Browsing by Author "Markel, Troy A."
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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 Accounting for early job turnover in recent pediatric surgery fellowship graduates: An American Pediatric Surgical Association Membership and Credentials Committee study(Elsevier, 2018-11) Crafts, Trevor D.; Bell, Teresa M.; Srisuwananukorn, Andrew; Applebaum, Harry; Markel, Troy A.; Surgery, School of MedicinePURPOSE: Employment opportunities for graduating pediatric surgeons vary from year to year. Significant turnover among new employees indicates fellowship graduates may be unsophisticated in choosing job opportunities which will ultimately be satisfactory for themselves and their families. The purpose of this study was to assess what career, life, and social factors contributed to the turnover rates among pediatric surgeons in their first employment position. METHODS: American Pediatric Surgical Association members who completed fellowship training between 2011 and 2016 were surveyed voluntarily. Only those who completed training in a pediatric surgery fellowship sanctioned by the American Board of Surgery and whose first employment involved the direct surgical care of patients were included. The survey was completed electronically and the results were evaluated using chi-squared analysis to determine which independent variables contributed to a dependent outcome of changing place of employment. RESULTS: 110 surveys were returned with respondents meeting inclusion criteria. 13 (11.8%) of the respondents changed jobs within the study period and 97 (88.2%) did not change jobs. Factors identified that likely contributed to changing jobs included a perceived lack of opportunity for career [p = <0.001] advancement and the desire to no longer work at an academic or teaching facility [p = 0.013]. Others factors included excessive case load [p = 0.006]; personal conflict with partners or staff [p = 0.007]; career goals unfulfilled by practice [p = 0.011]; lack of mentorship in partners [p = 0.026]; and desire to be closer to the surgeon's or their spouse's family [p = 0.002]. CONCLUSIONS: Several factors appear to play a role in motivating young pediatric surgeons to change jobs early in their careers. These factors should be taken into account by senior pediatric fellows and their advisors when considering job opportunities.Item Angiogenesis: A Cellular Response to Traumatic Injury(Wolters Kluwer, 2020) Pecoraro, Anthony R.; Hosfield, Brian D.; Li, Hongge; Shelley, W. Christopher; Markel, Troy A.; Surgery, School of MedicineThe development of new vasculature plays a significant role in a number of chronic disease states, including neoplasm growth, peripheral arterial disease, and coronary artery disease, among many others. Traumatic injury and hemorrhage, however, is an immediate, often dramatic pathophysiologic insult which can also necessitate neovascularization to promote healing. Traditional understanding of angiogenesis involved resident endothelial cells branching outward from localized niches in the periphery. Additionally, there are a small number of circulating endothelial progenitor cells which participate directly in the process of neovessel formation. The bone marrow stores a relatively small number of so-called pro-angiogenic hematopoietic progenitor cells (PACs) – that is, progenitor cells of a hematopoietic potential that differentiate into key structural cells and stimulate or otherwise support local cell growth/differentiation at the site of angiogenesis. Following injury, a number of cytokines and intercellular processes are activated or modulated to promote development of new vasculature. These processes initiate and maintain a robust response to vascular insult, allowing new vessels to canalize and anastomose and provide timely oxygen delivering to healing tissue. Ultimately as we better understand the key players in the process of angiogenesis we can look to develop novel techniques to promote healing following injury.Item Are Surgeons Behind the Scientific Eight Ball: Delayed Acquisition of the NIH K08 Mentored Career Development Award(Elsevier, 2020-02) Hosfield, Brian D.; John, Quincy E.; Seiler, Kristen M.; Good, Misty; Dunnington, Gary L.; Markel, Troy A.; Surgery, School of MedicineBackground: Surgery residents complete their research training early in residency. Non-surgical trainees typically have research incorporated toward the last two years of their fellowship, conferring an advantage to apply for grants with recent research experience and preliminary data. Methods: The NIH RePORTER database was queried for K08 awardees trained in medicine, pediatrics, and surgery from 2013 to 2017. 