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The current obesity epidemic has led to a dramatic increase in insulin resistance and type 2 diabetes mellitus among adolescents, along with other obesity-related comorbidities, such as hypertension, hyperlipidemia, obstructive sleep apnea, psychosocial impairment and nonalcoholic fatty liver disease. Medical treatment of severe obesity is effective in only a small percentage of adolescent patients. In light of the potentially life-threatening complications of obesity, bariatric surgery can be considered a treatment option for adolescent patients with morbid obesity. Indications for surgery rely on both BMI and comorbidity criteria, as well as the ability of the adolescents and their family to understand and comply with perioperative protocols. The long-term effects of bariatric surgery in adolescents are not known; therefore, participation in prospective outcome studies is important. The risk associated with bariatric surgery in adolescents seems to be similar to that observed in adult patients in the short term. Data suggest that bypass procedures successfully reverse or improve abnormal glucose metabolism in the majority of patients and may be more effective in adolescents than adults. This improvement in glucose metabolism occurs before marked weight loss in patients undergoing bypass procedures, suggesting a direct effect on the hormonal control of glucose metabolism.

The intestinal epithelium is in a constant state of renewal. The rapid turnover of cells is fed by a hierarchy of transit amplifying and stem/progenitor cells destined to give rise to the four differentiated epithelial lineages of the small intestine. Doxorubicin (Dox) is a commonly used chemotherapeutic agent that preferentially induces apoptosis in the intestinal stem cell zone (SCZ). We hypothesized that Dox treatment would initially decrease "+4" intestinal stem cell numbers with a subsequent expansion during mucosal repair. Temporal assessment following Dox treatment demonstrated rapid induction of apoptosis in the SCZ leading to a decrease in the number of intestinal stem/progenitor cells as determined by flow cytometry for CD45(-) SP cells, and immunohistochemistry of cells positive for putative +4 stem cell markers beta-cat(Ser552) and DCAMKL1. Between 96 and 168 h postinjection, overall proliferation in the crypts increased concomitant with increases in both absolute and relative numbers of goblet, Paneth, and enteroendocrine cells. This regeneration phase was also associated with increases of CD45(-) SP cells, beta-cat(Ser552)-positive cells, crypt fission, and crypt number. We used Lgr5-lacZ mice to assess behavior of Lgr5-positive stem cells following Dox and found no change in this cell population. Lgr5 mRNA level was also measured and showed no change immediately after Dox but decreased during the regeneration phase. Together these data suggest that, following Dox-induced injury, expansion of intestinal stem cells occurs during mucosal repair. On the basis of available markers this expansion appears to be predominantly the +4 stem cell population rather than those of the crypt base.

The epithelial cell lining of the gastrointestinal tract is the most rapidly proliferating tissue in the body. The constant state of renewal of differentiated epithelial cells is sustained by a continual supply of progeny from multipotent progenitors that originate from stem cells located within the intestinal crypts. In addition to supporting normal epithelial homeostasis, intestinal stem cells (ISC) are thought to play an important role in the rapid expansion of the gut during development, tissue regeneration following injury or surgical loss, and malignancy. Because of the lack of specific ISC markers required to isolate and characterize these cells, our current knowledge of the biology of ISC results largely from indirect measures of their behavior published during the past 40 years. The recent description of several potential ISC markers and the use of transgenic mice, both as a tool to lineage trace and to isolate specific cells expressing these markers, have provided a tremendous advancement to our current understanding of these cells. This brief review provides a general historical overview of our understanding of ISC and the tools available to study their behavior in the context of normal and pathological conditions, as well as potential future clinical applications that may result from this exciting area of research.

Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated beta-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.

Objectives: Type 2 diabetes mellitus is associated with obesity, dyslipidemia, and hypertension, all well-known risk factors for cardiovascular disease. Surgical weight loss has resulted in a marked reduction of these risk factors in adults. We hypothesized that gastric bypass would improve parameters of metabolic dysfunction and cardiovascular risk in adolescents with type 2 diabetes mellitus., Patients and Methods: Eleven adolescents who underwent Roux-en-Y gastric bypass at 5 centers were included. Anthropometric, hemodynamic, and biochemical measures and surgical complications were analyzed. Similar measures from 67 adolescents with type 2 diabetes mellitus who were treated medically for 1 year were also analyzed., Results: Adolescents who underwent Roux-en-Y gastric bypass were extremely obese (mean BMI of 50 +/- 5.9 kg/m(2)) with numerous cardiovascular risk factors. After surgery there was evidence of remission of type 2 diabetes mellitus in all but 1 patient. Significant improvements in BMI (-34%), fasting blood glucose (-41%), fasting insulin concentrations (-81%), hemoglobin A1c levels (7.3%-5.6%), and insulin sensitivity were also seen. There were significant improvements in serum lipid levels and blood pressure. In comparison, adolescents with type 2 diabetes mellitus who were followed during 1 year of medical treatment demonstrated stable body weight (baseline BMI: 35 +/- 7.3 kg/m(2); 1-year BMI: 34.9 +/- 7.2 kg/m(2)) and no significant change in blood pressure or in diabetic medication use. Medically managed patients had significantly improved hemoglobin A1c levels over 1 year (baseline: 7.85% +/- 2.3%; 1 year: 7.1% +/- 2%)., Conclusions: Extremely obese diabetic adolescents experience significant weight loss and remission of type 2 diabetes mellitus after Roux-en-Y gastric bypass. Improvements in insulin resistance, beta-cell function, and cardiovascular risk factors support Roux-en-Y gastric bypass as an intervention that improves the health of these adolescents. Although the long-term efficacy of Roux-en-Y gastric bypass is not known, these findings suggest that Roux-en-Y gastric bypass is an effective option for the treatment of extremely obese adolescents with type 2 diabetes mellitus.

