Long noncoding RNA GATA2-AS1 augments endothelial hypoxia inducible factor 1-α induction and regulates hypoxic signaling.

Vascular endothelial cells form the inner cellular lining of blood vessels and have myriad physiologic functions including angiogenesis and response to hypoxia. We recently identified a set of endothelial cell (EC)-enriched long noncoding RNAs (lncRNAs) in differentiated human primary cell types and described the role of the STEEL lncRNA in angiogenic patterning. We sought to further understand the role of EC-enriched lncRNAs in physiologic adaptation of the vascular endothelium. In this work, we describe an abundant, cytoplasmic, and EC-enriched lncRNA, GATA2-AS1, that is divergently transcribed from the EC-enriched developmental regulator, GATA2. While GATA2-AS1 is largely coexpressed with GATA2 in ECs, GATA2-AS1 and GATA2 appear to be complementary rather than synergistic as they have mostly distinct target genes. Common single nucleotide variants in GATA2-AS1 exons are associated with early-onset coronary artery disease and decreased expression of GATA2-AS1 in endothelial cell lines. In most cells, HIF1-α is central to the transcriptional response to hypoxia, while in ECs, both HIF1-α and HIF2-α are required to coordinate an acute and chronic response, respectively. In this setting, GATA2-AS1 contributes to the "HIF switch" and augments HIF1-α induction in acute hypoxia to regulate HIF1-α/HIF2-α balance. In hypoxia, GATA2-AS1 orchestrates HIF1-α-dependent induction of the glycolytic pathway and HIF1-α-independent maintenance of mitochondrial biogenesis. Similarly, GATA2-AS1 coordinates both metabolism and "tip/stalk" cell signaling to regulate angiogenesis in hypoxic ECs. Furthermore, we find that GATA2-AS1 expression patterns are perturbed in atherosclerotic disease. Together, these results define a role for GATA2-AS1 in the EC-specific response to hypoxia.

Introducing the Escalation Antibiogram: A Simple Tool to Inform Changes in Empiric Antimicrobials in the Nonresponding Patient.

BACKGROUND: Hospital antibiograms guide initial empiric antibiotic treatment selections, but do not directly inform escalation of treatment among nonresponding patients. METHODS: Using gram-negative bacteremia as an exemplar condition, we sought to introduce the concept of an escalation antibiogram. Among episodes of gram-negative bacteremia between 2017 and 2020 from 6 hospitals in the Greater Toronto Area, we generated escalation antibiograms for each of 12 commonly used agents. Among organisms resistant to that antibiotic, we calculated the likelihood of susceptibility to each of the other 11 agents. In subgroup analyses, we examined escalation antibiograms across study years, individual hospitals, community versus hospital onset, and pathogen type. RESULTS: Among 6577 gram-negative bacteremia episodes, the likelihood of coverage was ampicillin 31.8%, cefazolin 62.7%, ceftriaxone 67.1%, piperacillin-tazobactam 72.5%, ceftazidime 74.1%, trimethoprim-sulfamethoxazole 74.4%, ciprofloxacin 77.1%, tobramycin 88.3%, gentamicin 88.8%, ertapenem 91.0%, amikacin 97.5%, and meropenem 98.2%. The escalation antibiograms revealed marked shifts in likelihood of coverage by the remaining 11 agents. For example, among ceftriaxone-resistant isolates, piperacillin-tazobactam susceptibility (21.2%) was significantly lower than trimethoprim-sulfamethoxazole (54.2%, P < .0001), ciprofloxacin (63.0%, P < .0001), ertapenem (73.4%, P < .0001), tobramycin (80.1%, P < .0001), gentamicin (82.8%, P < .0001), meropenem (94.3%, P < .0001), and amikacin (97.1%, P < .0001). Trimethoprim-sulfamethoxazole was the second-ranked agent in the meropenem escalation antibiogram (49.6%) and first in the amikacin escalation antibiogram (86.0%). Escalation antibiograms were consistent across 4 study years and 6 hospitals. CONCLUSIONS: Escalation antibiograms can be generated to inform empiric treatment changes in nonresponding patients. These tools can yield important insights such as avoiding the common maneuver of escalating from ceftriaxone to piperacillin-tazobactam in suspected gram-negative bacteremia.

