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Massive intestinal loss resulting in short bowel syndrome has been linked to intestinal failure associated liver disease. Efforts to elucidate the driving force behind the observed hepatic injury have identified inflammatory mediators, alterations in the microbiome, extent of structural and functional intestinal adaptation, and toxic shifts in the bile acid pool. In the present study, we posit that ileocecal resection interrupts the delivery of these hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation, thereby shielding the liver from exposure to the aforementioned noxious stimuli. Mice underwent sham, 50% proximal, or 50% distal small bowel resection (SBR), with or without tauroursodeoxycolic acid supplementation. Enterohepatic signaling and nonsense-mediated ribonucleic acid (RNA) decay were evaluated and correlated with hepatic injury. When compared to 50% proximal SBR, mice that underwent ileocecal resection exhibited reduced hepatic oxidative stress and exhibited a more physiological bile acid profile with increased de novo bile acid synthesis, enhanced colonic bile acid signaling, and reduced hepatic proliferation. Distal intestinal resection promoted an adaptive response including via the nonsense-mediated RNA decay pathway to satisfactorily process injurious messenger RNA and successfully maintain homeostasis. By contrast, this adaptive response was not observed in the proximal SBR group and hepatic injury persisted. In summary, interruption of enterohepatic circulation via ileocecal resection abrogates the liver's exposure to toxic and inflammatory mediators while promoting physiological adaptations in bile acid metabolism and maintaining existing homeostatic pathways. [ABSTRACT FROM AUTHOR]

Interventional radiologic, endoscopic, and surgical approaches are commonly utilized to establish durable enteral access in adult patients. The purpose of this study is to examine differences in nutritional outcomes in a large cohort of patients undergoing enteral access creation. Adult patients who underwent enteral access procedures by interventional radiologists, gastroenterologists, and surgeons between 2018 and 2020 at a single institution were reviewed. Included access types were percutaneous endoscopic gastrostomy (PEG), open or laparoscopic gastrostomy, laparoscopic jejunostomy, and percutaneous gastrostomy (perc-G), percutaneous jejunostomy , or primary gastrojejunostomy. 912 patients undergoing enteral access cases met the criteria for inclusion. PEGs and perc-Gs were the most common procedures. PEGs had higher Charlson scores (4.5 [3.0-6.0] versus 2.0 [1.0-2.0], P = 0.007) and lower starting albumin (3.0 [2.6-3.4] versus 3.6 [3.5-3.8] g/dL, P < 0.0001). Time to goal feeds (4 [2-6] vs 4 [3-5] d, P = 0.970), delta prealbumin (3.6 [0-6.5] versus 6.2 [2.3-10] mg/L, P = 0.145), time to access removal (160 [60-220] versus 180 [90-300] d, P = 0.998), and enteral access-related complications (19% versus 16%, P = 0.21) between PEG and perc-G were similar and differences were not statistically significant. A greater percent change in prealbumin was noted for perc-G (10 [-3-20] versus 41.7% [11-65], P = 0.002). Despite having higher Charlson scores and worse preoperative nutrition, there is a similar incidence of enteral access-related complications, time to goal feeds, delta prealbumin, or time to access removal between PEG and perc-G patients. Our data suggest that access approach should be made on an individual basis, accounting for anatomy and technical feasibility. [ABSTRACT FROM AUTHOR]

Short bowel syndrome is the most common cause of intestinal failure, with morbidity and mortality linked to remanent small intestine length. There is no current standard for noninvasive bowel length measurement. The literature was systematically searched for articles describing measurements of small intestine length from radiographic studies. Inclusion required reporting intestinal length as an outcome and use of diagnostic imaging for length assessment compared to a ground truth. Two reviewers independently screened studies for inclusion, extracted data, and assessed study quality. Eleven studies met the inclusion criteria and reported small intestinal length measurement using four imaging modalities: barium follow-through, ultrasound, computed tomography, and magnetic resonance. Five barium follow-through studies reported variable correlations with intraoperative measurements (r = 0.43-0.93); most (3/5) reported underestimation of length. US studies (n = 2) did not correlate with ground truths. Two computed tomography studies reported moderate-to-strong correlations with pathologic (r = 0.76) and intraoperative measurements (r = 0.99). Five studies of magnetic resonance showed moderate-to-strong correlations with intraoperative or postmortem measurements (r = 0.70-0.90). Vascular imaging software was used in two studies, and a segmentation algorithm was used for measurements in one. Noninvasive measurement of small intestine length is challenging. Three-dimensional imaging modalities reduce the risk of length underestimation, which is common with two-dimensional techniques. However, they also require longer times to perform length measurements. Automated segmentation has been trialed for magnetic resonance enterography, but this method does not translate directly to standard diagnostic imaging. While three-dimensional images are most accurate for length measurement, they are limited in their ability to measure intestinal dysmotility, which is an important functional measure in patients with intestinal failure. Future work should validate automated segmentation and measurement software using standard diagnostic imaging protocols. [ABSTRACT FROM AUTHOR]

Parenteral nutrition associated cholestasis (PNAC) is a common morbidity in neonates requiring total parenteral nutrition (TPN). Previous studies in infants with intestinal failure have shown a benefit of mixed lipid emulsion (MLE) in reducing PNAC. It is not known whether this benefit extends to a general neonatal intensive care unit (NICU) population, where MLE is used on a selective basis. The objective of this study is to examine associations between MLE use and PNAC rate in the general NICU setting. This is a retrospective review of NICU patients who received TPN for 7 or more days. We compared patients born between 1/1/2014 and 12/31/2015 (pre-MLE) to patients born between 7/1/2017 and 12/31/2018 (post-MLE). Fisher's exact test and two-sample t -test were used to compare the two groups. There were 353 patients in 2014-2015 and 271 patients in 2017-2018. Demographics were similar between the two groups, but there were more patients with congenital heart disease in the MLE era (P < 0.001). Mortality was similar (6.2% pre-MLE versus 6.3% post-MLE). There was no significant difference in PNAC rate between the pre-MLE (11.5%) and post-MLE (14.1%) patient cohorts (P = 0.342). Among patients receiving MLE (n = 38), 58% developed PNAC, while only 6.4% of the post-MLE cohort not receiving MLE developed PNAC. Of the patients coded with a surgical diagnosis, there was no significant difference in PNAC rates between pre-MLE and post-MLE groups. Discharge rates of PNAC did differ between pre-MLE surgical patients (13.0%) and post-MLE surgical patients (8.2%). In the subgroup of post-MLE surgical patients, PNAC rate differed significantly between those receiving MLE (43.5%) and not receiving MLE (15.4%). However, this difference was resolved by discharge (8.7% versus 7.7%). There were no significant differences in PNAC rates between the pre-MLE and post-MLE cohorts. However, in surgical patients, MLE was associated with reduced PNAC at discharge, with levels equivalent to those seen in neonates receiving TPN for 7 or more days, despite having a higher starting rate of PNAC. Further studies are needed to determine whether the general NICU population may benefit from MLE or certain selective subpopulations like surgical patients. [ABSTRACT FROM AUTHOR]

Short bowel syndrome is a devastating gastrointestinal disorder in which decreased bowel length results in inadequate absorption causing nutritional deficiencies. Current treatment options are accompanied by significant morbidity. We have proposed spring-mediated distraction enterogenesis as a method to lengthen bowel with success seen in porcine jejunum. We hypothesize that spring-mediated distraction enterogenesis can be demonstrated in porcine ileum with preservation of ileal structure and function. Laparotomy was performed on juvenile female mini-Yucatan pigs and a gelatin-encapsulated compressed nitinol spring was inserted into the ileal lumen and affixed proximally and distally. A control segment distal to the spring segment was marked with sutures. Postoperatively, pigs were placed on a liquid diet and euthanized on postoperative day 7. Spring and control segments were measured and processed for immunohistochemistry to evaluate for the presence of vitamin B12–intrinsic factor cotransporter, chromogranin A-producing cells, and 5-HT producing cells. All seven pigs survived to postoperative day 7 with no adverse effects. On average, pigs gained 84.3 ± 66.4 g/d. Spring segments lengthened 1.5 ± 0.7 cm with a relative lengthening by 128% ± 56%, which was statistically significant when compared to control (P < 0.01). The average density of chromogranin-A cells in control compared to spring segments was not significantly changed (2.9 ± 1.1 cells/mm versus 3.2 ± 1.2 cells/mm, P = 0.17). Both vitamin B12–intrinsic factor cotransporter and 5-HT producing cells were present in both control and lengthened ileum. Intraluminal nitinol springs significantly lengthened porcine ileum. The increase in density of enteroendocrine cells may indicate enhanced endocrine function of the lengthened ileum. [ABSTRACT FROM AUTHOR]

