.