Gillian Fell

All Publications

• Repeated lengthening using distraction enterogenesis: A porcine model. Surgery Emengo, P., Fell, G. L., Nepomuceno, H., Thomas, A. L., Dunn, J. C. 2026; 194: 110159

  Abstract

  Spring-mediated distraction enterogenesis aims to use mechanical stretch to generate new functional intestinal tissue in patients with short bowel syndrome. Because of the incremental nature of spring-mediated distraction enterogenesis, patients may require multiple spring insertions to produce enough tissue to wean off parenteral nutrition. We aim to demonstrate the feasibility of repeated lengthening within the same intestinal segment.Juvenile Yucatan pigs underwent a laparotomy to introduce a gelatin-encapsulated nitinol spring into the jejunum. After 14-21 days, a second laparotomy was performed to remove the initial spring and insert a new compressed spring with a greater force constant into a portion of the previously lengthened jejunum. After 7 days, the pigs were killed, and samples were collected.Spring insertion produced a significant increase in jejunal length when compared to controls. Both the initial and the subsequent stronger springs produced an equivalent amount of lengthening. Crypt depth, mucosal thickness, muscularis thickness, and the outer serosal perimeter of the repeatedly lengthened jejunal segments all increased compared with control segments.Previously lengthened segments of jejunum were successfully relengthened using spring-mediated distraction enterogenesis in a porcine model. This suggests that patients with short bowel syndrome may be offered repeat distraction procedures to achieve a greater increase in bowel length than a single spring-mediated distraction enterogenesis procedure.

  View details for DOI 10.1016/j.surg.2026.110159

  View details for PubMedID 41880743

• A national database study of adjuvant steroids following Kasai portoenterostomy for biliary atresia. Pediatric surgery international Liang, N. E., Thobani, H., Moturu, A., Suh, E., Islam, S., Fell, G. L., Hyun, J. S., Sylvester, K. G., Chao, S. D., Dunn, J. C., Khan, F. A. 2026; 42 (1)

  Abstract

  Adjuvant steroids in the treatment of BA remains controversial. We sought to characterize variations in steroid use and their effect on postoperative outcomes in a multi-institutional cohort of BA patients.PHIS was queried for all patients between 2017 and 2024 who were diagnosed with BA and underwent KPE. Patients who received ≥ 3 contiguous days of steroids within 7 days of KPE were considered to have received postoperative steroids. The primary outcome was native liver survival, calculated using Kaplan-Meier analysis.504 patients from 37 hospitals with a median age of 52 days (IQR: 35-69 days) met inclusion criteria. 139 patients (28.6%) received adjuvant steroids. The steroid-treated cohort had a significantly longer postoperative LOS (P < 0.001) and high-volume-KPE hospitals were significantly more likely to use adjuvant steroids (P < 0.001). The majority of patients were started on steroids on POD#0. 5 hospitals utilized steroids in > 50% of their patients after KPE. Kaplan-Meier analysis showed no difference in two-year native liver survival.In this large multi-institutional cohort study, steroids were used early, with significant intra-hospital variation, and were associated with increased postoperative LOS and higher KPE volume. Larger multi-institutional studies with standardized steroid dosage regimens and extended long-term follow up are needed.III.

  View details for DOI 10.1007/s00383-026-06401-x

  View details for PubMedID 41865321

  View details for PubMedCentralID 4303045

• A Translational Surgical Porcine Model for Postoperative Intra-Abdominal Adhesion Formation. Journal of visualized experiments : JoVE Reveron-Thornton, R. F., Hsu, C. H., Bobst, W., Guo, J. L., Meany, E. L., M Williams, C., Berry, C., Fallah, M., Korah, M., P Agolia, J., Guo, C., Fell, G. L., Hyun, J., Wan, D. C., Norton, J. A., Appel, E., Longaker, M. T., Delitto, D., Foster, D. S. 2026

  Abstract

  A porcine model of postoperative intra-abdominal adhesion formation was established using Yucatan mini pigs. The protocol combines midline laparotomy, small bowel resection with two-layer primary anastomosis, and a unilateral, parietal peritoneal abrasion in the format of an open abdominal surgical procedure. Adhesion formation was assessed four weeks postoperatively using established gross and histologic scoring criteria, with evaluations performed by blinded observers. Adhesions developed in all animals using this model and were multifocal, involving bowel loops, between the bowel and abdominal wall, involving the peritoneum overlying other organs in the abdomen (e.g. the liver), and operative sites, with variable severity. Histological analysis at four weeks demonstrated adhesions composed predominantly of extracellular matrix, fibroblasts, and blood vessels, consistent with a remodeling-phase wound healing tissue phenotype. This model is relevant for the study of abdominal adhesion fibrosis biology and/or the translational evaluation of candidate anti-adhesion therapeutics. By integrating a clinically relevant intestinal surgical procedure with a defined peritoneal injury and a standardized assessment strategy, this protocol provides a reproducible approach for inducing and evaluating postoperative intra-abdominal adhesions in a large animal model.

  View details for DOI 10.3791/70377

  View details for PubMedID 41911229

• Epithelial Ion Transport in Spring-Lengthened Jejunum in a Porcine Model. Journal of pediatric surgery Joo, N. S., Thomas, A. L., Salimi-Jazi, F., Rafeeqi, T. A., Fell, G., Emengo, P., Nguyen, J. A., Diyaolu, M., Abazari, S., Sellers, Z. M., Dunn, J. C. 2025: 162880

  Abstract

  Loss of functional small intestine in short bowel syndrome results in profound nutrient malabsorption and diarrhea. We previously developed an expandable spring device that triggers intestinal lengthening. The aim of this study was to assess the functional ion transport capabilities of spring-lengthened jejunum.Mini-Yucatan pigs underwent laparotomy and spring placement in the jejunum. After 7 days, pigs were euthanized to retrieve spring-lengthened and distal control jejunum. Tissues were mounted in Ussing chambers to measure transepithelial resistance and short-circuit current (Isc). Forskolin and carbachol were used to measure cAMP- and calcium-mediated anion secretory capacities, and glucose was used for absorptive capacity. Tissue samples were then preserved for histopathology and immunochemistry.Intestinal segments exposed to springs became longer at euthanasia. Baseline transepithelial resistance and Isc were similar between spring-lengthened and control jejunum. Forskolin, carbachol, and glucose increased Isc above baseline in both lengthened and control jejunum. While glucose-stimulated Isc was similar between lengthened and control jejunum, forskolin- and carbachol-stimulated Isc were reduced. Spring-lengthened jejunum had greater mucosal area with deeper crypts and taller villi, but similar crypt: villus ratios as control jejunum. Spring-lengthened jejunum had thicker muscularis propria compared to controls.Spring-lengthening of small bowel does not disrupt mucosal barrier function, based on histological and functional assessments. While spring-lengthened jejunum showed reduced transepithelial secretory function, its absorptive function appears intact. This change may be related to early tissue remodeling during distraction enterogenesis and further investigation into the cellular changes induced by distraction enterogenesis are ongoing.

  View details for DOI 10.1016/j.jpedsurg.2025.162880

  View details for PubMedID 41423148

• Pediatric metabolic and bariatric surgery: When is the right time to operate? Current problems in pediatric and adolescent health care Shacker, M., Chinn, J., Pratt, J. S., Fell, G. L. 2025: 101882

  Abstract

  Pediatric obesity is a growing epidemic associated with serious long-term health consequences, including diabetes, cardiovascular disease, and reduced life expectancy. Metabolic and bariatric surgery (MBS) is a safe, effective, and durable treatment for adolescents with severe or refractory obesity; however, it remains significantly underutilized. As a consequence, children with severe obesity and associated comorbidities progress to an advanced stage of disease that can be even more challenging to treat than in adults. Current evidence demonstrates that MBS in adolescents achieves comparable or even superior weight loss and comorbidity resolution compared to adults, with favorable long-term safety profiles. In select cases, GLP-1 receptor agonists (GLP-1RAs), may be used as an adjunct to MBS. Current evidence for GLP-1RA use in the preoperative period is limited, although when reinitiated early in the postoperative period, they may be associated with improved weight loss outcomes. Despite strong guideline support, <0.05 % of eligible children undergo MBS, likely due to poor access to adolescent MBS centers, limited insurance coverage, and a lack of awareness or misinformation surrounding MBS, among other causes. Multidisciplinary support including preoperative teaching, mental health services, and long-term postoperative follow-up is essential to the success of the procedure. Further research is needed to better characterize the disparities in access, improve outreach and education efforts, combat the stigma associated with adolescent MBS, and address this growing public health crisis.