Short bowel syndrome (SBS) results from significant intestinal loss and is characterized by insufficient absorption of nutrients and fluids. Preclinical large animal SBS models typically require parenteral nutrition (PN) support and may not be appropriate for studying interventions to improve intestinal absorption or adaptation. Here, we describe the development of a porcine SBS model that does not require PN support. Eight male Yorkshire piglets underwent either a 75% or 90% jejunoileal resection (n = 5) or no resection (n = 3). Continuous enteral nutrition (EN) was provided via a gastrostomy tube. The final SBS model consisted of a 75% resection and nutrition provided via combination EN (60%) and per oral pig chow (40%). Body weight and concentration of fat-soluble vitamins were assessed on postoperative days (POD) 7, 14, and 21. For assessing fat malabsorption, the coefficient of fat absorption (CFA) was calculated following a 72-h stool collection. Resected animals had decreased weight gain compared to unresected controls (POD21 + 8.3% versus +28.8%, P = 0.048). Vitamin D concentration was significantly lower in resected animals compared to controls on POD 7, POD 14, and POD 21. Serum vitamin E concentration was also lower on POD 21. Resected animals developed fat malabsorption with lower CFA (76.5% versus 95.3%, P = 0.014). We describe the development of a porcine SBS model that does not require PN support. Piglets in this model gain less weight, demonstrate fat malabsorption, and develop fat-soluble vitamin deficiencies. This model will benefit investigations of intestinal absorption or adaptation while potentially decreasing costs and confounding complications related to PN administration. [ABSTRACT FROM AUTHOR]

Murine ileocecal resection (ICR) has been used to investigate intestinal adaptation. The established model often includes the sacrifice of significant length of the proximal colon. Here, we optimized a highly selective vascular approach to the ICR, with primary jejunal-colic anastomosis yielding maximal colonic preservation. Forty C57BL/6 mice underwent a highly vascularly selective ICR. The terminal branches of the ileocecal artery are isolated apart from the mesenteric branches supplying the small bowel to be resected. The distal 50% of small bowel and cecum are resected; a primary jejuno-colonic anastomosis is performed. Animals were sacrificed at postoperative weeks 2 (n = 10) and 10 (n = 29). Proximal 50% small bowel resection (SBR) with jejuno-ileal anastomosis was also performed for comparison. The entire colon (with exception of the cecum) was preserved in 100% of animals. Ninety-seven percent of animals survived to postoperative week 10, and all exhibited structural adaptation in the remnant small intestine epithelium. Crypts deepened by 175%, and villi lengthened by 106%, versus 39% and 29% in the proximal SBR cohort, respectively. Colonic proliferation, structural adaptation, and functional adaptation (measured by p-histone 3, luminal-facing apical crypt border size, and sucrase isomaltase, respectively) were increased in ICR compared with proximal SBR. Highly selective isolation of the cecal vasculature allows for greater colon preservation and yields enhanced remnant intestine epithelial adaptation. ICR is also associated with greater colonic adaptation and unique plasticity toward an intestinal phenotype. These findings underscore major differences between resection sites and offer insights into the critical adaptive mechanisms in response to massive intestinal loss. [ABSTRACT FROM AUTHOR]

Short bowel syndrome is a potentially fatal condition with inadequate management options. Tissue-engineered small intestine (TESI) is a promising solution, but confirmation of TESI function will be crucial before human application. We sought to define intestinal epithelial barrier function in human intestinal organoid (HIO)-derived TESI. HIOs were generated in vitro from human embryonic stem cells. After 1 mo, HIOs were collected for analysis or transplanted into the kidney capsule of immunocompromised mice. Transplanted HIOs (tHIOs) were harvested for analysis at 4 or 8 wk. Reverse transcription quantitative polymerase chain reaction and immunofluorescent staining were performed for tight junction components: claudin 3 (CLDN3), claudin 15 (CLDN15), occludin (OCLN), and zonula occludens-1, or tight junction protein-1 (TJP1/ZO-1). Four-week-old tHIOs demonstrated significantly (P < 0.05) higher levels of CLDN15 (6x), OCLN (4x), and TJP1/ZO-1 (3x) normalized to GAPDH than in vitro HIOs. Eight-week-old tHIOs demonstrated significantly (P < 0.05) higher expression levels of CLDN3 (26x), CLDN15 (29x), OCLN (4x), and TJP1/ZO-1 (5x) than in vitro HIOs. There was no significant difference in expression of these tight junction components between 4- and 8-week-old tHIOs. Immunofluorescent staining revealed the presence of claudin 3, claudin 15, occludin, and zonula occludens-1 in both in vitro HIOs and tHIOs; however, the morphology appeared more mature in tHIOs. In vitro HIOs have lower levels of tight junction mRNA, and tight junction proteins appear morphologically immature. Transplantation facilitates maturation of the HIOs and enhances select tight junction gene expression. [ABSTRACT FROM AUTHOR]

Short bowel syndrome resulting from small bowel resection (SBR) is associated with significant morbidity and mortality. Many adverse sequelae including steatohepatitis and bacterial overgrowth are thought to be related to increased bacterial translocation, suggesting alterations in gut permeability. We hypothesized that after intestinal resection, the intestinal barrier is altered via toll-like receptor 4 (TLR4) signaling at the intestinal level. B6 and intestinal-specific TLR4 knockout (iTLR4 KO) mice underwent 50% SBR or sham operation. Transcellular permeability was evaluated by measuring goblet cell associated antigen passages via two-photon microscopy. Fluorimetry and electron microscopy evaluation of tight junctions (TJ) were used to assess paracellular permeability. In parallel experiments, single-cell RNA sequencing measured expression of intestinal integral TJ proteins. Western blot and immunohistochemistry confirmed the results of the single-cell RNA sequencing. There were similar number of goblet cell associated antigen passages after both SBR and sham operation (4.5 versus 5.0, P > 0.05). Fluorescein isothiocyanate–dextran uptake into the serum after massive SBR was significantly increased compared with sham mice (2.13 ± 0.39 ng/μL versus 1.62 ± 0.23 ng/μL, P < 0.001). SBR mice demonstrated obscured TJ complexes on electron microscopy. Single-cell RNA sequencing revealed a decrease in TJ protein occludin (21%) after SBR (P < 0.05), confirmed with immunostaining and western blot analysis. The KO of iTLR4 mitigated the alterations in permeability after SBR. Permeability after SBR is increased via changes at the paracellular level. However, these alterations were prevented in iTLR4 mice. These findings suggest potential protein targets for restoring the intestinal barrier and obviating the adverse sequelae of short bowel syndrome. [ABSTRACT FROM AUTHOR]

Severe congenital chylothorax (SCC) may result in respiratory failure, malnutrition, immunodeficiency, and sepsis. Although typically managed with bowel rest, parenteral nutrition, and octreotide, persistent chylothoraces require surgical management. At our institution, a pleurectomy, unilateral or bilateral, in combination with mechanical pleurodesis and thoracic duct ligation is performed for SCC, and we describe our approach and outcomes. We reviewed over 15-year period neonatal patients with SCC managed surgically with pleurectomy after medical therapy was unsuccessful. Patients were divided into two groups: those who underwent pleurectomy within 28 d of diagnosis (early group) and those who underwent pleurectomy after 28 d (late group). Resolution of chylothorax was defined by the absence of clinical symptoms as well as absent or minimal pleural effusion on chest X-ray. Of 40 patients diagnosed with SCC over the study period, 15 underwent pleurectomy, eight early [mean time to operation = 20 (IQR 17, 23) d] and 7 late [59 (42, 75) d, P = 0.001]. Overall survival was 67% (10 of 15). Seven of 8 (88%) neonates who underwent early pleurectomy survived versus 3 of 7 (43%) who underwent late pleurectomy (P = 0.07). Length of stay was lower in the early group than the late group [73 (57, 79) versus 102 (109, 213) d, P = 0.05]. All patients who survived to discharge had resolution of their chylothorax. Pleurectomy with mechanical pleurodesis and thoracic duct ligation is effective in the management of severe congenital chylothorax. When performed earlier, pleurectomy for severe congenital chylothorax may be associated with improved survival and shorter hospital length of stay. [ABSTRACT FROM AUTHOR]

