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Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

Admission hematocrit predicts the need for transfusion secondary to hemorrhage in pediatric blunt trauma patients.

BACKGROUND Pediatric trauma uses a substantial amount of resources. Quick and cost-effective measures that can be used to identify children with clinically relevant injuries are essential to resource allocation and optimization of patient care. Admission hematocrit is rapid and inexpensive, causes minimal harm, and can potentially aid in critical decision making. We hypothesize that admission hematocrit predicts the need for transfusion in pediatric blunt trauma patients. METHODS Records of trauma patients age 0 year to 17 years (2005–2013) who presented to a pediatric Level 1 trauma center were retrospectively reviewed. Data collected include demographics, computed tomographic scan findings, need for an intervention secondary to bleeding (blood transfusion, angioembolization, or operation), and admission hematocrit. RESULTS We found a significant decrease in admission hematocrit between patients requiring a transfusion and patients who did not (27% vs. 36%, p < 0.01). We evaluated a subset of patients who had an abdominal computed tomographic scan and found a significant decrease in admission hemocrit between those who required a transfusion for an intra-abdominal injury and those who did not (29% vs 37%, p < 0.01). In this subset, serial hematocrit values remained significantly lower in the patients requiring a transfusion up to 67 hours after admission (p = 0.04). A cutoff admission hematocrit of 35% or less has a sensitivity of 94% and a negative predictive value of 99.9% in identifying children who need a transfusion after blunt trauma. CONCLUSION An admission hematocrit of 35% or less provides a reliable screening test because of its low false negative rate and high specificity for identifying patients at an increased risk of bleeding after injury. Admission hematocrit could be widely implemented to identify patients who may need a transfusion with low expense and minimal harm for our pediatric patients and may be able to alter the entire course of their trauma resuscitation. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level III.

Doxycycline Sclerotherapy Is Superior in the Treatment of Pediatric Lymphatic Malformations

PURPOSE To evaluate efficacy of sclerotherapy with doxycycline versus sodium tetradecyl sulfate (STS) for treatment of macrocystic and mixed lymphatic malformations (LMs). MATERIALS AND METHODS This single-center retrospective review identified 41 children (17 boys; 24 girls; age range, 1 month to 15.4 y) who underwent sclerotherapy with doxycycline (n = 32) or STS (n = 9) for macrocystic (n = 31) or mixed (n = 10) LMs. There were 114 treatments performed, averaging 2.8 treatments (range, 1-8 treatments) per patient. Average follow-up time was 10 months (range, 1-59 months). Clinical response was deemed excellent or moderate if > 90% or > 50% of LMs resolved based on visual estimate. RESULTS With doxycycline, 87% of patients (28 of 32) had excellent or moderate response with an average of 2.8 treatments (range, 1-7 treatments); 13% required subsequent resection. With 3% STS monotherapy, only 55% of patients (5 of 9) had excellent or moderate response with an average of 2.8 treatments (range, 1-8 treatments), and 33% required subsequent resection. Significantly fewer patients treated with STS responded well compared with patients treated with doxycycline (P = .03). Patients treated with STS had significantly longer follow-up than patients treated with doxycycline (27 months vs 6 months, P = .0001). CONCLUSIONS Doxycycline monotherapy resulted in a high rate of excellent clinical outcomes after a few treatments without increased need for subsequent operative resection. These results support use of doxycycline sclerotherapy as primary treatment for macrocystic and mixed LMs in children.

Liquid chromatography–mass spectroscopy as a tool in the rapid diagnosis of biliary atresia: a pilot study

INTRODUCTION Biliary atresia (BA) is a neonatal obstructive cholangiopathy requiring rapid intervention to prevent end-stage liver failure and death. Low bile acid levels in stool, detectable with high-performance liquid chromatography-mass spectroscopy, may reflect extrahepatic biliary obstruction in cholestasis. HYPOTHESIS Stool bile acid content can differentiate BA from non-BA forms of cholestasis. METHODS Stool samples from four healthy and nine cholestatic patients were collected following internal review board approval. Bile acids were extracted and separated on a 4000-Q-Trap HPLC-MS system. RESULTS Total bile acid content was highest in samples from healthy relative to cholestatic patients: 3354.01 ± 2102.56, 1476.27 ± 1361.07, and 34.29 ± 10.30 μM/mg of stool in healthy, total parenteral nutrition-associated cholestasis, and BA samples, respectively. Mean cholic acid and chenodeoxycholic acid concentrations in healthy samples (2017.5 ± 1413.6 and 876.83 ± 660.60 μM/mg) were higher than in TPN cholestatic samples (93.99±131.55 and 232.34 ± 293.41 μM/mg). The most dramatic reduction in cholic acid and chenodeoxycholic acid was observed in BA samples (0.65 ± 0.47 and 1.22 ± 0.80 μM/mg). CONCLUSION Bile acid content in stool is reduced in cholestatic patients relative to healthy patients with the most dramatic reduction observed in BA-patients.