Characterization of Patients with Ibuprofen Hypersensitivity.

BACKGROUND: Ibuprofen is the most frequently used over-the-counter nonsteroidal anti-inflammatory drug (NSAID) in North America. While it has been commonly implicated in drug-induced hypersensitivity reactions, there is limited literature specifically on ibuprofen hypersensitivity. OBJECTIVES: To characterize the demographics and clinical course of hypersensitivity reactions in a cohort of patients with ibuprofen allergy. METHODS: A retrospective chart review of patients diagnosed with ibuprofen allergy was conducted between 2008 and 2016 in an allergy clinic at a tertiary care academic institution. Demographics and clinical information were obtained, and severity of reactions was assessed by a standardized grading system. RESULTS: A total of 41 patients were included of whom 27 were female. The mean age at first reaction to ibuprofen was 33 ± 13.9 years. The medi an time from the first reaction to the time of diagnosis was 1 year (0-3). The median time from ibuprofen exposure to the onset of symptoms was 30 min (16-101). The median duration of symptoms was 180 min (60-1,440). Urticaria and angioedema were seen in 90% of patients. The reactions were either mild (46%) or moderate (51%) in severity, but 1 patient had severe anaphylaxis. Cross-reactivity to other NSAIDs or acetaminophen was seen and presented with mostly mild reactions. CONCLUSION: In our cohort of patients, ibuprofen hypersensitivity affected females more commonly than males, and presented with mainly cutaneous manifestations. Onset of symptoms was rapid (< 60 min). Reactions typically ranged in severity from mild to moderate although there was a risk of severe anaphylaxis. There was potential cross-reactivity with other NSAIDs or acetaminophen. The results of our study contribute to the understanding of the demographics and clinical course of ibuprofen hypersensitivity reactions.

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome.

OBJECTIVE: To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF). STUDY DESIGN: This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. RESULTS: All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of -41% and -45%, respectively, with 0.025 mg/kg/d teduglutide and by -25% and -52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and -6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and -1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size. CONCLUSIONS: Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01952080; EudraCT: 2013-004588-30.

Redo pullthrough for Hirschsprung disease.

Pullthrough procedures for Hirschsprung diseases typically have favorable results. However, some children experience long-term postoperative complications comprising stooling disorders, such as intermittent enterocolitis, severe stool retention, intestinal obstruction, as well as incontinence. Reoperative Hirschsprung Disease surgery is complex. This begins with the workup after the initial presentation following primary pullthrough, continues with the definitive surgical correction with redo pullthrough, and ends with long-term follow-up of individuals. The decision tree can be varied with each patient. The operating pediatric surgeon must be able to utilize different operations and treatment options available. While lesser procedures may provide relief in a select population, those with residual aganglionosis or transition zone pathology or mechanical problems will likely require a redo pullthrough. Thus, the diagnostic workup, treatment plan, and definitive surgical care should be coordinated, and executed by an experienced, specialized team at a pediatric referral center.

Magnetic resonance imaging (MRI)-assisted laparoscopic anorectoplasty for imperforate anus: a single center experience.