Background: Bile acid (BA) reclamation following ileo-cecal resection (ICR) may prevent colonic mucosa from chronic injury. In this study, we hypothesized that in a murine model of ICR the remnant colon would upregulate the cellular machinery necessary for BA reclamation and would do so in an FXR- and bacteria-dependent manner., Methods: Conventional (WT), conventional FXR knockout (FXR null) and germ-free (GF) mice were randomized to undergo either ICR or sham operation. The ascending colon was harvested for histology and immunohistochemistry and changes in bile acid homeostatic gene expression determined by real-time polymerase chain reaction (RT-PCR) 7 days following surgery., Results: Following ICR WT mice showed significant increases in the expression of genes regulating bile acid transport including IBABP, Asbt, Ost beta and FGF 15. Increased expression of IBABP and Asbt was confirmed by immunohistochemistry. Induction of bile acid transport genes was absent or attenuated in FXR null and GF mice., Conclusion: Bacterial dependent up regulation of IBABP is FXR mediated in the colon following ICR. Mice lacking microbiota (GF) or FXR are unable to increase the expression of IBABP or FGF 15.

This paper documents educational material presented at a joint IPEG/SAGES session entitled Challenges of Adolescent Bariatric Surgery at the IPEG/SAGES annual meeting in April 2006. This session was primarily intended for surgeons not actively engaged in adolescent bariatric surgery. The individual topics presented vary widely and were chosen in an effort to highlight important areas of clinical controversy, surgical complexity, and research opportunities. This case-based session was conducted using an interactive audience response system to capture live feedback from the attendees. Questions posed to the audience and their responses (with the number of responses) are provided. Results of the audience poll are presented for interest only and do not represent a scientifically valid consensus of IPEG members. The text is written in a dialog-type format to better represent the essence of the session and the context in which it was presented. Finally, the views and opinions expressed in this paper reflect the balanced examination of various issues related to pediatric bariatric surgery by the presenters but do not necessarily represent the opinions of the IPEG organization.

Sustained increases in mucosal surface area occur in remaining bowel following massive intestinal loss. The mechanisms responsible for expanding and perpetuating this response are not presently understood. We hypothesized that an increase in the number of intestinal stem cells (ISC) occurs following intestinal resection and is an important component of the adaptive response in mice. This was assessed in the jejunum of mice 2-3 days, 4-5 days, 6-7 days, 2 wk, 6 wk, and 16 wk following ileocecal resection (ICR) or sham operation. Changes in ISC following ICR compared with sham resulted in increased crypt fission and were assayed by 1) putative ISC population (SP) by flow cytometry, 2) Musashi-1 immunohistochemistry, and 3) bromodeoxyuridine (BrdU) label retention. Observed early increases in crypt depth and villus height were not sustained 16 wk following operation. In contrast, long-term increases in intestinal caliber and overall number of crypts per circumference appear to account for the enhanced mucosal surface area following ICR. Flow cytometry demonstrated that significant increases in SP cells occur within 2-3 days following resection. By 7 days, ICR resulted in marked increases in crypt fission and Musashi-1 immunohistochemistry staining. Separate label-retention studies confirmed a 20-fold increase in BrdU incorporation 6 wk following ICR, confirming an overall increase in the number of ISC. These studies support that expansion of ISC occurs following ICR, leading to an overall increase number of crypts through a process of fission and intestinal dilation. Understanding the mechanism expanding ISCs may provide important insight into management of intestinal failure.

Purpose of Review: Pneumonia in children is frequently complicated by pleural effusions, which rarely progress to empyema. Appropriate clinical management depends on correctly diagnosing the stage of the disease process. Recently, increasing use of video-assisted thoracic debridement has altered the traditional management of pleural effusions and empyema in children, resulting in decreasing reliance on thoracentesis and earlier surgical intervention., Recent Findings: We review the current literature supporting the clinical indications for video-assisted thoracic debridement compared with traditional management, including the use of thoracentesis, chest tube placement, fibrinolytic therapy and open thoracotomy in children with empyema. Recent studies support the early application of video-assisted thoracic debridement in children with empyema compared with traditional therapy, as it decreases the number of procedures and studies performed and the duration of chest tube drainage and is associated with less pain and shorter recovery period than open thoracotomy., Summary: We propose a clinical algorithm supporting the early use of video-assisted thoracic debridement in the management of empyema in children.