  View details for DOI 10.1016/j.cppeds.2025.101882

  View details for PubMedID 41344950

• The impact of social determinants of health on adolescent metabolic and bariatric surgical outcomes. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery Chinn, J. O., Herdes, R. E., Shacker, M., Santos, V., Fell, G. L., Pratt, J. S. 2025

  Abstract

  Prior research has shown higher rates of complications across a broad spectrum of surgeries in pediatric patients with higher Social Vulnerability Index (SVI).This study aims to compare how SVI impacts outcomes in adolescents undergoing metabolic and bariatric surgery (MBS).Academic Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-adolescent accredited care center METHODS: We performed a retrospective cohort study of 126 adolescents and young adults undergoing laparoscopic sleeve gastrectomy between September 2014 and April 2021. Comparative analysis was performed for demographics, percent total body weight loss (%TBWL), and complications between those with high (≥ .75) and low (<.75) SVI.There were 47 patients in the high SVI group and 79 in the low SVI group. Age at surgery, gender, primary language, and insurance type were similar between groups. Preoperative weight and body mass index (BMI) were higher in the high SVI group compared to the low SVI group (145 kg vs 136 kg, P = .033, BMI 52 vs 46, P < .001). Average distance to the hospital was similar (82 miles in high SVI group vs 100 miles in low SVI group, P = .079). The high SVI group had a trend towards a higher percentage of patients who identified as Hispanic/Latino (64% vs 47%, P = .064) and less patients who identified as white (28% vs 51%, P = .054). There was no significant difference in mean %TBWL at 3 months, 6 months, or 12 months (23% in high SVI group (N = 40) compared to 22% in low SVI group (N = 66), P = .4). Complication rates were low in both groups, with no difference between SVI groups (6.5% vs 5.1%, P = .707). While the number of patients with long-term data decreased over time, there was no difference in %TBWL at 2, 3, or 4 years after surgery.Despite a diverse patient population and significant geographic barriers, the outcomes between high and low SVI in this cohort were comparable. Continued efforts need to be made to expand access to MBS for socioeconomic disadvantaged adolescent patients with obesity.

  View details for DOI 10.1016/j.soard.2025.11.009

  View details for PubMedID 41339175

• Wound Healing and Management Considerations in the Pediatric Surgical Patient. Advances in wound care Liang, N. E., Jing, S. L., Suh, E. J., Wang, H. H., Pham, B. P., Chiu, B., Hyun, J. S., Griffin, M. F., Longaker, M. T., Fell, G. L. 2025

  Abstract

  Significance: Wound healing in pediatric patients is affected by physiology, growth, and development considerations unique from those in adults. In the following report, we review the primary literature on aging and wound healing and highlight clinical wound healing applications for the pediatric patient across age ranges from neonates and infants in the first year of life to adolescents (aged 10-19 years by World Health Organization definition). Recent Advances: We characterize the differences in wound healing biology between infants, adolescents, and adults and discuss wound care strategies for pediatric surgical patients, highlighting evidence-based guidelines for wound management. We discuss relevant animal models and review the multidisciplinary aspects of providing wound care for children. Critical Issues: Pediatric surgical patients have specialized wound care needs. Optimizing wound care outcomes for infants, children, and adolescents relies on an understanding of their wound-healing biology and unique physiological, psychological, and social considerations. Future Directions: Future directions in pediatric wound care will focus on validating and optimizing emerging technologies through pediatric-specific clinical trials, while also addressing key knowledge gaps in topical agent pharmacokinetics and advancing regenerative approaches like mesenchymal stem cell therapies tailored to the unique biology of infants and children.

  View details for DOI 10.1177/21621918251387640

  View details for PubMedID 41192826

• Submucosal Hydrogel for Spring-Mediated Intestinal Lengthening. Journal of biomedical materials research. Part A Salimi-Jazi, F., de Paiva Narciso, N., Fell, G., Thomas, A., Navarro, R. S., Rafeeqi, T., Baugh, N. J., Suhar, R. A., Nguyen, J., Lopez, N., Heilshorn, S. C., Dunn, J. C. 2025; 113 (10): e37986

  Abstract

  Spring-mediated distraction enterogenesis has shown success in intestinal lengthening, with spring confinement achieved by external plication with sutures to reduce the lumen diameter at both ends of the intestinal segment. Endoscopic spring placement would minimize the morbidity associated with device insertion. This study investigates the use of submucosal injection of engineered hydrogel to temporarily confine a compressed spring within an intestinal segment. Engineered hydrogels were composed of hyaluronic acid (HA) alone or HA with elastin-like protein (HELP). To simulate endoscopic injection in six juvenile pigs, hydrogel was injected into the submucosa in everted jejunum, followed by the placement of a gelatin-encapsulated, compressed nitinol spring. The jejunum was then unfolded over the spring, and hydrogel was injected distally into the submucosa. Sutures were placed as fiducial markers. After 7days on a liquid diet, the pigs were euthanized, and their intestinal segments were analyzed for lengthening and histological changes. The spring-containing jejunal segments expanded in all animals, lengthening to 132% in the HA group and 188% in the HELP group. HELP hydrogels exhibited slower biodegradation than HA-only hydrogels. Histological analysis showed increased crypt width and decreased crypt density in the spring-containing segments compared to controls. Hydrogel effectively provides temporary spring confinement within intestinal segments without adverse effects. The mechanical stimulation from the spring induces crypt fission, expanding the intestinal epithelium. These results support the feasibility of gel-enabled, spring-mediated distraction enterogenesis for intestinal lengthening.

  View details for DOI 10.1002/jbm.a.37986

  View details for PubMedID 40977628

• Metabolic and bariatric surgery in adolescents compared to young adults: an MBSAQIP database analysis. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery Shacker, M., Chao, S. D., Chinn, J. O., Fell, G. L., Mueller, C. M., Pratt, J. S. 2025

  Abstract

  Metabolic and bariatric surgery (MBS) is a highly durable, safe and effective treatment for severe obesity in adults. However, MBS remains underutilized in the pediatric and adolescent population, likely due to safety concerns of elective surgery in children.We aimed to analyze whether the benefits of MBS outweigh the risks in adolescents when compared to young adults.Multicenter, national database study.Patients aged 10-39 who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Patients with prior foregut surgery were excluded.556,628 patients were identified; 10,883 (2.0%) were aged 10-19 (adolescents), 161,938 (29.1%) were 20-29 (young adults), and 383,807 (69.0%) were 30-39 (adults). Preoperative body mass index (BMI) was clinically similar between groups, though statistically significant due to large sample size (10-19: 46, 20-29: 45, 30-39: 45 kg/m2, P < .001). SG was more common in younger cohorts (10-19: 86%, 20-29: 77%, 30-39: 75%, P < .001). At 30 days postoperatively, adolescents demonstrated marginally greater BMI reduction (10-19: 2.91, 20-29: 2.69, 30-39: 2.53 kg/m2, P < .001). Adolescents had fewer postoperative complications, including surgical site infections, gastrointestinal bleeding, and blood transfusions (P < .001). Among adolescents, SG (aOR: .39, CI: .31-.48, P < .001) was associated with reduced postoperative complications.Adolescents undergoing MBS have BMI reductions similar to those of young adults and have lower rates of complications and readmissions. MBS should be offered as a safe treatment for adolescents to treat morbid obesity with at least similar frequency as it is offered to adults.