PURPOSE: Surgical procedures for high imperforate anus have ranged from the posterior sagittal anorectoplasty (PSARP) to laparoscopic-assisted anorectoplasty (LAARP). PSARP bisects the sphincter muscle complex, introducing muscle injury and scarring. LAARP uses a straight trocar to traverse an often non-linear sphincter muscle complex. MRI-assisted LAARP (MRI-LAARP) guides the neorectum precisely through the middle of the entire sphincter complex along its trajectory. We present our experience utilizing MRI intraoperatively during LAARP. METHODS/PROCEDURE: Ten children underwent MRI-LAARP procedures. Intraoperative MRI was performed to delineate the sphincter complex, and to guide the advancement of an MRI-compatible needle through the center of the complex from skin to the peritoneal cavity. The remainder of the procedure was completed using the standard LAARP technique. RESULTS: All had successful MRI needle placement through the sphincter complex. Nine patients had successful laparoscopic pull-through procedures; one was converted to open due to severe intraperitoneal adhesions. Postoperative stay averaged 5.4 ± 4.4 days. Out of the ten patients, one child had mild dehiscence of the anal anastomosis requiring revision 11 days postoperatively. CONCLUSION: The theoretical advantage of the MRI-LAARP is placing the neorectum through the entire sphincter complex without transecting the muscle. Follow-up of these patients shows good short-term results; however, long-term follow-up will be needed to best assess sphincter and bowel function.

Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model.

Feeding strategies to care for patients who transition from enteral nutrient deprivation while on total parenteral nutrition (TPN) to enteral feedings generally proceed to full enteral nutrition once the gastrointestinal tract recovers; however, an increasing body of literature suggests that a subgroup of patients may actually develop an increased incidence of adverse events, including death. To examine this further, we studied the effects of acute refeeding in a mouse model of TPN. Interestingly, refeeding led to some beneficial effects, including prevention in the decline in intestinal epithelial cell (IEC) proliferation. However, refeeding led to a significant increase in mucosal expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), as well as an upregulation in Toll-like receptor 4 (TLR-4). Refeeding also failed to prevent TPN-associated increases in IEC apoptosis, loss of epithelial barrier function, and failure of the leucine-rich repeat-containing G protein-coupled receptor 5-positive stem cell expression. Transitioning from TPN to enteral feedings led to a partial restoration of the small bowel microbial population. In conclusion, while acute refeeding led to some restoration of normal gastrointestinal physiology, enteral refeeding led to a significant increase in mucosal inflammatory markers and may suggest alternative strategies to enteral refeeding should be considered.

Bacterial nutrient foraging in a mouse model of enteral nutrient deprivation: insight into the gut origin of sepsis.

Total parenteral nutrition (TPN) leads to a shift in small intestinal microbiota with a characteristic dominance of Proteobacteria This study examined how metabolomic changes within the small bowel support an altered microbial community in enterally deprived mice. C57BL/6 mice were given TPN or enteral chow. Metabolomic analysis of jejunal contents was performed by liquid chromatography/mass spectrometry (LC/MS). In some experiments, leucine in TPN was partly substituted with [13C]leucine. Additionally, jejunal contents from TPN-dependent and enterally fed mice were gavaged into germ-free mice to reveal whether the TPN phenotype was transferrable. Small bowel contents of TPN mice maintained an amino acid composition similar to that of the TPN solution. Mass spectrometry analysis of small bowel contents of TPN-dependent mice showed increased concentration of 13C compared with fed mice receiving saline enriched with [13C]leucine. [13C]leucine added to the serosal side of Ussing chambers showed rapid permeation across TPN-dependent jejunum, suggesting increased transmucosal passage. Single-cell analysis by fluorescence in situ hybridization (FISH)-NanoSIMS demonstrated uptake of [13C]leucine by TPN-associated bacteria, with preferential uptake by Enterobacteriaceae Gavage of small bowel effluent from TPN mice into germ-free, fed mice resulted in a trend toward the proinflammatory TPN phenotype with loss of epithelial barrier function. TPN dependence leads to increased permeation of TPN-derived nutrients into the small intestinal lumen, where they are predominately utilized by Enterobacteriaceae The altered metabolomic composition of the intestinal lumen during TPN promotes dysbiosis.

Small Bowel Diameter in Short Bowel Syndrome as a Predictive Factor for Achieving Enteral Autonomy.

Children with short bowel syndrome commonly have dilated small bowel. We found that the extent of dilation was associated with bowel length and that both were related to achieving enteral autonomy.

TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways.

Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO-TPN mice and prevents mucosal atrophy. C57Bl/6 and strain-matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF-α decreased in TLR4KO-TPN versus wild-type (WT)-TPN mice. Apoptotic positive crypt cells were 15-fold higher in WT-TPN versus TLR4KO-TPN mice. Bcl-2 was significantly increased in TLR4KO-TPN mice, while Bax decreased 10-fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO-sTPN mice. TLR4 blockade significantly prevented TPN-associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF-α abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN-associated atrophy.

Tight Junction Ultrastructure Alterations in a Mouse Model of Enteral Nutrient Deprivation.

BACKGROUND: Total parenteral nutrition (TPN), a necessary treatment for patients who cannot receive enteral nutrition, is associated with infectious complications due in part to a loss of intestinal epithelial barrier function (EBF). Using a mouse model of TPN, with enteral nutrient deprivation, we previously demonstrated an increase in mucosal interferon-γ and tumor necrosis factor-α; these cytokine changes are a major mediator driving a reduction in epithelial tight junction (TJ) protein expression. However, the exact ultrastructural changes to the intestinal epithelial barrier have not been previously described. AIM: We hypothesized that TPN dependence results in ultrastructural changes in the intestinal epithelial TJ meshwork. METHODS: C57BL/6 mice underwent internal jugular venous cannulation and were given enteral nutrition or TPN with enteral nutrient deprivation for 7 days. Freeze-fracture electron microscopy was performed on ileal tissue to characterize changes in TJ ultrastructure. EBF was measured using transepithelial resistance and tracer permeability, while TJ expression was measured via Western immunoblotting and immunofluorescence staining. RESULTS: While strand density, linearity, and appearance were unchanged, TPN dependence led to a mean reduction in one horizontal strand out of the TJ compact meshwork to a more basal region, resulting in a reduction in meshwork depth. These findings were correlated with the loss of TJ localization of claudin-4 and tricellulin, reduced expression of claudin-5 and claudin-8, and reduced ex vivo EBF. CONCLUSION: Tight junction ultrastructural changes may contribute to reduced EBF in the setting of TPN dependence.

Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model. METHODS: A losartan analog, CCG-203025 (C23H26ClN3O5S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days. RESULTS: In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines. CONCLUSIONS: This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

Development of an operative suspension system for the performance of MRI-OR-guided laparoscopic anoplasty.

BACKGROUND: MRI-guided laparoscopic assisted anorectoplasty (MRI-LAARP), a new approach for surgical correction of high imperforate anus, does not bisect the sphincter complex as in the PSARP and is able to pull the neorectum through the entire sphincter complex unlike the LAARP. There is no available MRI-compatible device to position and transport patients during this procedure. We report on the design of such a device here. METHODS AND DEVICE: The device was constructed from 1.0″ polyvinylchloride tubing and poly-methyl methacrylate (Plexiglass(®)) platform. The device has a stable, rigid base on which platform is secure. An adjustable and removable superstructure is secured to this base to suspend legs for lithotomy position. RESULTS: MRI-LAARP has been performed on 6 patients. The device has performed well and meets requirements set forth in development including construction with MRI-compatible materials, size fitting in the MRI bore, ability to hold patient in lithotomy position, ability to position and support MRI flex coils, and providing stability while transporting to a separate OR with needle in position. CONCLUSIONS: This device provides a stable structure to position and transport a patient with a needle in a tenuous position without dislodgement allowing this procedure, and potentially other procedures, to be done in hospitals without MROR capability.

Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study.

OBJECTIVES: In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. STUDY DESIGN: A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. RESULTS: A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. CONCLUSIONS: A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

Intestine, immunity, and parenteral nutrition in an era of preferred enteral feeding.