406 K08 recipients were identified and time from completion of clinical training to achieving a K08 award was measured. Data were compared using ANOVA and expressed as mean. P < 0.05 was considered significant. Results: Surgeons took longer to obtain a K08 than those trained in internal medicine (surgery = 3.7 years, internal medicine = 2.58 years p < 0.0001)). All K08 recipients without a PhD took longer to obtain a K08 than recipients with a PhD (MD = 3.50 years and MD/PhD = 2.42 years (p=<0.0001). Conclusions: Surgeons take longer to achieve a K08 award than clinicians trained in internal medicine, possibly due to an inherent disadvantage in training structure.Item The Assessment of Fecal Volatile Organic Compounds in Healthy Infants: Electronic Nose Device Predicts Patient Demographics and Microbial Enterotype(Elsevier, 2020-10) Hosfield, Brian D.; Pecoraro, Anthony R.; Baxter, Nielson T.; Hawkins, Troy B.; Markel, Troy A.; Surgery, School of MedicineBackground: The assessment of fecal volatile organic compounds (VOCs) has emerged as a noninvasive biomarker in many different pathologies. Before assessing whether VOCs can be used to diagnose intestinal diseases, including necrotizing enterocolitis (NEC), it is necessary to measure the impact of variable infant demographic factors on VOC signals. Materials and methods: Stool samples were collected from term infants at four hospitals in a large metropolitan area. Samples were heated, and fecal VOCs assessed by the Cyranose 320 Electronic Nose. Twenty-eight sensors were combined into an overall smellprint and were also assessed individually. 16s rRNA gene sequencing was used to categorize infant microbiomes. Smellprints were correlated to feeding type (formula versus breastmilk), sex, hospital of birth, and microbial enterotype. Overall smellprints were assessed by PERMANOVA with Euclidean distances, and individual sensors from each smellprint were assessed by Mann-Whitney U-tests. P < 0.05 was significant. Results: Overall smellprints were significantly different according to diet. Individual sensors were significantly different according to sex and hospital of birth, but overall smellprints were not significantly different. Using a decision tree model, two individual sensors could reliably predict microbial enterotype. Conclusions: Assessment of fecal VOCs with an electronic nose is impacted by several demographic characteristics of infants and can be used to predict microbiome composition. Further studies are needed to design appropriate algorithms that are able to predict NEC based on fecal VOC profiles.Item The Assessment of Microbiome Changes and Fecal Volatile Organic Compounds during Experimental Necrotizing Enterocolitis(Elsevier, 2021) Hosfield, Brian D.; Drucker, Natalie A.; Pecoraro, Anthony R.; Shelley, William C.; Li, Hongge; Baxter, Nielson T.; Hawkins, Troy B.; Markel, Troy A.; Surgery, School of MedicineIntroduction: Necrotizing enterocolitis (NEC) remains a devastating disease that affects the gastrointestinal tract of the preterm infant. Volatile organic compounds (VOCs) have emerged as a non-invasive biomarker in many diseases. We hypothesized that fecal VOC profiles would be significantly different between control and NEC pups in a NEC mouse model. Methods: Experimental NEC was induced in five-day-old mice. Breastfed and formula-fed control groups were also studied. After four days, pups were euthanized and intestines were H&E stained and blindly scored. Stool microbiome analysis was performed via 16S rRNA sequencing. VOC analysis was assessed by the CyranoseⓇ 320 eNose device and p<0.05 was significant. Results: NEC pups had severe intestinal injury when compared to controls. Microbiome analysis showed that both control groups had significantly higher microbial diversity and relative abundance of Lactobacillus than NEC, and lower relative abundance of Escherichia. Fecal VOC profile for NEC pups was significantly different from controls. Conclusions: Experimental NEC was associated with intestinal dysbiosis. Fecal VOC analysis by the CyranoseⓇ 320 eNose device can discriminate NEC pups from both breastfed and formula-fed controls. Further research is warranted to establish whether fecal VOCs can be used as a biomarker or predictive algorithm to diagnose NEC.Item Biobanking for necrotizing enterocolitis: Needs and standards(Elsevier, 2019) Chaaban, Hala; Markel, Troy A.; Canvasser, Jennifer; Good, Misty; Surgery, School of MedicineBackground Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that primarily affects premature infants. Despite medical advances, mortality and morbidity from NEC are still unacceptably high. This is partly because of the lack of specific biomarkers and therapies for this disease. Availability of high-quality biological samples and the associated data from premature infants are key to advance our understanding of NEC, and for biomarker discovery and drug development. To that end, the NEC Society Biorepository was established with the goal of promoting studies in human infants through sharing specialized biospecimen and data procurement for NEC research. Objective In this review, we will discuss the required infrastructure for biobanks, discuss the importance of informatics management, and emphasize the logistical requirements for sharing specimens. Finally, we will discuss the mechanism for how tissues and material will be shared between the institutions. Conclusion We have developed a state-of-the-art biobank for human infants to advance the field of NEC research. With the NEC Society Biorepository, we seek to facilitate and accelerate the basic and translational studies on NEC to provide hope to the infants afflicted with NEC and their families.Item Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency(AHA, 2019-11-08) Duan, Yaqian; Prasad, Ram; Feng, Dongni; Beli, Eleni; Calzi, Sergio