Short bowel syndrome (SBS) is a condition that results from inadequate intestinal absorptive capacity, usually after the loss of functional intestine. We have previously developed a severe model of SBS in zebrafish that demonstrated increased intestinal adaptation (IA) and epithelial proliferation in SBS zebrafish. However, many children with SBS do not have this extreme intestinal loss. Therefore, in this study, we developed a variation of this model to evaluate the effects of increasing intestinal length on IA and the complications of SBS. After Institutional Animal Care and Use Committee approval, adult male zebrafish were assigned to three groups: sham (n = 30), S1-SBS (n = 30), and S3-SBS (n = 30). Sham surgery included ventral laparotomy alone. S1-SBS surgery consisted of laparotomy with creation of a proximal stoma at S1 (jejunostomy equivalent) and ligation at S4. S3-SBS surgery had stoma creation at S3 (ileostomy equivalent) and the same ligation. Fish were harvested at 14 d. Markers of IA were measured from proximal intestinal segments, and the liver was analyzed for development of hepatic steatosis. At 14 d, S3-SBS fish lost less weight than S1-SBS and had increased markers of IA compared with sham fish, which were decreased compared with S1-SBS fish. S3-SBS fish had decreased proximal intestinal inflammation compared with S1-SBS fish. S1-SBS fish developed extensive hepatic steatosis. Although S3-SBS fish have increased hepatic steatosis compared with sham fish, it is decreased compared with S1-SBS. Longer remnant intestine decreases the extent of IA, inflammation, and hepatic steatosis in a zebrafish model of SBS. [ABSTRACT FROM AUTHOR]

Acute mesenteric ischemia is a life-threatening acute condition, which requires an interdisciplinary approach, including vascular recanalization and surgical treatment. Visual evaluation of intestinal perfusion might be misleading, and therefore, additional tools are necessary to reliably be able to resect the ischemic intestine. Hyperspectral imaging (HSI) has been shown to be feasible and safe for real-time assessment of tissue perfusion in visceral surgery but has never been used in cases of acute mesenteric ischemia. Therefore, we applied HSI in acute mesenteric ischemia to evaluate it for potential aid in the objectively discriminating ischemic and well-perfused intestine during explorative laparotomy. We recorded HSI measurements in 11 cases of acute mesenteric ischemia during explorative laparotomy. We evaluated the recorded images for macroscopic visual perfusion quality and divided it into three groups. Of those three groups, we calculated and compared the HSI indexes of tissue saturation, near-infrared perfusion index, organ hemoglobin index, and tissue water index, as well as the reflectance spectra. We found significant differences in tissue saturation (0.7% versus 0.45%; P = 0.002) and near-infrared perfusion index (0.58 versus 0.23; P < 0.001) in poorly perfused intestinal segments compared with the viable intestine. Furthermore, we could detect an increasing peak at 630 nm of the reflectance spectra in less viable tissues, indicating a maximum in necrotic tissues. We attributed this peak to an increase in met-hemoglobin content in necrotic tissues, which is supported by the increase in the HSI organ hemoglobin index. HSI is able to discriminate tissue perfusion in acute mesenteric ischemia reliably and therefore might be helpful for resection. In addition, HSI gives information on tissue viability via reflectance spectra. [ABSTRACT FROM AUTHOR]

Children with short bowel syndrome (SBS) frequently struggle with malabsorption and poor growth. The intestinal microbiota plays an important role in gut function, and children with SBS have known deficiencies in some commensal gut microbes. One strategy to enhance the gut microbiota is by taking probiotics. However, the efficacy of this approach is not well established. We hypothesized that probiotic supplementation would result in increased levels of the supplemented bacteria and improved growth. Children with SBS who had weaned from parenteral nutrition but with suboptimal growth were randomized to receive probiotics (Lactobacillus rhamnosus and Lactobacillus johnsonii) or placebo daily for 2 mo. The gut microbiota from monthly stool samples were compared between groups using 16S ribosomal ribonucleic acid sequencing and quantitative polymerase chain reaction. Growth between groups was also compared. Statistical analysis was completed using Mann-Whitney, Kruskal-Wallis, and chi-square tests as appropriate. Eighteen children with SBS completed the study (n = 9 per group). There were no significant changes to the major bacterial families in either group. Median relative abundance of Lactobacillus did not differ between groups at baseline or at the end of the study (7.67 versus 13.23, P = 0.523 and 1.93 versus 15.8, P = 0.161). Median z scores for weight and length did not differ between groups at the beginning or end of the study. The efficacy of daily probiotic use in children with intestinal failure is unknown. In this study, Lactobacillus probiotics did not result in a predictable change to the fecal microbiota or overall growth compared with placebo in these patients. [ABSTRACT FROM AUTHOR]

Abstract Background Parenterally administered selective serotonin reuptake inhibitors, such as citalopram, increase intestinal mucosal absorptive surface by day 7 of treatment. We hypothesized that enteral citalopram would also induce intestinal mucosal growth, thus allowing for therapy with an oral agent. Materials and methods Following a habituation period, C57BL/6 mice received peanut butter pellets containing 10, 50, or 100 mg/kg/d citalopram for 7 d (n = 5); or 25 mg/kg/d citalopram for 14 (n = 3) or 21 (n = 5) d; or plain peanut butter pellets for 7 (n = 2), 14 (n = 2), or 21 d (n = 3). Two-centimeter ileal segments were harvested and prepared for microscopic assessment of villus height (VH), crypt depth, villus width (VW), and crypt width. Mucosal surface area (MSA) was calculated and data were compared using Student's t -test. Results Enteral administration of citalopram had virtually no effect on VH, VW, or crypt depth after 7 d; crypt width decreased significantly (P value range 0.0002 to <0.0001), likely contributing to the increases in MSA (P value range 0.0578 to 0.0006). After 14 d of treatment, citalopram significantly increased VH (P < 0.0001), VW (P = 0.0058), and ileal MSA per mm2 (P = 0.0007). The increase in MSA was sustained at 21 d (P < 0.0001). Conclusions Enteral citalopram given for 14 d results in increased VH and ileal MSA, which remains increased by day 21. Selective serotonin reuptake inhibitors show potential as oral therapy for serious intestinal disorders such as short bowel syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Short bowel syndrome (SBS) results from extensive bowel resection. Patients with SBS require total parenteral nutrition (TPN) for survival. Understanding mechanisms contributing to TPN-associated liver injury and gut atrophy are critical in developing SBS therapies. Existing SBS models using tethered animals have significant limitations and are unlike ambulatory human SBS patients. We hypothesized that we could induce SBS in piglets and develop an ambulatory TPN-SBS model. Material and methods Eighteen neonatal pigs received duodenal and jugular catheters. They were fitted with a jacket holding TPN and a miniaturized pump. Six piglets had 90% small bowel resection and catheter placement (SBS group). Non-SBS piglets were randomized into enteral nutrition (EN) or TPN. Results Bowel resection was successfully accomplished in SBS animals. Weight gain was similar in all groups. SBS animals had increased serum bilirubin compared to EN. Mean conjugated bilirubin ± SD was 0.045 ± 0.01 for EN, (P = 0.03 EN versus TPN and P = 0.03 SBS versus EN) and 1.09 ± 1.25 for TPN, (P = 0.62 TPN versus SBS). Gut density was reduced in the TPN group compared to EN and SBS groups. Mean gut density ± SD was 0.11 ± 0.04 for TPN (P = 0.0004 TPN versus SBS and P = 0.00007 TPN versus EN) and not statistically different for EN versus SBS (P = 0.32). Conclusions We created a novel, ambulatory TPN-SBS model using piglets, mimicking long-term TPN delivery in human SBS patients. Our model demonstrated TPN-related conjugated hyperbilirubinemia and compensatory gut hypertrophy, as noted in humans with SBS. This model holds great potential for future research. [ABSTRACT FROM AUTHOR]