  View details for DOI 10.1016/j.soard.2025.08.010

  View details for PubMedID 40946077

• Pediatric Metabolic and Bariatric Surgery and Anti-Obesity Medications: Weighing Efficacy, Risks, and Future Directions. The Journal of pediatrics Chinn, J. O., Baidal, J. W., Pratt, J. S., Shepard, W. E., Fell, G. L. 2025: 114610

  View details for DOI 10.1016/j.jpeds.2025.114610

  View details for PubMedID 40252955

• BA-ECM Score: Automated Quantification of Liver Fibrosis Architecture in Biliary Atresia with Potential for Prognostic Value - A Pilot Study. Annals of surgery Liang, N. E., Guo, J. L., Griffin, M. F., Bauer-Rowe, K. E., Narang, A., Januszyk, M., Fell, G. L., Dunn, J. C., Chao, S. D., Tan, S. Y., Longaker, M. T., Hyun, J. S. 2025

  Abstract

  To quantify liver fibrosis in infants with biliary atresia (BA) through automated analysis of collagen extracellular matrix (ECM) ultrastructure in index liver biopsies and use a composite fibrosis architecture score to predict native liver survival.Despite early management with Kasai portoenterostomy , BA remains the leading indication for pediatric liver transplantation. There is no established method for quantitatively assessing liver fibrosis in patients with BA, and no factors to accurately predict which patients will ultimately require transplantation early versus late.Index liver biopsies from 12 BA patients were retrieved from our pathology archives Masson's Trichrome-stained biopsies were scanned, tiled, binarized, and quantified for 147 ECM features. These features were reduced by Uniform Manifold Approximation and Projection. Pseudotime analysis was applied to summarize global variations in architecture and assign BA-ECM scores to all biopsy images. Retrospective chart review was performed to correlate clinical characteristics with BA-ECM score.BA-ECM score, a multi-dimensional fibrosis architecture score, was significantly higher for biopsies from listed patients compared to non-listed patients (35.9 vs. 22.9, *P<0.0001). High BA-ECM score was characterized by thick, patchy, irregular ECM, while low BA-ECM score was associated with large-volume thin, porous collagen fibers. Survival analysis stratified by the third quartile BA-ECM score of all data points demonstrated a significant difference in native liver survival (*P=0.02).We present the application of an automated ECM ultrastructure analysis tool designed to capture and quantify 147 aspects of fibrotic tissue heterogeneity. These manifold features are summarized using a multi-dimensional BA-ECM score that could be used to prognosticate disease course for BA patients.

  View details for DOI 10.1097/SLA.0000000000006698

  View details for PubMedID 40109267

• Dipeptidylpeptidase 4 Is Overexpressed in the Extracellular Matrix of Biliary Atresia-Associated Liver Fibrosis Liang, N., Griffin, M., Parker, J. B. L., Guo, J. L., Bauer-Rowe, K. E., Fell, G. L., Dunn, J. C. Y., Tan, S. Y. S., Hyun, J. S., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2024: S347-S348

  View details for Web of Science ID 001348680702168

• Pediatric metabolic and bariatric surgery: indications and preoperative multidisciplinary evaluation. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery Mangarelli, C., Fell, G., Hobbs, E., Lowry, K. W., Williams, E., Pratt, J. S. 2024

  Abstract

  The standard of care for pediatric patients with severe obesity considering metabolic and bariatric surgery is a preoperative multidisciplinary evaluation. A multidisciplinary team allows for the efficient use of variable personnel expertise to evaluate, manage, and support a pediatric patient and family through metabolic and bariatric surgery. This review discusses the purpose, recommended team members, patient selection, content, and benefits of the multidisciplinary preoperative evaluation. This evaluation should reduce barriers to care and optimize patient safety and outcomes while taking into consideration the unique developmental needs of this age group.

  View details for DOI 10.1016/j.soard.2024.08.025

  View details for PubMedID 39304458

• A medium-chain fatty acid analogue prevents hepatosteatosis and decreases inflammatory lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis PLOS ONE Cho, B. S., Fligor, S. C., Fell, G. L., Secor, J. D., Tsikis, S. T., Pan, A., Yu, L. J., Ko, V. H., Dao, D. T., Anez-Bustillos, L., Hirsch, T. I., Lund, J., Rustan, A. C., Fraser, D. A., Gura, K. M., Puder, M. 2023; 18 (12): e0295244

  Abstract

  Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis.Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro.In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake.SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.

  View details for DOI 10.1371/journal.pone.0295244

  View details for Web of Science ID 001123215100020

  View details for PubMedID 38039287

  View details for PubMedCentralID PMC10691711

• beta-Endorphin mediates radiation therapy fatigue SCIENCE ADVANCES Hermann, A. L., Fell, G. L., Kemeny, L., Fung, C. Y., Held, K. D., Biggs, P. J., Rivera, P. D., Bilbo, S. D., Igras, V., Willers, H., Kung, J., Gheorghiu, L., Hideghety, K., Mao, J., Woolf, C. J., Fisher, D. E. 2022; 8 (50): eabn6025

  Abstract

  Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. β-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as β-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived β-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma β-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either β-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived β-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.

  View details for DOI 10.1126/sciadv.abn6025

  View details for Web of Science ID 000917907400012

  View details for PubMedID 36525492

  View details for PubMedCentralID PMC9757747

• Structurally-engineered fatty acid 1024 (SEFA-1024) improves diet-induced obesity, insulin resistance, and fatty liver disease LIPIDS Secor, J. D., Cho, B. S., Yu, L. J., Pan, A., Ko, V. H., Dao, D. T., Feigh, M., Anez-Bustillos, L., Fell, G. L., Fraser, D. A., Gura, K. M., Puder, M. 2022; 57 (4-5): 241-255

  Abstract

  Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

  View details for DOI 10.1002/lipd.12351

  View details for Web of Science ID 000819665500001

  View details for PubMedID 35778847

  View details for PubMedCentralID PMC9463121

• Reduced MC4R signaling alters nociceptive thresholds associated with red hair SCIENCE ADVANCES Robinson, K. C., Kemeny, L., Fell, G. L., Hermann, A. L., Allouche, J., Ding, W., Yekkirala, A., Hsiao, J. J., Su, M. Y., Theodosakis, N., Kozak, G., Takeuchi, Y., Shen, S., Berenyi, A., Mao, J., Woolf, C. J., Fisher, D. E. 2021; 7 (14)

  Abstract

  Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.

  View details for DOI 10.1126/sciadv.abd1310

  View details for Web of Science ID 000636455600005

  View details for PubMedID 33811065

  View details for PubMedCentralID PMC11057701

• Optimizing Duration of Empiric Management of Suspected Central Line-Associated Bloodstream Infections in Pediatric Patients with Intestinal Failure JOURNAL OF PEDIATRICS Fell, G. L., Cho, B. S., Anez-Bustillos, L., Dao, D. T., Baker, M. A., Nandivada, P., O'Loughlin, A. A., Hurley, A. P., Mitchell, P. D., Rangel, S., Gura, K. M., Puder, M. 2020; 227: 69-+

  Abstract

  To assess whether a 24-hour length of hospitalization and empiric antibiotic therapy to exclude central line-associated bloodstream infection (CLABSI) in children with intestinal failure is potentially as safe as 48 hours, which is the duration most commonly used but not evidence based.A prospective single-institution observational cohort study was conducted among pediatric patients with intestinal failure from July 1, 2015, through June 30, 2018, to identify episodes of suspected CLABSI. The primary end point was time from blood sampling to positive blood culture. Secondary end points included presenting symptoms, laboratory test results, responses to a parent/legal guardian-completed symptom survey, length of inpatient stay, costs, and charges.Seventy-three patients with intestinal failure receiving nutritional support via central venous catheters enrolled; 35 were hospitalized with suspected CLABSI at least once during the study. There were 49 positive blood cultures confirming CLABSI in 128 episodes (38%). The median time from blood sampling to positive culture was 11.1 hours. The probability of a blood culture becoming positive after 24 hours was 2.3%. Elevated C-reactive protein and neutrophil predominance in white blood cell count were associated with positive blood cultures. Estimated cost savings by transitioning from a 48-hour to a 24-hour admission to rule-out CLABSI was $4639 per admission.A 24-hour duration of empiric management to exclude CLABSI may be appropriate for patients with negative blood cultures and no clinically concerning signs. A multi-institutional study would more robustly differentiate patients safe for discharge after 24 hours from those who warrant longer empiric treatment.

