Browsing by Author "Markel, Troy A."
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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 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 Direct Peritoneal Resuscitation Improves Mesenteric Perfusion by Nitric Oxide Dependent Pathways(Elsevier, 2017-06) Khaneki, Sina; Jensen, Amanda R.; Drucker, Natalie A.; Markel, Troy A.; Department of Surgery, IU School of MedicineBackground Direct peritoneal resuscitation (DPR) has been shown to increase survival after intestinal ischemia and reperfusion injury (I/R). We have previously appreciated that minimum essential medium (MEM), a synthetic cell culture medium with bovine serum, glutamine, and antibiotics, contributes to these benefits. We hypothesized that (1) DPR using MEM as a dialysate would increase mesenteric perfusion, improve intestinal mucosal injury, and limit intestinal and hepatic inflammation after intestinal I/R and (2) these improvements would be dependent on endothelial nitric oxide pathways. Methods Eight-week-old C57Bl6J wild-type (WT) and eNOS Knock Out (eNOS KO) male mice were anesthetized and intestinal ischemia was induced for 60 min. After ischemia, 1 mL of phosphate buffered saline vehicle or MEM was injected into the abdominal cavity. Intestinal perfusion was reassessed after 48 h. Animals were then euthanized, and intestines and livers explanted for histologic and molecular analyses. Results DPR with MEM significantly improved mesenteric perfusion compared with vehicle (phosphate buffered saline) as measured by Laser Doppler Imaging (WT + MEM 91.58 ± 13.74%, WT + Vehicle 44.27 ± 11.93%, P < 0.05); however, these benefits were lost when endothelial nitric oxide signaling pathways were ablated (eNOS KO + MEM 21.72 ± 5.67 %, eNOS KO + Vehicle 45.24± 11.31%). WT mice treated with MEM also had significantly better preservation of their mucosal architecture (WT + MEM Mdn = 1.0, interquartile range [IQR] = 1.25, WT + Vehicle Mdn = 3.0, IQR = 2.0, P < 0.05). When we compared eNOS KO mice treated with either MEM or vehicle the protective effect of MEM disappeared (eNOS KO + MEM Mdn = 2.0, IQR = 2.25, eNOS KO + Vehicle Mdn = 2.0, IQR = 1.0 P > 0.05). Intestinal levels of interleukin (IL)-1β were increased in WT animals treated with MEM compared with eNOS KOs, whereas concentrations of intestinal IL-6 were similar between groups. Hepatic levels of both IL-1β and IL-6 were significantly elevated in eNOS KOs compared with WT treated with MEM. Conclusions DPR with MEM has significant therapeutic potential for improving mesenteric perfusion, intestinal injury, and the local inflammatory response after intestinal I/R. These benefits appear to be dependent on nitric oxide signaling within the endothelium.Item Effects of Manganese Porphyrins on Cellular Sulfur Metabolism(MDPI, 2020-02) Olson, Kenneth R.; Gao, Yan; Steiger, Andrea K.; Pluth, Michael D.; Tessier, Charles R.; Markel, Troy A.; Boone, David; Stahelin, Robert V.; Batinic-Haberle, Ines; Straubg, Karl D.; Pediatrics, School of MedicineManganese porphyrins (MnPs), MnTE-2-PyP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are superoxide dismutase (SOD) mimetics and form a redox cycle between O2 and reductants, including ascorbic acid, ultimately producing hydrogen peroxide (H2O2). We previously found that MnPs oxidize hydrogen sulfide (H2S) to polysulfides (PS; H2Sn, n = 2–6) in buffer. Here, we examine the effects of MnPs for 24 h on H2S metabolism and PS production in HEK293, A549, HT29 and bone marrow derived stem cells (BMDSC) using H2S (AzMC, MeRho-AZ) and PS (SSP4) fluorophores. All MnPs decreased intracellular H2S production and increased intracellular PS. H2S metabolism and PS production were unaffected by cellular O2 (5% versus 21% O2), H2O2 or ascorbic acid. We observed with confocal microscopy that mitochondria are a major site of H2S production in HEK293 cells and that MnPs decrease mitochondrial H2S production and increase PS in what appeared to be nucleoli and cytosolic fibrillary elements. This supports a role for MnPs in the metabolism of H2S to PS, the latter serving as both short- and long-term antioxidants, and suggests that some of the biological effects of MnPs may be attributable to sulfur metabolism.Item Endangered academia: preserving the pediatric surgeon scientist(Elsevier, 2017-07) Markel, Troy A.; Valsangkar, Nakul P.; Bell, Teresa M.; Kiel, Brandon A.; Zimmers, Teresa A.; Koniaris, Leonidas G.; Department of Pediatrics, School of MedicineBackground Pediatric surgery is one of the most difficult surgical fellowships to obtain. It requires stellar academic credentials and, often, dedicated time pursuing research. It is unknown, however, if pediatric surgeons maintain high academic output as faculty members. We hypothesized that the majority of pediatric surgeons do not pursue robust research activities as faculty, and therefore, over time, their academic productivity decreases. Methods Numbers of publications, citations, H-index, and NIH funding rates were determined for 4354 surgical faculty at the top-55 NIH based departments of surgery using websites, Scopus, NIH RePORTER, and Grantome. Continuous variables were compared with ANOVA and post-hoc Bonferroni; categorical variables by χ2 test. p < 0.05 was significant. Results In this dataset, 321 pediatric surgery (PS) faculty represented 7.4% of the cohort. Among PS faculty, 31% were assistant professors, 24% associate professors, 31% full professors and 13% had no academic rank. PS faculty had significantly more publications, a