Abstract Background Early identification of patients with acute mesenteric ischemia (AMI) involving the large bowel may play a decisive role in improving the prognosis of AMI. This study aims to compare the outcomes between patients with isolated AMI and AMI patients with colon involvement (CI) and to identify the predictors of worse outcomes. The different surgical modalities for AMI patients with CI were also evaluated. Methods This retrospective cohort study included 199 AMI patients admitted from January 2005 to January 2014. Based on colonoscopy and pathology reports, 39 patients were diagnosed as AMI with CI, and 160 were AMI patients without CI. The clinical outcomes and different surgical modalities were compared. Risk factors of 30-d mortality and short bowel syndrome (SBS) were identified. Results The 30-d mortality (10% versus 49%, P < 0.01) and SBS incidence (19% versus 49%, P < 0.01) were higher in AMI patients with CI than AMI patients without CI. AMI patients with CI have higher rate of bowel resection (68% versus 95%, P < 0.001) and second-look laparotomy (25% versus 54%, P < 0.001) than patients with AMI alone. For AMI patients with CI, emergent laparotomy was associated with shorter hospital stay (P = 0.04) and less incidence of SBS (74% versus 25%, P < 0.001) than initial endovascular therapy. Patients with ostomy had less repeated bowel resection (11% versus 63%, P = 0.001) and rate of SBS (21% versus 79%, P < 0.001) than patients with primary bowel anastomosis. Serum procalcitonin level and colon ischemia were risk factors of 30-d mortality and SBS for AMI. Conclusions AMI patients with CI represent a special cohort of AMI patients with higher risk of poor outcome. Compared to initial endovascular therapy, emergent laparotomy was associated with shorter length of hospital stay and reduced incidence of SBS. [ABSTRACT FROM AUTHOR]

Abstract Background Parenteral nutrition for intestinal failure (IF) often requires a tunneled central venous catheter (CVC). The purpose of this study was to characterize complications after CVC placement and contributors to line loss in pediatric IF patients. Methods An institutional review board–approved retrospective review of pediatric (<18 y) IF patients who had a silicone tunneled CVC newly inserted or exchanged from 2012 to 2016 in an IF center was conducted. Patient demographics, procedure service (surgery versus interventional radiology), procedure type (new versus exchange), vessel, and complications related to CVCs were evaluated. Complications included dislodgement, infection, break, occlusion/malfunction, and others. An ethanol-lock protocol for silicone CVCs in IF patients was instituted in January 2012. Results Twenty-nine IF patients with tunneled CVCs were identified with 182 lines and 18,534 line d. Median age at line insertion was 17.1 mo (interquartile range [IQR] 7.6-31.5) with a median of five catheters (IQR 2-8) per patient. There were 19.2 complications per 1000 line d. Occlusions/malfunctions were the most common complication (6.0/1000 line d) followed by breaks (5.6/1000 line d). Median life of catheters was 51.5 d (IQR 21-129). On regression, adjusting for age, insertion service, and procedure type, shorter line life was associated with younger age (P = 0.04) and placement by interventional radiology (P < 0.01). Dislodgement was associated with newly placed lines relative risk 6.5 (95% CI 2.2-28.8). Conclusions CVCs in pediatric IF patients have frequent complications and short line lifetimes. Dislodgement of CVC was an unexpectedly common complication with loss of access in newly placed lines. There may be modifiable processes to mitigate CVC complications. [ABSTRACT FROM AUTHOR]

Background Improving treatment for short bowel syndrome requires a better understanding of how intestinal adaptation is affected by factors like mechanoluminal stimulation. We hypothesized that in mice, luminal diversion via an ileostomy would drive adaptive changes similar to those seen in human intestine after diversion while offering the opportunity to study the immediate events after resection that precede intestinal adaptation. Materials and methods With Institutional Animal Care and Use Committee approval, a distal ileostomy with a long distal Hartman's was created in 9- to 14-week-old C57/B6 mice ( n = 8). Control mice only had a midline laparotomy without stoma formation ( n = 5). A rim of tissue from the proximal stoma was resected as a historical control for the proximal segment. Postoperatively, mice received a high-protein liquid diet and water ad libitum . On day 3, tissue from both the proximal and distal limbs were collected for histologic and RNA analysis. Morphometric measures, immunofluorescent antigen detection, and RNA expression were compared with Student paired t -tests with a P value < 0.05 considered significant. Results At 3 d, survival for mice with an ileostomy was 87% and average weight loss was 12.5% of initial weight compared to 6.05% for control mice. Compared to the distal limb, the proximal limb in mice with an ileostomy demonstrated significantly taller villi with deeper and wider crypts. The proximal limb also had decreased expression of intestinal stem cell markers lgr5, bmi1, sox9 , and ascl2 . Fewer goblet and enteroendocrine cells per hemivillus were also noted in the proximal limb. In control mice, none of these measures were significant between proximal and distal ileum except for villus height. Conclusions This new murine ileostomy model allows study of intestinal adaptation without intestinal anastomosis, which can be technically challenging and morbid. [ABSTRACT FROM AUTHOR]

Background Gastrostomy tube placement is a common procedure that can be accomplished with a variety of techniques, each with its attendant complications. In an effort to standardize practice at our institution, we retrospectively evaluated complications including early dislodgement requiring operative repair, leaks, and granulation tissue to determine the optimal technique. Materials and methods A retrospective cohort study (June 2008-July 2014) evaluating children (<18) receiving gastrostomy tubes was completed. We recorded demographic data, placement technique, and postoperative complications within 120 days. The seven techniques in use at our institution were categorized into three groups: standard pull-type techniques for percutaneous endoscopic gastrostomies (PEGs), “push” techniques using transabdominal sutures or T-fasteners for securement of the stomach, and “fascial” techniques using sutures directly from the stomach to the abdominal fascia at the stoma site. Descriptive statistics were analyzed using t test and Kruskal-Wallis tests as appropriate, and outcomes with P < 0.05 were considered significant. Results Of the 450 patients, 255 (56.7%) were male. Median age and weight at the time of operation were 19.3 months (interquartile range, 6.5-89.6 months) and 9.0 kg (interquartile range, 5.7-17.1 kg) respectively. By technique, 245 patients underwent fascial placement (54.4%), 112 underwent push (24.9 %), and 93 underwent PEG (20.7%). Push and fascial techniques were less likely become dislodged than PEG, with odds ratios (ORs) of 0.14 (confidence interval CI 0.02-0.66) and 0.31 (CI 0.11-0.83), respectively. Fascial techniques had more granulation tissue than either push or PEG pull methods, OR 2.39 (CI 1.20-3.36), and more leakage, OR 2.22 (CI 1.19-4.15). Conclusions Dislodgement is most likely with PEG techniques. Granulation and leakage are most likely with fascial suture techniques. Push techniques are associated with the lowest complication rate. [ABSTRACT FROM AUTHOR]

Background Distraction enterogenesis has been investigated as a novel treatment for short bowel syndrome (SBS). With variable intestinal sizes, it is critical to determine safe, translatable spring characteristics in differently sized animal models before clinical use. Nitinol springs have been shown to lengthen intestines in rats and pigs. Here, we show spring-mediated intestinal lengthening is scalable and feasible in a murine model. Materials and methods A 10-mm nitinol spring was compressed to 3 mm and placed in a 5-mm intestinal segment isolated from continuity in mice. A noncompressed spring placed in a similar fashion served as a control. Spring parameters were proportionally extrapolated from previous spring parameters to accommodate the smaller size of murine intestines. After 2-3 wk, the intestinal segments were examined for size and histology. Results Experimental group with spring constants, k = 0.2-1.4 N/m, showed intestinal lengthening from 5.0 ± 0.6 mm to 9.5 ± 0.8 mm ( P < 0.0001), whereas control segments lengthened from 5.3 ± 0.5 mm to 6.4 ± 1.0 mm ( P < 0.02). Diameter increased similarly in both groups. Isolated segment perforation was noted when k ≥ 0.8 N/m. Histologically, lengthened segments had increased muscularis thickness and crypt depth in comparison to normal intestine. Conclusions Nitinol springs with k ≤ 0.4 N/m can safely yield nearly 2-fold distraction enterogenesis in length and diameter in a scalable mouse model. Not only does this study derive the safe ranges and translatable spring characteristics in a scalable murine model for patients with short bowel syndrome, it also demonstrates the feasibility of spring-mediated intestinal lengthening in a mouse, which can be used to study underlying mechanisms in the future. [ABSTRACT FROM AUTHOR]