  View details for DOI 10.1016/j.jpeds.2020.07.044

  View details for Web of Science ID 000591926500013

  View details for PubMedID 32687916

• Trends of INR and Fecal Excretion of Vitamin K During Cholestasis Reversal: Implications in the Treatment of Neonates With Intestinal Failure-Associated Liver Disease JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Dao, D. T., Anez-Bustillos, L., Finkelstein, A. M., Mitchell, P. D., O'Loughlin, A. A., Fell, G. L., Baker, M. A., Potemkin, A. K., Gura, K. M., Puder, M. 2020; 44 (5): 951-958

  Abstract

  Vitamin K is a fat-soluble compound that plays important roles in coagulation. In children with intestinal failure-associated liver disease (IFALD), the disrupted enterohepatic circulation can lead to intestinal loss of vitamin K. Fish oil-based lipid emulsion (FOLE) has proven effective in treating IFALD. As biliary excretion is restored during cholestasis reversal, the accelerated vitamin K loss can pose a risk for deficiency.Ten neonates with IFALD and receiving FOLE monotherapy were prospectively enrolled in the study from 2016 to 2018. In addition to weekly measurements of international normalized ratio (INR) and direct bilirubin (DB), ostomy output was collected for determination of fecal concentrations of phylloquinone (PK). Trends of DB, INR, and fecal PK concentrations were summarized with locally estimated scatterplot smoothing.The median time (interquartile range) from FOLE initiation to cholestasis reversal was 59 (19-78) days. During cholestasis reversal, INR remained relatively unchanged, whereas the mean (95% confidence interval) daily fecal excretion of PK increased from 25.1 (5.0-158.5) ng at the time of FOLE initiation to 158.5 (31.6-1000.0) ng at complete reversal. Examination of individual trends in fecal PK excretion and INR revealed little correlation between the 2 measurements (r = -0.10; P = 0.50).Children with IFALD are at risk for vitamin K deficiency during cholestasis reversal. Close monitoring and quantified supplementation of vitamin K may be warranted during this period. However, this should not be guided by INR alone, as it is a poor indicator of vitamin K status.

  View details for DOI 10.1002/jpen.1677

  View details for Web of Science ID 000547970500025

  View details for PubMedID 31282035

  View details for PubMedCentralID PMC6944781

• Omega-3 fatty acids are protective in hepatic ischemia reperfusion injury in the absence of GPR120 signaling JOURNAL OF PEDIATRIC SURGERY Baker, M. A., Nandivada, P., Mitchell, P. D., Fell, G. L., Pan, A., Cho, B. S., De la Flor, D. J., Anez-Bustillos, L., Dao, D. T., Nose, V., Puder, M. 2019; 54 (11): 2392-2397

  Abstract

  A single dose of IV fish oil (FO) before hepatic ischemia reperfusion injury (HIRI) increases hepatocyte proliferation and reduces necrosis in wild type (WT) mice. It has been suggested that the GPR120 receptor on Kupffer cells mediates FO's ability to reduce HIRI. The purpose of this study was to determine whether GPR120 is required for FO to reduce HIRI.Sixty-four (n = 8/group) adult male WT (C57BL/6) and GPR120 knockout (KO) mice received IV FO (1 g/kg) or saline 1 h prior to HIRI or sham operation. Mice were euthanized 24 h postoperatively for analysis of hepatic histology, NFκB activity, and serum alanine transaminase (ALT) levels.FO pretreated livers had less necrosis after HIRI than saline pretreated livers in both WT (mean ± SEM 25.9 ± 7.3% less, P = 0.007) and KO (36.6 ± 7.3% less, P < 0.0001) mice. There was no significant difference in percent necrosis between WT-FO and KO-FO groups. Sham groups demonstrated minimal necrosis (0-1.9%). Mean [95% CI] ALT after HIRI was significantly higher (P = 0.04) in WT-Saline mice (1604 U/L [751-3427]) compared to WT-FO (321 U/L [150-686]) but was not significantly higher in KO-Saline mice compared to KO-FO. There were no differences in ALT between WT-FO and KO-FO mice who underwent HIRI or between groups who underwent sham surgery. There were no differences in NFκB or IKKβ activation among groups as measured by Western blot analysis.IV FO pretreatment was able to reduce HIRI in GPR120 KO mice, suggesting the hepatoprotective effects of FO are not mediated by GPR120 alone.

  View details for DOI 10.1016/j.jpedsurg.2019.04.003

  View details for Web of Science ID 000498851100031

  View details for PubMedID 31036368

  View details for PubMedCentralID PMC6790164

• Effects of dietary omega-3 fatty acids on bones of healthy mice CLINICAL NUTRITION Anez-Bustillos, L., Cowan, E., Cubria, M. B., Villa-Camacho, J. C., Mohamadi, A., Dao, D. T., Pan, A., Fell, G. L., Baker, M. A., Nandivada, P., Nazarian, A., Puder, M. 2019; 38 (5): 2145-2154

  Abstract

  Altering the lipid component in diets may affect the incidence of metabolic bone disease in patients dependent on parenteral nutrition. Consumption of polyunsaturated fatty acids (PUFA) can impact bone health by modulating calcium metabolism, prostaglandin synthesis, lipid oxidation, osteoblast formation, and osteoclastogenesis. The aim of this study was to evaluate the dietary effects of PUFA on murine bone health.Three-weeks-old male (n = 30) and female (n = 30) C57BL/6J mice were randomized into one of three dietary groups. The diets differed only in fat composition: soybean oil (SOY), rich in ω-6 PUFA; docosahexaenoic acid alone (DHA), an ω-3 PUFA; and DHA with arachidonic acid, an ω-6 PUFA, at a 20:1 ratio (DHA/ARA). After 9 weeks of dietary treatment, femurs were harvested for micro-computed tomographic analysis and mechanical testing via 3-point bending. Separate mice from each group were used solely for serial blood draws for measurement of biomarkers of bone formation and resorption.At the microstructural level, although some parameters in cortical bone reached differences that were statistically significant in female mice, these were too small to be considered biologically relevant. Similarly, trabecular bone parameters in male mice were statistically different in some dietary groups, although the biological interpretation of such subtle changes translate into a lack of effect in favor of any of the experimental diets. No differences were noted at the mechanical level and in blood-based biomarkers of bone metabolism across dietary groups within gender.Subtle differences were noted at the bones' microstructural level, however these are likely the result of random effects that do not translate into changes that are biologically relevant. Similarly, differences were not seen at the mechanical level, nor were they reflected in blood-based biomarkers of bone metabolism. Altogether, dietary consumption of PUFA do not seem to affect bone structure or metabolism in a healthy model of growing mice.

  View details for DOI 10.1016/j.clnu.2018.08.036

  View details for Web of Science ID 000492797600021

  View details for PubMedID 30224305

  View details for PubMedCentralID PMC6465171

• Alpha-tocopherol in intravenous lipid emulsions imparts hepatic protection in a murine model of hepatosteatosis induced by the enteral administration of a parenteral nutrition solution PLOS ONE Fell, G. L., Anez-Bustillos, L., Dao, D. T., Baker, M. A., Nandivada, P., Cho, B. S., Pan, A., O'Loughlin, A. A., Nose, V., Gura, K. M., Puder, M. 2019; 14 (7): e0217155

  Abstract

  Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

  View details for DOI 10.1371/journal.pone.0217155

  View details for Web of Science ID 000484951800004

  View details for PubMedID 31295333

  View details for PubMedCentralID PMC6622470

• Fish oil-based injectable lipid emulsions containing medium-chain triglycerides or added α-tocopherol offer anti-inflammatory benefits in a murine model of parenteral nutrition-induced liver injury AMERICAN JOURNAL OF CLINICAL NUTRITION Baker, M. A., Cho, B. S., Anez-Bustillos, L., Dao, D. T., Pan, A., O'Loughlin, A. A., Lans, Z. M., Mitchell, P. D., Nose, V., Gura, K. M., Puder, M., Fell, G. L. 2019; 109 (4): 1038-1050