PURPOSE OF REVIEW: To review the benefits of enteral nutrition in contrast to the inflammatory consequences of administration of parenteral nutrition and enteral deprivation. To present the most recent evidence for the mechanisms of these immunologic changes and discuss potential areas for modification to decrease infectious complications of its administration. RECENT FINDINGS: There is significant data supporting the early initiation of enteral nutrition in both medical and surgical patients unable to meet their caloric goals via oral intake alone. Despite the preference for enteral nutrition, some patients are unable to utilize their gut for nutritious gain and therefore require parenteral nutrition administration, along with its infectious complications. The mechanisms behind these complications are multifactorial and have yet to be fully elucidated. Recent study utilizing both animal and human models has provided further information regarding parenteral nutrition's deleterious effect on intestinal epithelial barrier function along with the complications associated with enterocyte deprivation. SUMMARY: Changes associated with parenteral nutrition administration and enteral deprivation are complex with multiple potential areas for modification to allow for safer administration. Recent discovery of the mechanisms behind these changes present exciting areas for future study as to make parenteral nutrition administration in the enterally deprived patient safer.

Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition.

Small intestine luminal nutrient sensing may be crucial for modulating physiological functions. However, its mechanism of action is incompletely understood. We used a model of enteral nutrient deprivation, or total parenteral nutrition (TPN), resulting in intestinal mucosal atrophy and decreased epithelial barrier function (EBF). We examined how a single amino acid, glutamate (GLM), modulates intestinal epithelial cell (IEC) growth and EBF. Controls were chow-fed mice, T1 receptor-3 (T1R3)-knockout (KO) mice, and treatment with the metabotropic glutamate receptor (mGluR)-5 antagonist MTEP. TPN significantly changed the amount of T1Rs, GLM receptors, and transporters, and GLM prevented these changes. GLM significantly prevented TPN-associated intestinal atrophy (2.5-fold increase in IEC proliferation) and was dependent on up-regulation of the protein kinase pAkt, but independent of T1R3 and mGluR5 signaling. GLM led to a loss of EBF with TPN (60% increase in FITC-dextran permeability, 40% decline in transepithelial resistance); via T1R3, it protected EBF, whereas mGluR5 was associated with EBF loss. GLM led to a decline in circulating glucagon-like peptide 2 (GLP-2) during TPN. The decline was regulated by T1R3 and mGluR5, suggesting a novel negative regulator pathway for IEC proliferation not previously described. Loss of luminal nutrients with TPN administration may widely affect intestinal taste sensing. GLM has previously unrecognized actions on IEC growth and EBF. Restoring luminal sensing via GLM could be a strategy for patients on TPN.

Surgical management and morbidity of pediatric magnet ingestions.

BACKGROUND: Foreign body ingestion remains a common reason for emergency room visits and operative interventions in the pediatric population. Rare earth magnet ingestion represents a low percentage of all foreign bodies swallowed by children; however, magnets swallowed in multiplicity can result in severe injuries. MATERIALS AND METHODS: Pediatric surgeons with membership in the Surgical Section of the American Academy of Pediatrics were surveyed to determine the magnitude and consequences of magnet ingestions in the pediatric population. RESULTS: About 100 (16%) participant responses reported on 99 magnet ingestions. The median age at ingestion was 3.7 y, and the majority of ingestions (71%) occurred after year 2010. Thirty-two children underwent endoscopy with successful removal in 70% of cases, and multiple magnets were found in 65% of these patients. Seventy-three children required either laparotomy (51) or laparoscopy (22) for magnet removal, and 90% of these children were discovered to have ingested more than one magnet. In addition, 17% of the children were found to have at least one perforation or fistula, and 34% of the children had multiple perforations or fistulae. Nine children required long-term care for their injuries including repeat endoscopies. One child died after hemorrhage from an esophago-aortic fistula. CONCLUSIONS: These results demonstrated the increasing need for magnet regulations and public awareness to prevent potentially serious complications.

The Impact of Pollution Prevention on Toxic Environmental Releases from U.S. Manufacturing Facilities.