Background Significant quantities of serotonin (5-hydroxytryptamine; 5-HT) are found in the intestine, and studies have demonstrated that 5-HT can stimulate enterocyte cell division, suggesting regulatory roles in mucosal homeostasis and intestinal adaptation. We hypothesized that excess enteric 5-HT signaling enhances mucosal growth without changing intestinal villous cellular makeup. Methods Mice lacking the serotonin reuptake transporter (SERT) and wild-type littermates (WTLM) were euthanized and their ileum analyzed. Villus height (VH), crypt depth (CD), and enterocyte height (EH) were measured. Enterocyte cell division was measured using Ki-67 immunofluorescence to calculate crypt proliferation index (CPI). Cellular distribution along villi was investigated by immunofluorescent staining for enterocytes, enteroendocrine cells, and goblet cells. Group measurements were compared using t -test and chi-squared test. Results SERT knock-out (SERTKO) mice had significantly taller villi, deeper crypts, and taller enterocytes compared with WTLM ( P < 0.0001). Similarly, enterocyte proliferation was greater in SERTKO compared with WTLM ( P < 0.01). For SERTKO, mean values were: VH, 255.6 μm; CD, 66.7 μm; EH, 21.2 μm; and CPI, 52.8%. For WTLM, corresponding values were: VH, 207.8 μm; CD, 56.1 μm; EH, 19.5 μm; and CPI, 31.9%. The cellular composition along villi was not significantly different between genotypes ( P > 0.05). Conclusions Enhancing 5-HT signaling in mice increases VH, CD, EH, and crypt cell proliferation in the intestinal mucosa. 5-HT-associated growth did not alter the cellular composition of the villi. Serotonin may represent an important physiologic regulator of intestinal growth and adaptation and holds promise as a target for therapies aimed at enhancing intestinal recovery after injury or mucosal surface area loss. [ABSTRACT FROM AUTHOR]

Purpose Small intestinal length has prognostic significance for patients with short bowel syndrome, and accurate measurement of Roux-en-Y limbs is considered important. The flexible elasticity of bowel makes its measurement highly subjective, yet a recommended method for intestinal measurement allowing accurate comparisons between surgeons remains undefined. Measurement of intestinal length has been described, but no comparison of the fidelity of measurement technique has been made. We hypothesized that silk suture and umbilical tape would yield the most consistent measurements. Methods This institutional review board–approved prospective trial enrolled 12 volunteer surgeons and two Institutional Animal Care and Use Committee-donated rabbits. Participants were asked to measure short, medium, and long segments of small intestine in a euthanized rabbit using common operating room tools: 18-in silk suture, 75-cm umbilical tape, 15-cm straight ruler, laparoscopic Dorsey bowel graspers. Data were analyzed by analysis of variance repeated measures model. Results Over short segments, intestinal measurements by grasper were significantly shorter than those by tape ( P = 0.002) and ruler ( P = 0.039). Over medium lengths of bowel, measurements by grasper were significantly shorter than those by suture ( P = 0.032) and tape ( P = 0.046), and measurements by ruler also were significantly shorter than those by suture ( P = 0.008). Over the long intestinal segment, measurements by ruler resulted in the greatest variability, and comparison of variance across all possible pairs of groups found significant difference by method of measurement ( P = 0.049). There was a significant difference in measurements taken along the mesenteric border compared with those taken along the antimesenteric border ( P = 0.001). Conclusions Measurement technique along short segments matters less; however, rigid tools underestimate length, and smaller variances in measurement by silk suture and umbilical tape suggest that these methods are more reliable across longer distances. [ABSTRACT FROM AUTHOR]

Background Short bowel syndrome is a life-threatening condition with few solutions. Tissue-engineered intestine (TEI) is a potential treatment, but donor intestine is a limiting factor. Expanded epithelial surrogates termed enteroids may serve as a potential donor source. Materials and methods To produce TEI from enteroids, crypts were harvested from mice and enteroid cultures established. Enteroids were seeded onto polymer scaffolds using Matrigel or culture medium and implanted in immunosuppressed mice for 4 wk. Histology was analyzed using Periodic acid–Schiff staining and immunofluorescence. Neomucosa was quantified using ImageJ software. To determine whether TEI could be produced from enteroids established from small intestinal biopsies, 2 × 2–mm pieces of jejunum were processed for enteroid culture, enteroids were expanded and seeded onto scaffolds, and scaffolds implanted for 4 wk. Results Enteroids in Matrigel produced TEI in 15 of 15 scaffolds, whereas enteroids in medium produced TEI in 9 of 15 scaffolds. Use of Matrigel led to more neomucosal surface area compared to media (10,520 ± 2905 μm versus 450 ± 127 μm, P < 0.05). Histologic examination confirmed the presence of crypts and blunted villi, normal intestinal epithelial lineages, intestinal subepithelial myofibroblasts, and smooth muscle cells. Crypts obtained from biopsies produced an average of 192 ± 71 enteroids. A single passage produced 685 ± 58 enteroids, which was adequate for scaffold seeding. TEI was produced in 8 of 9 scaffolds seeded with expanded enteroids. Conclusions Enteroids can be obtained from minimal starting material, expanded ex vivo , and implanted to produce TEI. This method shows promise as a solution to the limited donor intestine available for TEI production in patients with short bowel syndrome. [ABSTRACT FROM AUTHOR]

Background Treatment of short bowel syndrome (SBS) remains difficult, entailing severe morbidity and mortality. Accepted surgical treatment modalities for SBS are the Bianchi intestinal lengthening procedure and reversed-segment procedure. We seek to investigate the short-term effects regarding growth, nutrition, and microscopic and functional adaptation after the intestinal lengthening and RS procedures in a piglet SBS-model. Material and methods Twenty-four piglets (Sus scrofa, ±30 kg) were divided into four groups ( n = 6 each) as follows: sham, SBS, Bianchi lengthening procedure (BIA), and reversed-segment (RS). At day one either sham laparotomy (sham) or 75% small bowel resection (SBS, BIA, and RS) was performed. After 2 wk sham laparotomy (sham and SBS), BIA, or RS procedure was performed. After 8 wk all animals were terminated. During the experimental time course, the following parameters were assessed: body weight, intestinal length, diameter, and weight, fat absorption, and biochemical parameters from serum and urine. Citrulline was used as a marker of absorptive enteral mass to demonstrate massive functional bowel loss. Intestinal biopsies were obtained for histologic analysis and electrophysiological measurements to analyze glucose absorptive capacity. Results Eight weeks after bowel resection, piglet growth was reduced in SBS, BIA, and RS piglets as demonstrated by reduced weight (51 ± 4 kg, 47 ± 2 kg, and 53 ± 1 kg, respectively) compared with sham (69 ± 3 kg; P < 0.01), with no demonstrable difference between SBS and treatment groups. Malabsorption and malnutrition occurred in SBS, BIA, and RS piglets reflected by increased fecal fat loss per 24 h (35 ± 4%, 30 ± 2%, and 32 ± 4%, respectively versus 18 ± 1% in sham; P < 0.01) and reduced serum albumin levels (24 ± 1 g/L, 22 ± 1 g/L, and 24 ± 1 g/L, respectively versus sham 33 ± 1 g/L; P < 0.01), but there was no significant difference between SBS and treatment groups. Serum citrulline levels reflected massive functional bowel loss (SBS 36 ± 7 μmol/L, BIA 23 ± 1 μmol/L, and RS 24 ± 2 μmol/L) compared with sham (64 ± 5 μmol/L; P < 0.01). Electrophysiological measurements demonstrated reduced glucose absorption after intestinal resection, which did not return to base levels within the experimental time course. However, the intestine of BIA and RS piglets adapted more profoundly than SBS piglets, as reflected by a greater crypt depth (490 ± 25 μm and 492 ± 21 μm versus 388 ± 20 μm; P < 0.01); and BIA piglets showed greater villus length (884 ± 58 μm) than RS or SBS piglets (715 ± 30 μm and 737 ± 64 μm, respectively; P < 0.01) after 8 wk. [ABSTRACT FROM AUTHOR]