  Abstract

  Fish oil (FO) intravenous lipid emulsions (ILEs) are used as a monotherapy to treat parenteral nutrition (PN)-associated liver disease and provide essential fatty acids (EFAs) needed to sustain growth and prevent EFA deficiency (EFAD). Studies have suggested that medium-chain triglycerides (MCTs) and α-tocopherol have anti-inflammatory properties.The purpose of this study was to test whether FO-ILEs containing MCTs and/or additional α-tocopherol decrease the inflammatory response to an endotoxin challenge compared with FO-ILE alone and preserve the ability to prevent PN-induced liver injury in mice.A murine model of PN-induced hepatosteatosis was used to compare the effects of ILEs formulated in the laboratory containing varying ratios of FO and MCTs, and subsequently FO- and 50:50 FO:MCT-ILE plus 500 mg/L α-tocopherol (FO + AT and 50:50 + AT, respectively). C57BL/6 mice receiving unpurified diet (UPD), PN-equivalent diet (PN) + saline, and PN + soybean oil (SO)-ILE served as controls. After 19 d, mice received an intraperitoneal saline or endotoxin challenge 4 h before being killed. Serum and livers were harvested for histologic analysis, fatty acid profiling, and measurement of systemic inflammatory markers (tumor necrosis factor-α, interleukin-6).All ILEs were well tolerated and prevented biochemical EFAD. Livers of mice that received saline and SO developed steatosis. Mice that received 30:70 FO:MCT developed mild hepatosteatosis. All other FO-containing ILEs preserved normal hepatic architecture. Mice that received FO- or SO-ILE had significantly elevated systemic inflammatory markers after endotoxin challenge compared with UPD-fed controls, whereas 50:50 FO:MCT, 30:70 FO:MCT, FO + AT, and 50:50 + AT groups had significantly lower inflammatory markers similar to those seen in UPD-fed controls.Mixed FO/MCT and the addition of α-tocopherol to FO improved the inflammatory response to endotoxin challenge compared with FO-ILE alone while still preventing PN-induced liver injury and EFAD in mice. There was no synergistic relation between α-tocopherol and MCTs.

  View details for DOI 10.1093/ajcn/nqy370

  View details for Web of Science ID 000478064700003

  View details for PubMedID 30882140

  View details for PubMedCentralID PMC6462433

• Fish oil protects the liver from parenteral nutrition-induced injury via GPR120-mediated PPARγ signaling PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS Fell, G. L., Cho, B. S., Dao, D. T., Anez-Bustillos, L., Baker, M. A., Nandivada, P., Pan, A., O'Loughlin, A. A., Mitchell, P. D., Nose, V., Gura, K. M., Puder, M. 2019; 143: 8-14

  Abstract

  Intravenous fish oil lipid emulsions (FOLE) can prevent parenteral nutrition (PN)-induced liver injury in murine models and reverse PN-induced cholestasis in pediatric patients. However, the mechanisms by which fish oil protects the liver are incompletely characterized. Fish oil is rich in omega-3 fatty acids, which are ligands for the G-protein coupled receptor 120 (GPR120), expressed on hepatic Kupffer cells. This study tested the hypothesis that FOLE protects the liver from PN-induced injury through GPR120 signaling. Utilizing a previously described murine model of PN-induced liver injury in which mice develop steatosis in response to an oral parenteral nutrition diet, FOLE was able to preserve normal hepatic architecture in wild type mice, but not in congenic GPR120 knockout (gpr120-/-) mice. To further characterize the requirement of intact GPR120 for FOLE-mediated hepatic protection, gene expression profiles of key regulators of fat metabolism were measured. PPARγ was identified as a gene that is up-regulated by the PN diet and normalized with the addition of FOLE in wild type, but not in gpr120-/- mice. This was confirmed at the protein expression level. A PPARγ expression array further identified CD36 and SCD1, both down-stream effectors of PPARγ, to be up-regulated in PN-fed wild type mice yet normalized upon FOLE administration in wild type but not in gpr120-/- mice. Together, these results suggest that FOLE protects the liver, in part, through activation of GPR120 and the downstream effectors PPARγ and CD36. Identification of key genetic determinants of FOLE-mediated hepatic protection may provide targets for small molecule-based hepatic protection strategies.

  View details for DOI 10.1016/j.plefa.2019.02.003

  View details for Web of Science ID 000466261800002

  View details for PubMedID 30975380

  View details for PubMedCentralID PMC6642797

• A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor PLOS ONE Dao, D. T., Anez-Bustillos, L., Jabbouri, S. S., Pan, A., Kishikawa, H., Mitchell, P. D., Fell, G. L., Baker, M. A., Watnick, R. S., Chen, H., Rogers, M. S., Bielenberg, D. R., Puder, M. 2018; 13 (12): e0208579

  Abstract

  Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 μg/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2α, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway.

  View details for DOI 10.1371/journal.pone.0208579

  View details for Web of Science ID 000453779300050

  View details for PubMedID 30566445

  View details for PubMedCentralID PMC6300284

• Vascular Endothelial Growth Factor Enhances Compensatory Lung Growth in Piglets SURGERY Dao, D. T., Anez-Bustillos, L., Pan, A., O'Loughlin, A. A., Mitchell, P. D., Fell, G. L., Baker, M. A., Cho, B. S., Nandivada, P., Nedder, A. P., Smithers, C. J., Chen, N., Comeau, R., Holmes, K., Kalled, S., Norton, A., Zhang, B., Puder, M. 2018; 164 (6): 1279-1286

  Abstract

  Vascular endothelial growth factor has been found to accelerate compensatory lung growth after left pneumonectomy in mice. The aim of this study was to determine the natural history and the effects of vascular endothelial growth factor on compensatory lung growth in a large animal model.To determine the natural history of compensatory lung growth, female Yorkshire piglets underwent a left pneumonectomy on days of life 10-11. Tissue harvest and volume measurement of the right lung were performed at baseline (n = 5) and on postoperative days 7 (n = 5), 14 (n = 4), and 21 (n = 5). For pharmacokinetic studies, vascular endothelial growth factor was infused via a central venous catheter, with plasma vascular endothelial growth factor levels measured at various time points. To test the effect of vascular endothelial growth factor on compensatory lung growth, 26 female Yorkshire piglets underwent a left pneumonectomy followed by daily infusion of vascular endothelial growth factor at 200 µg/kg or isovolumetric 0.9% NaCl (saline control). Lungs were harvested on postoperative day 7 for volume measurement and morphometric analyses.Compared with baseline, right lung volume after left pneumonectomy increased by factors of 2.1 ± 0.6, 3.3 ± 0.6, and 3.6 ± 0.4 on postoperative days 7, 14, and 21, respectively. The half-life of VEGF ranged from 89 to 144 minutes. Lesser doses of vascular endothelial growth factor resulted in better tolerance, volume of distribution, and clearance. Compared with the control group, piglets treated with vascular endothelial growth factor had greater lung volume (P < 0.0001), alveolar volume (P = 0.001), septal surface area (P = 0.007) and total alveolar count (P = 0.01).Vascular endothelial growth factor enhanced alveolar growth in neonatal piglets after unilateral pneumonectomy.

  View details for DOI 10.1016/j.surg.2018.07.003

  View details for Web of Science ID 000452245600023

  View details for PubMedID 30193736

  View details for PubMedCentralID PMC6446901

• Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy ANGIOGENESIS Dao, D. T., Anez-Bustillos, L., Ourieff, J., Pan, A., Mitchell, P. D., Kishikawa, H., Fell, G. L., Baker, M. A., Watnick, R. S., Chen, H., Hamilton, T. E., Rogers, M. S., Bielenberg, D. R., Puder, M. 2018; 21 (4): 837-848

  Abstract

  Children with hypoplastic lung diseases, such as congenital diaphragmatic hernia, can require life support via extracorporeal membrane oxygenation and systemic anticoagulation, usually in the form of heparin. The role of heparin in angiogenesis and organ growth is inconclusive, with conflicting data reported in the literature. This study aimed to investigate the effects of heparin on lung growth in a model of compensatory lung growth (CLG). Compared to the absence of heparin, treatment with heparin decreased the vascular endothelial growth factor (VEGF)-mediated activation of VEGFR2 and mitogenic effect on human lung microvascular endothelial cells in vitro. Compared to non-heparinized controls, heparinized mice demonstrated impaired pulmonary mechanics, decreased respiratory volumes and flows, and reduced activity levels after left pneumonectomy. They also had lower lung volume, pulmonary septal surface area and alveolar density on morphometric analyses. Lungs of heparinized mice displayed decreased phosphorylation of VEGFR2 compared to the control group, with consequential downstream reduction in markers of cellular proliferation and survival. The use of bivalirudin, an alternative anticoagulant that does not interact with VEGF, preserved lung growth and pulmonary mechanics. These results demonstrated that heparin impairs CLG by reducing VEGFR2 activation. These findings raise concern for the clinical use of heparin in the setting of organ growth or regeneration.