Between 1991 and 2012, the facilities that reported to the U.S. Environmental Protection Agency's Toxic Release Inventory (TRI) Program conducted 370,000 source reduction projects. We use this data set to conduct the first quasi-experimental retrospective evaluation of how implementing a source reduction (pollution prevention) project affects the quantity of toxic chemicals released to the environment by an average industrial facility. We use a differences-in-differences methodology, which measures how implementing a source reduction project affects a facility's releases of targeted chemicals, relative to releases of (a) other untargeted chemicals from the same facility, or (b) the same chemical from other facilities in the same industry. We find that the average source reduction project causes a 9-16% decrease in releases of targeted chemicals in the year of implementation. Source reduction techniques vary in effectiveness: for example, raw material modification causes a large decrease in releases, while inventory control has no detectable effect. Our analysis suggests that in aggregate, the source reduction projects carried out in the U.S. since 1991 have prevented between 5 and 14 billion pounds of toxic releases.

Total parenteral nutrition-associated lamina propria inflammation in mice is mediated by a MyD88-dependent mechanism.

Enteral nutrient deprivation via total parenteral nutrition (TPN) administration leads to local mucosal inflammatory responses, but the underlying mechanisms are unknown. Wild-type (WT) and MyD88(-/-) mice underwent jugular vein cannulation. One group received TPN without chow, and controls received standard chow. After 7 d, we harvested intestinal mucosally associated bacteria and isolated small-bowel lamina propria (LP) cells. Bacterial populations were analyzed using 454 pyrosequencing. LP cells were analyzed using quantitative PCR and multicolor flow cytometry. WT, control mucosally associated microbiota were Firmicutes-dominant, whereas WT TPN mice were Proteobacteria-domiant. Similar changes were observed in MyD88(-/-) mice with TPN administration. UniFrac analysis showed divergent small bowel and colonic bacterial communities in controls, merging toward similar microbiota (but distinct from controls) with TPN. The percentage of LP T regulatory cells significantly decreased with TPN in WT mice. F4/80(+)CD11b(+)CD11c(dull/-) macrophage-derived proinflammatory cytokines significantly increased with TPN. These proinflammatory immunologic changes were significantly abrogated in MyD88(-/-) TPN mice. Thus, TPN administration is associated with significant expansion of Proteobacteria within the intestinal microbiota and increased proinflammatory LP cytokines. Additionally, MyD88 signaling blockade abrogated decline in epithelial cell proliferation and epithelial barrier function loss.

Anti-TNF-α treatment for post-anastomotic ulcers and inflammatory bowel disease with Crohn's-like pathologic changes following intestinal surgery in pediatric patients.

PURPOSE: To report a previously poorly recognized process of secondary formation of inflammatory bowel disease (IBD)-like process, specifically Crohn's-like changes in pediatric surgery patients who underwent major small bowel and colorectal surgery. We describe potential etiologies, presenting symptoms and treatment approaches. METHODS: Retrospective chart review of patients with history of either chronic, partial gastrointestinal (GI) obstruction or Hirschsprung disease (HD) and subsequent histopathologic findings similar to IBD. Pathology and case histories were reviewed and treatments were compared. RESULTS: Over the last 20 years, a total of nine patients were identified that had the diagnoses of either HD (n = 3) or chronic GI partial obstruction (n = 6) with subsequent development of histopathologic changes similar to those seen in IBD. Overall meantime to diagnosis of IBD-like changes after intestinal resection was 7.70 ± 5.6 years. Half of the patients were also being managed for short bowel syndrome (SBS), and associated GI symptoms may have prolonged the time to identifying these IBD-like changes. When SBS patients were excluded, mean time to IBD changes after pull through for HD was 2.4 ± 0.24 years and after chronic GI partial obstruction was 6.3 ± 2.1 years. Two of the nine patients who underwent a resection of this IBD-like lesion developed a recurrence of this lesion. Anti-TNF-α treatment was used in three of the GI partial obstruction cases: two with complete relief and one with partial response that was supplemented with steroids. Two HD patients were treated with anti-TNF-α and both had marked improvement of symptoms. CONCLUSION: We describe IBD-like intestinal changes following intestinal resection in the pediatric age group. We also present the novel finding that these lesions are responsive to anti-IBD treatment, including anti-TNF-α, and recommend it as part of the medical treatment regiment offered for such patients.