Background Short bowel syndrome causes significant morbidity and mortality. Tissue-engineered intestine may serve as a viable replacement. Tissue-engineered small intestine (TESI) has previously been generated in the mouse model from donor cells that were harvested and immediately reimplanted; however, this technique may prove impossible in children who are critically ill, hemodynamically unstable, or septic. We hypothesized that organoid units (OU), multicellular clusters containing epithelium and mesenchyme, could be cryopreserved for delayed production of TESI. Methods OU were isolated from <3 wk-old mouse or human ileum. OU were then cryopreserved by either standard snap freezing or vitrification. In the snap freezing protocol, OU were suspended in cryoprotectant and transferred directly to -80°C for storage. The vitrification protocol began with a stepwise increase in cryoprotectant concentration followed by liquid supercooling of the OU solution to -13°C and nucleation with a metal rod to induce vitrification. Samples were then cooled to -80°C at a controlled rate of -1°C/min and subsequently plunged into liquid nitrogen for long-term storage. OU from both groups were maintained in cryostorage for at least 72 h and thawed in a 37°C water bath. Cryoprotectant was removed with serial sucrose dilutions and OU were assessed by Trypan blue assay for post-cryopreservation viability. Via techniques previously described by our laboratory, the thawed murine or human OU were either cultured in vitro or implanted on a scaffold into the omentum of a syngeneic or irradiated Nonobese Diabetic/Severe Combined Immunodeficiency, gamma chain deficient adult mouse. The resultant TESI was analyzed by histology and immunofluorescence. Results After cryopreservation, the viability of murine OU was significantly higher in the vitrification group (93 ± 2%, mean ± standard error of the mean) compared with standard freezing (56 ± 6%) (P < 0.001, unpaired t-test, n = 25). Human OU demonstrated similar viability after vitrification (89 ± 2%). In vitro culture of thawed OU produced expanding epithelial spheres supported by a layer of mesenchyme. TESI was successfully generated from the preserved OU. Hematoxylin and eosin staining demonstrated a mucosa composed of a simple columnar epithelium whereas immunofluorescence staining confirmed the presence of both progenitor and differentiated epithelial cells. Furthermore, beta-2-microglobulin confirmed that the human TESI epithelium originated from human cells. Conclusions We demonstrated improved multicellular viability after vitrification over conventional cryopreservation techniques and the first successful vitrification of murine and human OU with subsequent TESI generation. Clinical application of this method may allow for delayed autologous implantation of TESI for children in extremis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Application of distractive forces to small bowel induces intestinal growth, or enterogenesis. This emerging area of research may provide treatment for short bowel syndrome. Glucagon-like peptide 2(GLP-2) has also been reported to induce small bowel growth after bowel resection. We hypothesized that exogenous GLP-2 will result in enhanced distraction-induced enterogenesis. Methods: Distraction-induced model was performed in 10-wk-old C57BL/6 mice using osmotic forces with high molecular weight polyethylene glycol (PEG)-stretch. Four groups were studied: Control group (PEG-/GLP-2–); PEG-stretch (PEG+/GLP-2–); GLP-2 control (PEG-/GLP-2+); and GLP-2 stretch (PEG+/GLP-2+). GLP-2 was given via subcutaneous osmotic pump over the 5 d of experiment. Morphology was measured by histomicrography. Epithelial cell (EC) proliferation was measured with proliferating cell nuclear antigen immunofluorescent staining. Total intestinal growth and blood vessel volume was assessed with Micro computed tomography volumetry. Vascular endothelial growth factor, fibroblast growth factor 1 and 2, and platelet-derived growth factor were measured by reverse-transcriptase polymerase chain reaction. Results: EC proliferation increased significantly in all groups compared with controls, but was greatest in the GLP-2 stretch group. Diameter and length significantly increased in the PEG-stretch and GLP-2 stretch groups. Moreover, there was statistically greater diameter, crypt depth and EC proliferation in the GLP-2 stretch versus PEG-stretch groups. GLP-2 stretch vessel volume was greater than all other groups and was significantly increased compared with controls. The relative expression of platelet-derived growth factor increased significantly in the PEG-stretch group versus the Control group. Conclusions: GLP-2 had an additive effect on EC proliferation, tissue growth, histomorphology, and vascularization. We also demonstrated a unique action of GLP-2, the enhancement of intestinal vascularization. The combination of enterogenesis and GLP-2 may yield an improved approach to treat short bowel syndrome. [Copyright &y& Elsevier]

Background: Interposition of a reversed intestinal segment as a factor facilitating intestinal adaptation has been experimentally investigated. Controversy exists about its efficacy in terms of body weight improvement, direction of luminal changes, and underlying mechanisms. This study aims to provide a comprehensive approach. Methods: The pigs were randomly allocated to two groups: (1) short bowel (SB) group (n = 8) and (2) short bowel reverse jejunal segment (SB-RS) group (n = 8). On postoperative d 3, 30, and 60, intestinal transit time was measured; body weight and serum albumin were measured on baseline, as well as on postoperative d 30 and 60. After sacrifice, histopathologic and immunohistochemical (PCNA, activated caspase-3) evaluation followed. Results: Transit time was numerically longer in SB-RS group at all time points; the difference reached statistical significance on d 60. No statistically significant differences were observed concerning body weight or serum albumin. In the SB-RS group, a statistically significant increase in muscle thickness, crypt depth, villus height, and PCNA immunostaining, and a decrease in caspase-3 positive (+) cell count were documented both at the jejunal and ileal level. Conclusions: The reversed jejunal segment seemed able to enhance intestinal adaptation at a histopathologic level, as well as to favorably modify transit time. These putatively beneficial actions were not reflected upon body weight. The decrease in apoptosis was caspase-3-dependent. [ABSTRACT FROM AUTHOR]

Background: We previously demonstrated that hepatocyte growth factor (HGF) increases mucosal protein and DNA content at single time points during intestinal adaptation in rats. This study evaluates mucosal changes after massive small bowel resection (MSBR) and with the addition of IV HGF measured over the timeframe of intestinal adaptation. Methods: Sixty adult female Sprague-Dawley rats were divided into three groups and underwent massive small bowel resection (MSBR), MSBR+HGF (intravenous 150 mg/kg/d), or sham operation (control). Five animals per group were sacrificed at 7, 14, 21, and 28 d. Ileal mucosa was harvested and DNA and protein extracted. DNA content (ug/mg mucosa) was measured at 260 nm and protein content (ug/mg mucosa) was measured using the Bradford assay. MIB-5 immunohistochemical staining was done to confirm that the increased DNA content was due to proliferation. Statistical analysis was by ANOVA with post-hoc Tukey’s HSD test. Results: At 7 and 14 d, protein concentration was increased following HGF administration in comparison to MSBR alone and in control rats (P < 0.05 and P < 0.03, respectively). Mucosal DNA content in the MSBR-HGF rats was significantly increased over MSBR and control groups at 21 and 28 d (P < 0.02 and P < 0.004, respectively). MIB-5 immunohistochemical staining correlated with mucosal DNA content at 21 and 28 d (P < 0.0005 and P < 0.002, respectively). Conclusions: The mucosal response to MSBR for the period 7–14 d after surgery demonstrates that protein content is increased due to an emphasis on hypertrophy, whereas at 21–28 d hyperplasia is the primary change as demonstrated by the increase in DNA content. This response was enhanced by HGF. This is the first demonstration correlating the bimodal gene response during intestinal adaptation to the bimodal mucosal response. Also, this is the first demonstration of a biphasic response by the mucosa to HGF during intestinal adaptation. [ABSTRACT FROM AUTHOR]

Background: We tested the coupling portion of a prototype intraluminal distraction enterogenesis device to allow flow-through of simulated enteric contents (SEC) in both pig and human jejunum. Materials and Methods: SEC was made using 80% corn syrup. Ten-cm pig and human intestinal segments had a spoke-shaped 2.2 cm coupling adaptor sutured in place, intraluminally. The adaptor had a flow-through area of 33.6 mm2. SEC was pumped into the proximal part of the intestinal segment at 0.083 mL/s. The times to first passage of SEC through the coupler (first drop), 10 mL, and 20mL of SEC eluted from the distal end were recorded. Results: Mean time to first drop elution was 155 ± 38 s with pig, and 149 ± 22 s with human bowel (P = 0.8). This corresponded to a hydrostatic pressure of 37.5 mmHg before the initial drop passed through. Mean flow rates were 0.094 mL/s in pig bowel and 0.084 mL/s in human bowel (P = 0.09). To account for occlusion from luminal debris, a 75% occlusion of coupler holes was studied in the smaller pig bowel to investigate if reductions in flow-through area could be tolerated. Mean time to first drop increased slightly to 171±15 s, but the elution rate stayed the same (P = 0.5). Conclusions: After a physiologic level of initial pressure buildup allowing the first drop of SEC to pass the coupling adaptor, our prototype intestinal coupling adaptor did not obstruct flow-through of SEC, even after a 75% decrease in flow-through area. This type of attachment represents a viable approach to placing a device in-continuity without obstructing flow of enteric contents. [Copyright &y& Elsevier]