  View details for DOI 10.1007/s10456-018-9628-3

  View details for Web of Science ID 000448518400014

  View details for PubMedID 29956017

  View details for PubMedCentralID PMC6463887

• Intranasal delivery of VEGF enhances compensatory lung growth in mice PLOS ONE Dao, D. T., Vuong, J. T., Anez-Bustillos, L., Pan, A., Mitchell, P. D., Fell, G. L., Baker, M. A., Bielenberg, D. R., Puder, M. 2018; 13 (6): e0198700

  Abstract

  Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5-50 μg/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 μg/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen.

  View details for DOI 10.1371//journal.pone.0198700

  View details for Web of Science ID 000434384900074

  View details for PubMedID 29879188

  View details for PubMedCentralID PMC5991715

• Vascular endothelial growth factor accelerates compensatory lung growth by increasing the alveolar units PEDIATRIC RESEARCH Dao, D. T., Nandivada, P., Vuong, J. T., Anez-Bustillos, L., Pan, A., Kishikawa, H., Mitchell, P. D., Baker, M. A., Fell, G. L., Martin, T., Puder, M. 2018; 83 (6): 1182-1189

  Abstract

  BackgroundDeficiency of vascular endothelial growth factor (VEGF) is associated with hypoplastic lung diseases, such as congenital diaphragmatic hernia. Provision of VEGF has been demonstrated to be beneficial in hyperoxia-induced bronchopulmonary dysplasia, and hence could induce lung growth and improve the outcome in hypoplastic lung diseases. We aimed to determine the effects of exogenous VEGF in a rodent model of compensatory lung growth after left pneumonectomy.MethodsEight-to-ten-week-old C57Bl6 male mice underwent left pneumonectomy, followed by daily intra-peritoneal injections of saline or VEGF (0.5 mg/kg). Lung volume measurement, pulmonary function tests, and morphometric analyses were performed on post-operative day (POD) 4 and 10. The pulmonary expression of angiogenic factors was analyzed by quantitative polymerase chain reaction and western blot.ResultsLung volume on POD 4 was higher in the VEGF-treated mice (P=0.03). On morphometric analyses, VEGF increased the parenchymal volume (P=0.001), alveolar volume (P=0.0003), and alveolar number (P<0.0001) on POD 4. The VEGF group displayed higher levels of phosphorylated-VEGFR2/VEGFR2 (P=0.03) and epidermal growth factor (EGF) messenger RNA (P=0.01).ConclusionVEGF accelerated the compensatory lung growth in mice, by increasing the alveolar units. These changes may be mediated by VEGFR2 and EGF-dependent mechanisms.

  View details for DOI 10.1038/pr.2018.41

  View details for Web of Science ID 000436345400016

  View details for PubMedID 29638228

  View details for PubMedCentralID PMC6019135

• Pretreatment with intravenous fish oil reduces hepatic ischemia reperfusion injury in a murine model Baker, M. A., Nandivada, P., Mitchell, P. D., Fell, G. L., Pan, A., Anez-Bustillos, L., Dao, D. T., Gura, K. M., Nose, V., Puder, M. MOSBY-ELSEVIER. 2018: 1035-1039

  Abstract

  Ischemia reperfusion injury is a barrier to liver surgery and transplantation, particularly for steatotic livers. The purpose of this study was to determine if pretreatment with a single dose of intravenous fish oil decreases hepatic ischemia reperfusion injury and improves recovery of injured livers.Sixty adult male C57BL/6 mice received 1 g/kg intravenous fish oil (Omegaven, Fresenius Kabi) or isovolumetric 0.9% NaCl (saline) via tail vein 1 hour before 30 minutes of 70% hepatic ischemia. Animals were killed 4, 8, or 24 hours postreperfusion, and livers were harvested for histologic analysis.Four hours postreperfusion, saline-treated livers demonstrated marked ischemia diffusely around the central veins, while intravenous fish oil-treated livers demonstrated only patchy necrosis with intervening normal parenchyma. Eight hours postreperfusion, all livers demonstrated pale areas of cell loss with surrounding regenerating hepatocytes. Ki67 staining confirmed 14.4/10 high-powered field (95% confidence interval, 3.2-25.6) more regenerating hepatocytes around areas of necrosis in intravenous fish oil-treated livers. Twenty-four hours postreperfusion, all livers demonstrated patchy areas of necrosis, with an 89% (95% confidence interval, 85-92) decrease in the area of necrosis in intravenous fish oil-treated livers.Intravenous fish oil treatment prior to hepatic ischemia reperfusion injury decreased the area of hepatic necrosis and increased hepatocyte regeneration compared to saline treatment in a mouse model.

  View details for DOI 10.1016/j.surg.2017.10.071

  View details for Web of Science ID 000431940600011

  View details for PubMedID 29358007

  View details for PubMedCentralID PMC5936675

• Parenteral Soybean Oil Induces Hepatosteatosis Despite Addition of Fish Oil in a Mouse Model of Intestinal Failure-Associated Liver Disease JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Nandivada, P., Fell, G. L., Pan, A. H., Nose, V., Mitchell, P. D., Gura, K. M., Puder, M. 2018; 42 (2): 403-411

  Abstract

  Replacement of parenteral soybean oil (SO) with fish oil (FO) is an effective therapy for intestinal failure-associated liver disease (IFALD) in children. However, practitioners remain concerned about the risk of essential fatty acid deficiency (EFAD) and sometimes treat IFALD with a combination of 50% SO and 50% FO emulsions. The purpose of this study was to determine if mixing 50% SO and 50% FO emulsions would prevent hepatosteatosis in a murine model of parenteral nutrition (PN)-induced hepatosteatosis.C57BL/6 mice were randomized to receive oral PN with parenteral saline, FO, SO, or a mixture of 50% FO and 50% SO for 19 days. Fatty acid analysis, histologic evaluation, Nonalcoholic Steatohepatitis Clinical Research Network (NSCRN) scores, and reverse-transcriptase polymerase chain reaction for key lipogenic genes were performed.The PN + saline group was the only group with EFAD, with a serum and hepatic triene/tetraene ratio of 0.53. NSCRN scores were highest in the PN + SO group (5.5; 95% confidence interval [CI], 4.9-6.1), followed by the PN + FO/SO (4.5; 95% CI, 3.5-5.5) group, with the lowest score in the PN + FO (2.0; 95% CI, 1.1-2.9) group. Acetyl CoA carboxylase α and acetyl CoA carboxylase β expression was lower in the PN + FO group than in the PN + FO/SO or PN + SO groups.Our data demonstrate that a mixed fat emulsion of 50% SO and 50% FO is inferior to 100% FO in reducing hepatosteatosis in this model. These data suggest that use of parenteral SO with parenteral FO, in a 1:1 ratio, may still contribute to liver injury, although it is less hepatotoxic than pure SO.

  View details for DOI 10.1177/0148607117695249

  View details for Web of Science ID 000425094500017

  View details for PubMedID 29187040

• Characterization of Fatty Acid Profiles in Infants With Intestinal Failure-Associated Liver Disease JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Baker, M. A., Mitchell, P. D., O'Loughlin, A. A., Potemkin, A. K., Anez-Bustillos, L., Dao, D. T., Fell, G. L., Gura, K. M., Puder, M. 2018; 42 (1): 71-77

  Abstract

  The purpose of this study was to characterize fatty acid profiles (FAPs) in parenteral nutrition (PN)-dependent infants with intestinal failure-associated liver disease (IFALD) receiving soybean oil-based lipid emulsion (SO) doses of ∼3 and ∼1 g/kg/d.Prospectively collected data were retrospectively reviewed. Serum FAPs of patients <1 year old who experienced development of IFALD while receiving standard PN with SO were examined before transitioning to a fish oil-based lipid emulsion for IFALD treatment. Time on SO, dose, gestational age, and weight- and length-for-age z scores were also reviewed.Among the 49 patients analyzed, there were no differences in demographics or anthropometrics between patients who received standard SO (SO-S) (n = 14, range of dosage 2.06-3.31 g/kg/d) and reduced SO (SO-R) (n = 35, range of dosage 0.90-1.34 g/kg/d). Patients received SO for a median of 53 days (interquartile range 39, 73) before FAP measurement. Patients who received SO-R had significantly higher Mead acid and lower α-linolenic, eicosapentaenoic, linoleic, stearic, total ω-3, and total ω-6 fatty acid levels than patients who received SO-S (P < .01). Triene:tetraene ratios were higher in patients who received SO-R (P = .0009), and no patients experienced biochemical essential fatty acid deficiency (EFAD).PN-dependent infants with IFALD receiving SO-R have different FAPs than patients receiving SO-S. No patients in either group had biochemical EFAD.