Li; Longhini, Ana Leda F.; Lamendella, Regina; Floyd, Jason L.; Dupont, Mariana; Noothi, Sunil K.; Sreejit, Gopal Krishan; Athmanathan, Baskaran; Wright, Justin; Jensen, Amanda R.; Oudit, Gavin Y.; Markel, Troy A.; Nagareddy, Prabhakara R; Obukhov, Alexander G.; Grant, Maria B.; Anatomy and Cell Biology, School of MedicineRationale: There is incomplete knowledge of the impact of bone marrow (BM) cells on the gut microbiome and gut barrier function. Objective: We postulated that diabetes and systemic angiotensin-converting enzyme 2 (ACE2) deficiency would synergize to adversely impact both the microbiome and gut barrier function. Methods and Results: Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from WT, ACE2−/y, Akita (type 1 diabetic, T1D), and ACE2−/y-Akita mice. Gut barrier integrity was assessed by immunofluorescence, and BM cell extravasation into the small intestine was evaluated by flow cytometry. In the ACE2−/y-Akita or Akita mice, the disrupted barrier was associated with reduced levels of myeloid angiogenic cells (MACs), but no increase in inflammatory monocytes was observed within the gut parenchyma. Genomic and metatranscriptomic analysis of the microbiome of ACE2−/y-Akita mice demonstrated a marked increase in peptidoglycan (PGN) producing bacteria. When compared to control cohorts treated with saline, intraperitoneal administration of MACs significantly decreased the microbiome gene expression associated with PGN biosynthesis and restored epithelial and endothelial gut barrier integrity. Also indicative of diabetic gut barrier dysfunction, increased levels of PGN and intestinal fatty acid binding protein-2 (FABP-2) were observed in plasma of human subjects with T1D (n=21) and Type 2 diabetes (T2D, n=23) compared to non-diabetic controls (n=23). Using human retinal endothelial cells, we determined that PGN activates a non-canonical Toll-like receptor-2 (TLR2) associated MyD88-ARNO-ARF6 signaling cascade, resulting in destabilization of p120-catenin and internalization of VE-cadherin as a mechanism of deleterious impact of PGN on the endothelium. Conclusion: We demonstrate for the first time that the defect in gut barrier function and dysbiosis in ACE2−/y-Akita mice can be favorably impacted by exogenous administration of MACs.Item Chondroitin sulfate supplementation improves clinical outcomes in a murine model of necrotizing enterocolitis(Wiley, 2023) Manohar, Krishna; Hosfield, Brian D.; Mesfin, Fikir M.; Colgate, Cameron; Shelley, William Christopher; Liu, Jianyun; Zeng, Lifan; Brokaw, John P.; Markel, Troy A.; Surgery, School of MedicineNecrotizing enterocolitis (NEC) continues to be a devastating disease in preterm neonates and has a paucity of medical management options. Chondroitin sulfate (CS) is a naturally occurring glycosaminoglycan (GAG) in human breast milk (HM) and has been shown to reduce inflammation. We hypothesized that supplementation with CS in an experimental NEC model would alter microbial diversity, favorably alter the cytokine profile, and (like other sulfur compounds) improve outcomes in experimental NEC via the eNOS pathway. NEC was induced in 5-day-old pups. Six groups were studied (n = 9-15/group): (1) WT breastfed and (2) Formula fed controls, (3) WT NEC, (4) WT NEC + CS, (5) eNOS KO (knockout) NEC, and (6) eNOS KO NEC + CS. Pups were monitored for clinical sickness score and weights. On postnatal day 9, the pups were killed. Stool was collected from rectum and microbiome analysis was done with 16 s rRNA sequencing. Intestinal segments were examined histologically using a well-established injury scoring system and segments were homogenized and analyzed for cytokine profile. Data were analyzed using GraphPad Prism with p < 0.05 considered significant. CS supplementation in formula improved experimental NEC outcomes when compared to NEC alone. CS supplementation resulted in similar improvement in NEC in both the WT and eNOS KO mice. CS supplementation did not result in microbial changes when compared to NEC alone. Our data suggest that although CS supplementation improved outcomes in NEC, this protection is not conferred via the eNOS pathway or alteration of microbial diversity. CS therapy in NEC does improve the intestinal cytokine profile and further experiments will explore the mechanistic role of CS in altering immune pathways in this disease.Item Congenital cecal diverticulitis in a pediatric patient(Elsevier, 2021-09) Lee, Zachary W.; Albright, Eric A.; Brown, Brandon P.; Markel, Troy A.; Surgery, School of MedicineDiverticulitis in the pediatric population is a very rare cause of abdominal pain. When present in the cecum or ascending colon, it is often incorrectly diagnosed preoperatively as acute appendicitis. This is especially true in Western countries where right-sided diverticulitis is less common. Here we detail a case of a pediatric patient with complicated congenital cecal diverticulitis and review the literature on pertinent management. An extensive work up with imaging and endoscopy was completed and definitive surgical treatment with diverticulectomy an appendectomy was performed. As the incidence of diverticular disease in younger individuals increases, right sided diverticulitis is worthy of consideration on the differential diagnosis.