Background: Intestinal failure (IF) is associated with significant and life-threatening complications. Recent studies suggest that treatments for IF in the pediatric population are improving over time. Based on this, we examined whether pediatric IF survival rates have improved in our patient population over the past two decades, and secondarily examined which aspects of patient care contributed to changes in survival. Methods: We conducted a retrospective chart review of all pediatric patients with IF at our children’s hospital from 1990 through 2009. Cox regression analyses were used to determine change in survival rates over time (5-y cohorts), and we examined multiple covariates to determine their potential influence on survival rates over time. Results: A significant improvement in survival of 171 children with IF was noted over the past two decades. Children with an onset of IF in the 1990–1994 cohort had significantly decreased survival compared with children in all subsequent cohorts (P = 0.011). The only intervention that was identified between this time period and future periods was the establishment of a comprehensive intestinal failure clinical care team. While the latter three cohorts were not significantly different, progressively increased survival was noted. Ability to wean off parenteral nutrition (PN) and small bowel length greater than 10% of the expected length were significantly associated with improved survival over this time period (P < 0.01). Other tested covariates, including the more recent use of ethanol lock therapy (to prevent catheter sepsis) and lipid reduction strategies (to treat PN-associated cholestasis) failed to show a significant impact on improved survival. Conclusions: Despite a striking improvement in survival of children with IF over the past two decades, the only identified intervention that significantly impacted survival was establishment of a comprehensive care team. These findings emphasize the need for multi-disciplinary efforts to care for such complex and challenging children. [Copyright &y& Elsevier]

Background: Recent studies have demonstrated that the small intestine can be lengthened by applying mechanical forces to the bowel lumen—distraction-induced enterogenesis. However, the mechanisms which account for this growth are unknown, and might be best examined using a mouse model. The purpose of this study is to establish the feasibility of developing distractive-induced small bowel growth in mouse. Methods: Twelve-week old C57BL/6J mice had a jejunal segment taken out of continuity, and distended with polyethylene glycol (PEG: 3350 KDa); this group was compared with a control group without stretching. Segment length and diameter were measured intra-operatively and after 5 d. Villus height, crypt depth, and muscle thickness in the isolated segment were assessed. Rate of epithelial cell proliferation (5-bromo-2-deoxyuridine: BrdU incorporation) in crypts were also examined. The mucosal mRNA expression of targeted factors was performed to investigate potential mechanisms which might lead to distraction-induced enterogenesis. Results: At harvest, the PEG-stretched group showed a significant increase in length and diameter versus controls. Villus height, crypt depth, and muscular layer thickness increased in the PEG group. The PEG group also showed significantly increased rates of epithelial cell proliferation versus controls. Real-time PCR showed a trend toward higher β-catenin and c-myc mRNA expression in the PEG-stretched group; however, this difference was not statistically significant. Conclusions: Radial distraction-induced enterogenesis with PEG is a viable method for increasing small intestinal length and diameter. This model may provide a new method for studying the mechanisms leading to distraction-induced enterogenesis. [Copyright &y& Elsevier]

Background: Distraction enterogenesis is a novel method for increasing small bowel length by the application of linearly directed forces. However, the magnitude of distractive forces that human and animal small bowel can safely withstand is unknown. Methods: Acute ex vivo force-displacement curves for human (n = 5) and pig (n = 6) small intestine (with and without mesentery) were made by applying increasing amounts of distractive forces to bowel immersed in normal saline (39°C). Progressive load was applied until gross disruption of the tissue was detected, or the applied force reached 1000 gram-force (gf). Histology was used to detect evidence of load-induced damage. In vivo blood flow to pig bowel with distractive loads (30–200 gf) was measured by laser Doppler. Results: The relationship between the level of force and degree of displacement was linear. The presence of a mesentery increased stiffness of pig bowel, but did not affect human bowel. Gross tissue disruption in pig and human tissue was seen at forces between 235 and 295 gf, respectively. However, in grossly undamaged areas, histology was unchanged even after application of higher loads. With in vivo testing, mesenteric blood flow was present up to 200 gf; however, blood flow to the bowel wall was reduced to undetectable levels at loads exceeding 100 gf. Conclusions: While whole bowel tissue may tolerate greater applied loads, blood flow to the bowel wall was compromised at loads over 100 gf, suggesting that any higher forces place the bowel at risk for ischemia. These measurements will help guide the clinical application of distraction enterogenesis. [ABSTRACT FROM AUTHOR]

Background: Tissue-engineered small intestine, stomach, large intestine, esophagus, and gastroesophageal (GE) junction have been successfully formed from syngeneic cells, and employed as a rescue therapy in a small animal model. The purpose of this study is to determine if engineered intestine and stomach could be generated in an autologous, preclinical large animal model, and to identify if the tissue-engineered intestine retained features of an intact stem cell niche. Methods: A short segment of jejunum or stomach was resected from 6-wk-old Yorkshire swine. Organoid units, multicellular clusters with predominantly epithelial content, were generated and loaded onto biodegradable scaffold tubes. The constructs were then implanted intraperitoneally in the autologous host. Seven wk later, all implants were harvested and analyzed using histology and immunohistochemistry techniques. Results: Autologous engineered small intestine and stomach formed. Tissue-engineered intestinal architecture replicated that of native intestine. Histology revealed tissue-engineered small intestinal mucosa composed of a columnar epithelium with all differentiated intestinal cell types adjacent to an innervated muscularis mucosae. Intestinal subepithelial myofibroblasts, specialized cells that participate in the stem cell niche formation, were identified. Moreover, cells positive for the putative intestinal stem cell marker, doublecortin and CaM kinase-like-1 (DCAMKL-1) expression were identified at the base of the crypts. Finally, tissue-engineered stomach also formed with antral-type mucosa (mucus cells and surface foveolar cells) and a muscularis. Conclusion: We successfully generated tissue-engineered intestine with correct architecture, including features of an intact stem cell niche, in the pig model. To our knowledge, this is the first demonstration in which tissue-engineered intestine was successfully generated in an autologous manner in an animal model, which may better emulate a human host and the intended therapeutic pathway for humans. [Copyright &y& Elsevier]

Background: Thyroid hormone acts on structural and functional maturation of the mammalian small intestine, mitochondrial pathways, and several protein–gene interactions. Therefore, it is one of the most important regulators of intestinal epithelial differentiation. The aim of the study was to evaluate the effects of thyroid hormone on the adaptation in an experimental model of short bowel syndrome. Methods: Rats were divided into three groups: sham (bowel transection and anastomosis), short bowel syndrome-saline (75% bowel resection and anastomosis), and short bowel syndrome-thyroid hormone (75% bowel resection and anastomosis, and was administered triiodothyronine). The evaluation of adaptation parameters, histopathological and biochemical analysis were performed in all groups. Results: Triiodothyronine treatment resulted in a significant increase in adaptation parameters, villus height-crypt depth, and enterocyte proliferation, whereas significant decrease was seen in apoptotic index in jejunum. Enterocyte proliferation and most of the adaptation parameters changed significantly in ileum following the treatment with triiodothyronine as in jejunum. The changes in ileal villus height-crypt depth and apoptotic index were not statistically significant. Serum levels of free triiodothyronine were lower in the short bowel syndrome-saline group. Conclusions: Our results suggest that thyroid hormone treatment in the hypothyroid phase of SBS enhances intestinal adaptive response. [Copyright &y& Elsevier]

Background: The application of longitudinal mechanical force induces lengthening of the small intestine. The purpose of this study is to evaluate the contractile function of the mechanically lengthened jejunum in a rodent model. Materials and methods: Three groups of rats including normal jejunum, isolated jejunal segment without mechanical lengthening, and isolated lengthened jejunal segment, were studied for contractile function. The isometric contractions of jejunal segments were investigated in organ baths for spontaneous activity and response to potassium chloride and cholinergic carbachol. Results: The normal control group showed a basal spontaneous activity with an average frequency of 33 ± 0.68 contractions per min (cpm). The basal spontaneous activity for the isolated group had an average frequency of 26 ± 2.7 cpm and for the lengthened group had an average frequency of 24 ± 5.7 cpm. Although the normal control group had a higher frequency of basal spontaneous activity as compared to either the isolated or lengthened groups, there was no statistically significant difference between the frequencies in the isolated and the lengthened groups. All three groups demonstrated a sustained increase in tension upon administration of either potassium chloride or carbachol. Conclusions: The response to pharmacological stimulation, as measured by total area under the tension curve and maximal change in basal tone, was larger in the normal group than in the isolated groups. The addition of longitudinal mechanical force to lengthen the isolated jejunal segment did not further alter this change. [Copyright &y& Elsevier]