  View details for DOI 10.1002/jpen.1026

  View details for Web of Science ID 000427254700010

  View details for PubMedID 29505154

  View details for PubMedCentralID PMC5841610

• Reducing Time to Antibiotics in Children With Intestinal Failure, Central Venous Line, and Fever PEDIATRICS Hudgins, J. D., Goldberg, V., Fell, G. L., Puder, M., Eisenberg, M. A. 2017; 140 (5)

  Abstract

  Children with intestinal failure (IF) on parenteral nutrition (PN) are at high risk for bacteremia, and delays in antibiotic administration have been associated with increased morbidity and mortality. We designed an emergency department (ED) quality improvement (QI) initiative to reduce time to administration of intravenous antibiotics in febrile children with IF on PN.Our aim was to decrease the mean time for febrile children with IF on PN to receive intravenous antibiotics by 50% to <60 minutes over a 12-month period. Secondary outcome measures were ED, hospital, and ICU length of stay (LOS). Our process measure was the rate of ordering recommended antibiotics, and our balancing measure was the rate of hypoglycemia. Interventions included increasing provider knowledge of IF, streamlining order entry, providing individualized feedback, and standardizing the triage process. Results were analyzed by using statistical process control methodology and time series analysis.We identified 149 eligible ED patients, of which 62 (41.6%) had bacteremia. The mean time to antibiotics decreased after the onset of the QI initiative from 112 to 39 minutes, and the ED LOS decreased from 286 to 247 minutes, but the total length of hospital and ICU stays were unchanged. The rate of hypoglycemia was also unchanged.Our QI intervention for febrile children with IF on PN shortened the time to receive antibiotics. Larger studies are needed to demonstrate the impact on overall LOS and mortality.

  View details for DOI 10.1542/peds.2017-1201

  View details for Web of Science ID 000414119600031

  View details for PubMedID 29066581

• Risk of post-procedural bleeding in children on intravenous fish oil AMERICAN JOURNAL OF SURGERY Nandivada, P., Anez-Bustillos, L., O'Loughlin, A. A., Mitchell, P. D., Baker, M. A., Dao, D. T., Fell, G. L., Potemkin, A. K., Gura, K. M., Neufeld, E. J., Puder, M. 2017; 214 (4): 733-737

  Abstract

  Intestinal failure-associated liver disease (IFALD) can be treated with parenteral fish oil (FO) monotherapy, but practitioners have raised concerns about a potential bleeding risk. This study aims to describe the incidence of clinically significant post-procedural bleeding (CSPPB) in children receiving FO monotherapy.A retrospective chart review was performed on patients at our institution treated with intravenous FO for IFALD. CSPPB was defined as bleeding leading to re-operation, transfer to the intensive care unit, re-admission, or death, up to one month after any invasive procedure.From 244 patients reviewed, 183 underwent ≥1 invasive procedure(s) (n = 732). Five (0.68%, 95% CI 0.22-1.59%) procedures resulted in CSPPB. FO therapy was never interrupted. No deaths due to bleeding occurred.Findings suggest that FO therapy is safe, with a CSPPB risk no greater than that reported in the general population. O3FA should not be held in preparation for procedures or in the event of bleeding.

  View details for DOI 10.1016/j.amjsurg.2016.10.026

  View details for Web of Science ID 000415220000029

  View details for PubMedID 27979360

  View details for PubMedCentralID PMC5464992

• Long-Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure-Associated Liver Disease JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Nandivada, P., Fell, G. L., Mitchell, P. D., Potemkin, A. K., O'Loughlin, A. A., Gura, K. M., Puder, M. 2017; 41 (6): 930-937

  Abstract

  Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF-associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long-term PN and FOLE therapy due to chronic IF.A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease.Of 215 patients with IFALD treated from 2004-2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight-for age and length-for-age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term.Children with IFALD who required long-term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.

  View details for DOI 10.1177/0148607116633796

  View details for Web of Science ID 000412492900004

  View details for PubMedID 26962059

• Response to Driscoll JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Fell, G. L., Gura, K. M., Puder, M. 2017; 41 (5): 704-705

  View details for DOI 10.1177/0148607117703961

  View details for Web of Science ID 000406629400002

  View details for PubMedID 28754084

• Technique and perioperative management of left pneumonectomy in neonatal piglets JOURNAL OF SURGICAL RESEARCH Dao, D. T., Anez-Bustillos, L., O'Loughlin, A. A., Pan, A., Nedder, A. P., Bolgen, D., Smithers, C., Zalieckas, J., Lillehei, C. W., Nandivada, P., Baker, M. A., Fell, G. L., Cho, B. S., Puder, M. 2017; 212: 146-152

  Abstract

  Although commonly performed in adult swine, unilateral pneumonectomy in piglets requires significant modifications in the surgical approach and perioperative care because of their smaller size and limited physiological reserve.Nineteen neonatal piglets underwent a left pneumonectomy. They were allowed 5-7 d of preoperative acclimation and nutritional optimization. Preoperative weight gain and laboratory values were obtained before the time of surgery. A "ventro-cranial" approach is adopted where components of the pulmonary hilum were sequentially identified and ligated, starting from the most ventral and cranial structure, the superior pulmonary vein. The principle of gentle ventilation was followed throughout the entire operation.The median age of the piglets at the time of surgery was 12 (10-12) d. The median preoperative weight gain and albumin level were 20% (16-26%) and 2.3 (2.1-2.4) g/dL, respectively. The median operative time was 59 (50-70) min. Five of the first nine piglets died from complications, two from poor preoperative nutritional optimization (both with <10% weight gain and 2 g/dL for albumin), one from an intubation complication, one from intra-operative bleeding, and one in the postoperative period from a ruptured bulla. No mortality occurred for the next 10 cases.Successful outcomes for unilateral pneumonectomy in piglets require special attention to preoperative nutritional optimization, gentle ventilation, and meticulous surgical dissection. Preoperative weight gain and albumin levels should be used to identify appropriate surgical candidates. The "ventro-cranial" approach allows for a technically straightforward completion of the procedure.

  View details for DOI 10.1016/j.jss.2017.01.010

  View details for Web of Science ID 000405362700019

  View details for PubMedID 28550900

  View details for PubMedCentralID PMC5839113

• A Comparison of Fish Oil Sources for Parenteral Lipid Emulsions in a Murine Model JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Fell, G. L., Cho, B. S., Pan, A., Nose, V., Anez-Bustillos, L., Dao, D. T., Baker, M. A., Nandivada, P., Gura, K. M., Puder, M. 2017; 41 (2): 181-187

  Abstract

  Fat emulsions are important components of parenteral nutrition (PN). Fish oil (FO) emulsions reverse cholestasis in PN-associated liver disease. There are 2 FO monographs. One is "FO; rich in omega-3 fatty acids" (NFO). The other, "omega-3 acids," (PFO), is enriched in omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The purpose of this study is to compare the effects of 20% NFO and PFO emulsions produced in the laboratory in a murine model.Emulsions were compounded containing different oils: soybean oil (SO), NFO, and two PFOs differing in percentage of fatty acids as triglycerides (PFO66 and PFO90). Chow-fed mice received saline, one of the above emulsions, or a commercial FO (OM) intravenously (2.4 g/kg/day) for 19 days. On day 19, animals were euthanized. Livers, spleens, and lungs were procured for histologic analysis.OM, SO, NFO, and PFO90 were well-tolerated clinically. PFO66 resulted in tachypnea and lethargy for ~1 minute following injections. At euthanasia, PFO66 and PFO90 groups had organomegaly. Histologically, these groups had splenic and hepatic fat-laden macrophages, and lungs had scattered fat deposits. Other groups had normal organs.PFO emulsions present an attractive possibility for improving inflammation in PN-dependent patients by concentrating anti-inflammatory EPA and DHA. However, 20% PFO emulsions were poorly tolerated and precipitated adverse end organ sequelae, suggesting that they may not be safe. Development of novel manufacturing methods may achieve safe 20% PFO parenteral emulsions, but by established formulation methods, these emulsions were clinically suboptimal despite meeting pharmacopeial standards.