higher H index, and more high level NIH funding early in their careers at the assistant professor level compared to general surgeons. PS faculty at the associate professor level had equivalent high level NIH funding, but lower recentness and academic power compared to general surgeons. Professors of PS rebounded slightly, with only observed deficiencies in number of citations compared to general surgeons. Conclusions PS faculty in assistant professor ranks has higher scholarly productivity compared to equivalently ranked general surgeons. Despite some mild academic setbacks in midcareer, pediatric surgeons are able to maintain similar academic productivity to their general surgery colleagues by the time they are full professors. Level of evidence 2.Item Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia(Elsevier, 2009-04) Erwin, Graham S.; Crisostomo, Paul R.; Wang, Yue; Wang, Meijing; Markel, Troy A.; Guzman, Mike; Sando, Ian C.; Sharma, Rahul; Meldrum, Daniel R.; Surgery, School of MedicineBACKGROUND: Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Our lab has recently shown that gender differences exist in mesenchymal stem cell (MSC) paracrine function. Estrogen is implicated in the cardioprotection found in females. It remains unknown whether 17beta-estradiol (E2) affects MSC paracrine function and whether E2-treated MSCs may better protect injured cardiac tissue. We hypothesize that E2-exposed MSCs infused into hearts prior to ischemia may demonstrate increased vascular endothelial growth factor (VEGF) production and greater protection of myocardial function compared to untreated MSCs. MATERIALS AND METHODS: Untreated and E2-treated MSCs were isolated, cultured, and plated and supernatants were harvested for VEGF assay (enzyme-linked immunosorbent assay). Adult male Sprague-Dawley rat hearts (n = 13) were isolated and perfused via Langendorff model and subjected to 15 min equilibration, 25 min warm global ischemia, and 40 min reperfusion. Hearts were randomly assigned to perfusate vehicle, untreated male MSC, or E2-treated male MSC. Transcoronary delivery of 1 million MSCs was performed immediately prior to ischemia in experimental hearts. RESULTS: E2-treated MSCs provoked significantly more VEGF production than untreated MSCs (933.2 +/- 64.9 versus 595.8 +/- 10.7 pg/mL). Postischemic recovery of left ventricular developed pressure was significantly greater in hearts infused with E2-treated MSCs (66.9 +/- 3.3%) than untreated MSCs (48.7 +/- 3.7%) and vehicle (28.9 +/- 4.6%) at end reperfusion. There was also greater recovery of the end diastolic pressure with E2-treated MSCs than untreated MSCs and vehicle. CONCLUSIONS: Preischemic infusion of MSCs protects myocardial function and viability. E2-treated MSCs may enhance this paracrine protection, which suggests that ex vivo modification of MSCs may improve therapeutic outcome.Item Harvest Tissue Source Does Not Alter the Protective Power of Stromal Cell Therapy Following Intestinal Ischemia and Reperfusion Injury(Elsevier, 2016-08) Jensen, Amanda R.; Manning, Morenci M.; Khaneki, Sina; Drucker, Natalie A.; Markel, Troy A.; Medicine, School of MedicineBackground Transplantation of mesenchymal stromal cells (MSCs) may be a novel treatment for intestinal ischemia. The optimal stromal cell source that could yield maximal protection following injury, however, has not been identified. We hypothesized that: 1) MSCs would increase survival and mesenteric perfusion, preserve intestinal histological architecture, and limit inflammation following intestinal ischemia and reperfusion injury (I/R), and 2) MSCs harvested from different sources of tissue would have equivalent protective properties to the intestine following I/R. Methods Adult male mice were anesthetized and a midline laparotomy performed. The intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using Laser Doppler Imaging (LDI). Intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 minutes with a non-crushing clamp. Following ischemia, the clamp was removed and the intestines were allowed to recover. Prior to abdominal closure, 2 × 106 human umbilical (USCs), bone-marrow (BMSCs) derived MSCs, or keratinocytes in 250μl of phosphate-buffered saline (PBS) vehicle were injected into the peritoneum. Animals were allowed to recover for 12 or 24 hours (perfusion, histology, inflammatory studies), or 7 days (survival studies). Survival data was analyzed using log rank test. Perfusion was expressed as percentage of baseline and 12 and 24 hour data was analyzed using one way ANOVA and student’s t-test. Non parametric data was compared using Mann-Whitney-U test. A p-value of less than 0.05 was significant. Results All MSCs increased seven day survival following I/R and were superior to vehicle or keratinocytes (P<0.05). All MSCs increased mesenteric perfusion above vehicle at 12 and 24 hours following injury (P<0.05). All MSCs provided superior perfusion compared to keratinocytes at 24 hours post-injury (P<0.05). Administration of each MSC line improved intestinal histology after I/R (P<0.05). Multiple pro-inflammatory chemokines were down-regulated following application of MSCs suggesting a decreased inflammatory response following MSC therapy. Conclusion Transplantation of MSCs following intestinal I/R, irrespective of source tissue, significantly increases survival and mesenteric perfusion while limiting intestinal damage and inflammation. Further studies are needed to identify the mechanism that these cells utilize to promote improved outcomes following injury.