Background: To investigate the clinical significance of serum citrulline in evaluating the remnant small bowel enterocytes mass and absorptive function in short bowel (SB) patients. Materials and methods: Serum citrulline concentrations were determined using high-performance liquid chromatography (HPLC) in 22 SBS patients and 33 healthy controls. Five-hour urine D-xylose excretion and digestive protein absorption were measured using HPLC and micro-Kjeldahl method, respectively. Small bowel length and surface area were assessed on X-ray radiograph. Correlations between serum citrulline levels and small bowel length, small bowel surface, and nutritional substrate digestive absorption percentage were analyzed. For six patients receiving bowel rehabilitation therapy, serum citrulline, D-xylose excretion, and intestinal protein absorption were measured pre- and immediately postmanagement, and their correlations were analyzed. Results: Serum citrulline levels were significantly lower in SB patients compared with healthy controls. In SB patients, they correlated well with remnant small bowel length (r = 0.82, P &#60; 0.001), surface area (r = 0.86, P &#60; 0.001), 5-h urine D-xylose excretion (r = 0.56, P = 0.007), and digestive protein absorption (r = 0.48, P = 0.046). The increased percentage of serum citrulline level in six patients receiving rehabilitation therapy followed a trend of correlating with that of intestinal protein absorption (r = 0.79, P = 0.063) and urine D-xylose excretion (r = 0.81, P = 0.053). Conclusions: In patients with short bowel syndrome, serum citrulline is a simple and accurate biomarker for the severity of intestinal failure and may be a candidate marker for the gut-trophic effects of bowel rehabilitation therapies. [Copyright &y& Elsevier]

Background. Sodium-dependent brush-border nutrient transport is decreased 2 weeks after massive enterectomy. This down-regulation is ameliorated by a 1-week infusion of parenteral growth hormone (GH) and epidermal growth factor (EGF) started 1 week after resection. We hypothesize that glutamine (GLN) transport will be enhanced by earlier and longer growth factor infusion, with differential effects on the Na+-dependent GLN transport systems A, B0,+, and B0/ASCT2.Materials and methods. New Zealand White rabbits underwent 70% small bowel resection then immediately received parenteral EGF, GH, both EGF and GH, or neither for 2 weeks. Na+-dependent 3H-GLN uptake by jejunal and ileal brush-border membrane vesicles was measured and the contribution of systems A, B0,+, and B0 was then determined by competitive inhibition. Data were analyzed using one-way analysis of variance.Results. In nonresected animals, the relative contribution of the systems was similar in jejunum (A 9%, B0,+ 20%, and B0 71%) and ileum (A 13%, B0,+ 27%, and B0 60%). Na+-dependent GLN uptake was reduced by one half in resected untreated controls, primarily because of decreased B0 activity. EGF or GH alone did not affect Na+-dependent GLN transport, but, as a combination, there was increased uptake in the residual ileum and jejunum by 144% and 150%, respectively, over resected controls (P < 0.05). This was twice that achieved by delayed and shorter-duration combination treatment. This augmentation was a result of a 6.1–8.2-fold increase in system A as well as a 3.8–3.9-fold enhancement of system B0,+ activity in remnant ileum and jejunum (P < 0.01).Conclusions. Parenteral EGF and GH, given in combination for 2 weeks immediately after massive enterectomy, synergistically enhance GLN uptake by systems A and B0,+. [Copyright &y& Elsevier]

Background: Sodium-dependent brush border nutrient transport is decreased 2 weeks after massive enterectomy. This downregulation is ameliorated by a 1-week infusion of parenteral growth hormone (GH) and epidermal growth factor (EGF) started 1 week after resection. We hypothesized that glutamine (GLN) transport would be enhanced by earlier and longer growth factor infusion, with differential effects on the Na+-dependent GLN transport systems A, B0,+, and B0/ASCT2. Materials and methods: New Zealand White rabbits underwent 70% small bowel resection then immediately received parenteral EGF, GH, both, or neither for 2 weeks. Na+-dependent 3H-GLN uptake by jejunal and ileal brush-border membrane vesicles was measured and the contribution of systems A, B0,+, and B0 then determined by competitive inhibition. Data were analyzed using one-way analysis of variance. Results: In nonresected animals, the relative contribution of the systems was similar in jejunum (A, 9%, B0,+, 20%; and B0, 71%) and ileum (A, 13%; B0,+, 27%; and B0, 60%). Na+-dependent GLN uptake was reduced by half in resected, untreated controls, primarily because of decreased B0 activity. EGF or GH alone did not affect Na+-dependent GLN transport, but as a combination, increased uptake in the residual ileum and jejunum by 144% and 150%, respectively, over resected controls (P < 0.05). This was twice that achieved by delayed and shorter-duration combination treatment. This augmentation was due to a 6.1- to 8.2-fold increase in system A as well as a 3.8- to 3.9-fold enhancement of system B0,+ activity in remnant ileum and jejunum (P < 0.01).Conclusions: Parenteral EGF and GH, given in combination for 2 weeks immediately after massive enterectomy, synergistically enhance GLN uptake by systems A and B0,+. [Copyright &y& Elsevier]

Objective. TGF-α has recently been shown to stimulate enterocyte proliferation. In the present study we investigated the effect of TGF-α on enterocyte proliferation and loss via apoptosis and its effects on intestinal adaptation in a rat following massive bowel resection.Methods. Male Sprague–Dawley rats underwent bowel transection and reanastomosis (sham group) or 75% small bowel resection and anastomosis (SBS group) and were treated with intraperitoneal TGF-α (75 μg/kg) from the ninth postoperative day (SBS–TGF-α group). Parameters of intestinal adaptation (overall bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth), enterocyte proliferation, and apoptosis were determined on day 15. Statistical significance was determined by ANOVA with a P < 0.05 considered significant.Results. SBS–TGF-α rats demonstrated a significant increase (vs SBS) in duodenal, jejunal, and ileal overall bowel and mucosal weights; ileal mucosal DNA and protein; and jejunal and ileal villus height. SBS–TGF-α rats also showed an increased cell proliferation index in jejunum (704 ± 43 vs 499 ± 63 BrdU-positive cells/10 crypts, P < 0.05) and ileum (715 ± 84 vs 529 ± 40 BrdU-positive cells/10 crypts, P < 0.05) and decreased apoptotic index in ileum (8.7 ± 1.1 vs 21.8 ± 3.2 apoptotic cells/1000 villus cells, P < 0.05) compared to SBS animals.Conclusions. In a rat model of SBS, TGF-α enhances intestinal adaptation. Possible mechanisms may include increased cell proliferation and decreased enterocyte loss via apoptosis. [Copyright &y& Elsevier]

Background. Prior indirect studies have suggested that a functional epidermal growth factor receptor (EGFR) appears to be indispensable for the adaptive response of the remnant intestine to massive small bowel resection (SBR). The recent availability of a specific pharmacologic EGFR inhibitor enabled us to more directly test the hypothesis that EGFR signaling is required for postresection intestinal adaptation.Methods. Mice (C57B1/6, n = 26) underwent a 50% SBR or sham operation and were then given orogastric EGFR inhibitor (ZD1839, 50 mg/kg/day) or vehicle. After 3 days, indices of adaptation (wet weight, crypt depth, and villus height) and apoptotic index (number of apoptotic bodies per crypt) were calculated in the ileum. The expression of proliferating cell nuclear antigen (PCNA) and activated EGFR was measured by Western blotting.Results. ZD1839 prevented EGFR activation and the normal postresection increases in ileal wet weight, villus height, and crypt depth. Enterocyte proliferation was reduced twofold in the SBR group by ZD1839. Although not statistically significant, rates of enterocyte apoptosis were the highest in the inhibitor-treated mice.Conclusion. Following massive SBR, pharmacologic inhibition of the EGFR attenuates proliferation and the normal adaptive response of the intestine. These results more directly confirm the requirement of a functional EGFR as a mediator of the postresection adaptation response. This study demonstrates an in vivo application of a novel selective EGFR inhibitor and offers a unique experimental model to gain mechanistic insight into understanding postresection intestinal adaptation. [Copyright &y& Elsevier]