  View details for DOI 10.1177/0148607116640275

  View details for Web of Science ID 000394896800006

  View details for PubMedID 26993989

  View details for PubMedCentralID PMC5438312

• Methods to reduce medication errors in a clinical trial of an investigational parenteral medication CONTEMPORARY CLINICAL TRIALS COMMUNICATIONS Fell, G. L., O'Loughlin, A. A., Nandivada, P., Potemkin, A. K., Mitchell, P. D., Mahoney, J., Gura, K. M., Puder, M. 2016; 4: 64-67

  Abstract

  There are few evidence-based guidelines to inform optimal design of complex clinical trials, such as those assessing the safety and efficacy of intravenous drugs administered daily with infusion times over many hours per day and treatment durations that may span years. This study is a retrospective review of inpatient administration deviation reports for an investigational drug that is administered daily with infusion times of 8-24 hours, and variable treatment durations for each patient. We report study design modifications made in 2007-2008 aimed at minimizing deviations from an investigational drug infusion protocol approved by an institutional review board and the United States Food and Drug Administration. Modifications were specifically aimed at minimizing errors of infusion rate, incorrect dose, incorrect patient, or wrong drug administered. We found that the rate of these types of administration errors of the study drug was significantly decreased following adoption of the specific study design changes. This report provides guidance in the design of clinical trials testing the safety and efficacy of study drugs administered via intravenous infusion in an inpatient setting so as to minimize drug administration protocol deviations and optimize patient safety.

  View details for DOI 10.1016/j.conctc.2016.06.005

  View details for Web of Science ID 000399161400011

  View details for PubMedID 27489888

  View details for PubMedCentralID PMC4967555

• Intravenous Fat Emulsion Formulations for the Adult and Pediatric Patient: Understanding the Differences NUTRITION IN CLINICAL PRACTICE Anez-Bustillos, L., Dao, D. T., Baker, M. A., Fell, G. L., Puder, M., Gura, K. M. 2016; 31 (5): 596-609

  Abstract

  Intravenous fat emulsions (IVFEs) provide essential fatty acids (EFAs) and are a dense source of energy in parenteral nutrition (PN). Parenterally administered lipid was introduced in the 17th century but plagued with side effects. The formulation of IVFEs later on made it a relatively safe component for administration to patients. Many ingredients are common to all IVFEs, yet the oil source(s) and its (their) percentage(s) makes them different from each other. The oil used dictates how IVFEs are metabolized and cleared from the body. The fatty acids (FAs) present in each type of oil provide unique beneficial and detrimental properties. This review provides an overview of IVFEs and discusses factors that would help clinicians choose the optimal product for their patients.

  View details for DOI 10.1177/0884533616662996

  View details for Web of Science ID 000383020700003

  View details for PubMedID 27533942

  View details for PubMedCentralID PMC5438313

• Predictors of failure of fish-oil therapy for intestinal failure-associated liver disease in children AMERICAN JOURNAL OF CLINICAL NUTRITION Nandivada, P., Baker, M. A., Mitchell, P. D., O'Loughlin, A. A., Potemkin, A. K., Anez-Bustillos, L., Carlson, S. J., Dao, D. T., Fell, G. L., Gura, K. M., Puder, M. 2016; 104 (3): 663-670

  Abstract

  Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease.We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines.Prospectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy.Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure.Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104.

  View details for DOI 10.3945/ajcn.116.137083

  View details for Web of Science ID 000382420900017

  View details for PubMedID 27510535

  View details for PubMedCentralID PMC4997303

• Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia LIPIDS Nandivada, P., Fell, G. L., Pan, A. H., Nose, V., Ling, P., Bistrian, B. R., Puder, M. 2016; 51 (6): 703-714

  Abstract

  Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloric ketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate-based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each diet group were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge, hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-α in the postabsorptive period, with a fivefold higher expression of hepatic NFκB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice.

  View details for DOI 10.1007/s11745-016-4156-7

  View details for Web of Science ID 000376940200005

  View details for PubMedID 27117864

• Lipid emulsions in the treatment and prevention of parenteral nutrition-associated liver disease in infants and children AMERICAN JOURNAL OF CLINICAL NUTRITION Nandivada, P., Fell, G. L., Gura, K. M., Puder, M. 2016; 103 (2): 629S-634S

  Abstract

  Long-term parenteral nutrition (PN) carries the risk of progressive liver disease in infants with intestinal failure. Although PN-associated liver disease (PNALD) is multifactorial in etiology, components of soybean oil lipid emulsions have been implicated in the disease's pathogenesis. Historically, infants with PNALD who were unable to wean from PN to full enteral feeding developed cirrhosis and end-stage liver disease, which require liver transplantation to survive. Over the past 2 decades, novel strategies for the management of parenteral lipids have improved morbidity and mortality from PNALD in infants with intestinal failure. Current strategies for the treatment of PNALD include restricting the dose of parenteral soybean oil lipid emulsion and/or replacing the soybean oil with a parenteral fish-oil lipid emulsion or emulsions of mixed-lipid sources. The purpose of this report is to review published data that evaluate these strategies in parenteral lipid management for the treatment and prevention of PNALD.

  View details for DOI 10.3945/ajcn.114.103986

  View details for Web of Science ID 000461987400005

  View details for PubMedID 26791189

  View details for PubMedCentralID PMC4733251

• Monitoring Repair of UV-Induced 6-4-Photoproducts with a Purified DDB2 Protein Complex PLOS ONE Dreze, M., Calkins, A. S., Galicza, J., Echelman, D. J., Schnorenberg, M. R., Fell, G. L., Iwai, S., Fisher, D. E., Szuets, D., Iglehart, J., Lazaro, J. 2014; 9 (1): e85896

  Abstract

  Because cells are constantly subjected to DNA damaging insults, DNA repair pathways are critical for genome integrity [1]. DNA damage recognition protein complexes (DRCs) recognize DNA damage and initiate DNA repair. The DNA-Damage Binding protein 2 (DDB2) complex is a DRC that initiates nucleotide excision repair (NER) of DNA damage caused by ultraviolet light (UV) [2]-[4]. Using a purified DDB2 DRC, we created a probe ("DDB2 proteo-probe") that hybridizes to nuclei of cells irradiated with UV and not to cells exposed to other genotoxins. The DDB2 proteo-probe recognized UV-irradiated DNA in classical laboratory assays, including cyto- and histo-chemistry, flow cytometry, and slot-blotting. When immobilized, the proteo-probe also bound soluble UV-irradiated DNA in ELISA-like and DNA pull-down assays. In vitro, the DDB2 proteo-probe preferentially bound 6-4-photoproducts [(6-4)PPs] rather than cyclobutane pyrimidine dimers (CPDs). We followed UV-damage repair by cyto-chemistry in cells fixed at different time after UV irradiation, using either the DDB2 proteo-probe or antibodies against CPDs, or (6-4)PPs. The signals obtained with the DDB2 proteo-probe and with the antibody against (6-4)PPs decreased in a nearly identical manner. Since (6-4)PPs are repaired only by nucleotide excision repair (NER), our results strongly suggest the DDB2 proteo-probe hybridizes to DNA containing (6-4)PPs and allows monitoring of their removal during NER. We discuss the general use of purified DRCs as probes, in lieu of antibodies, to recognize and monitor DNA damage and repair.

  View details for DOI 10.1371/journal.pone.0085896

  View details for Web of Science ID 000330510000022

  View details for PubMedID 24489677

  View details for PubMedCentralID PMC3904869