Background & Aims: Math1 (Atoh1) is a basic helix-loop-helix transcription factor important for intestinal secretory cell differentiation. We hypothesized that Math1 is important in cell fate commitment, and therefore mediates proliferative homeostasis and the adaptive response following intestinal resection in the adult intestine., Methods: We generated mice with an intestine-specific mosaic deletion of Math1 (Math1(Delta intestine)) using the Cre/loxP system. Histologic analysis in adult Math1(Delta intestine) and wild-type littermates at baseline and following small bowel resection or sham surgery was performed., Results: We observed loss of Paneth, goblet, and enteroendocrine cells in Math1-null crypts. In addition, aberrant activation of the Math1 promoter occurred in absorptive enterocytes derived from Math1-null crypts, suggesting a change in cell fate. Proliferation was increased but apoptosis unchanged in Math1-mutant crypts compared to adjacent wild-type crypts. Math1(Delta intestine) mice and wild-type littermates displayed similar physiologic adaptive responses to small bowel resection as measured by changes in body weight and ileal wet weight. In contrast, Math1-mutant crypts displayed a blunted adaptive response compared to adjacent wild-type crypts., Conclusions: We show that Math1 is essential for adult intestinal secretory cell production, and in its absence cells destined to a secretory phenotype instead adopt an absorptive phenotype. Subtle abnormalities of proliferation within Math1-null crypts in Math1(Delta intestine) mice were identified, together with a substantial defect in the adaptive response of Math1-null crypts following small bowel resection. Our results suggest that Math1 is critical for both cell fate determination within the intestinal epithelium and for regulation of the response to intestinal resection.

Following massive small bowel resection (SBR) in mice, there are sustained increases in crypt depth and villus height, resulting in enhanced mucosal surface area. The early mechanisms responsible for resetting and sustaining this increase are presently not understood. We hypothesized that expansion of secretory lineages is an early and sustained component of the adaptive response. This was assessed in the ileum by quantitative morphometry at 12 h, 36 h, 7 days, and 28 days and by quantitative RT-PCR of marker mRNAs for proliferation and differentiated goblet, Paneth cell, and enterocyte genes at 12 h after 50% SBR or sham operation. As predicted, SBR elicited increases of both crypt and villus epithelial cells, which were sustained though the 28 days of the experiment. Significant increases in the overall number and percentage of both Paneth and goblet cells within intestinal epithelium occurred by 12 h and were sustained up to 28 days after SBR. The increases of goblet cells after SBR were initially observed within villi at 12 h, with marked increases occurring in crypts at 36 h and 7 days. Consistent with this finding, qRT-PCR demonstrated significant increases in the expression of mRNAs associated with proliferation (c-myc) and differentiated goblet cells (Tff3, Muc2) and Paneth cells (lysozyme), whereas mRNA associated with differentiated enterocytes (sucrase-isomaltase) remained unchanged. From these data, we speculate that early expansion of intestinal secretory lineages within the epithelium of the ileum occurs following SBR, possibly serving to amplify the signal responsible for initiating and sustaining intestinal adaptation.

Glucagon-like peptide-2 (GLP-2) is a gut hormone that is secreted in response to enteral feeding and stimulates small intestinal mucosal growth. We have previously shown that GLP-2 infusion acutely increases portal venous blood flow in TPN-fed piglets. The aim of this study was to localize the vasoactive effect of GLP-2 within the gastrointestinal tissues and other visceral organs in TPN-fed piglets. Tissue blood flow rates were quantified using fluorescent microsphere deposition in anesthetized TPN-fed piglets given intravenous infusion of GLP-2 at either 500 pmol x kg(-1) x h(-1) (low GLP-2, n = 7 pigs) or 2,000 pmol x kg(-1) x h(-1) (high GLP-2, n = 8 pigs) for 2 h. Compared with baseline, the low and the high GLP-2 treatment significantly increased the blood flow rate in the duodenum (+77%) and jejunum (+40% and 80%), respectively, but blood flow to the distal small intestine and colon (-15%) was unchanged or slightly decreased. Baseline mucosal blood flow was five-fold higher than serosal blood flow; however, high GLP-2 treatment increased serosal (+140%) to a larger degree than mucosal blood flow (+73%). The high GLP-2 dose increased pancreatic flow (+34%) but decreased blood flow in the kidneys (-14%) and stomach (-12%), whereas the spleen and brain were unaffected. These findings suggest that the acute GLP-2-mediated stimulation of portal blood flow in TPN-fed piglets occurs principally via increased blood flow through the superior mesenteric artery to the proximal small intestine, a tissue region where the GLP-2R mRNA abundance and trophic GLP-2 effects are greatest.

The etiology of ovarian cysts varies with the developmental stage and hormonal milieu of the patient. In general, most ovarian cysts are functional in nature and usually resolve without treatment. Treatment is indicated if the diagnosis is in question, the cyst persists, or the patient is symptomatic. Laparoscopy has become the approach favored by most pediatric surgeons for the treatment of ovarian cysts. All surgical procedures for ovarian cysts should spare functional ovary as much as is technically possible. Simple cysts should be fenestrated. Complex or functional cysts should be excised, with preservation of the remaining ovary.

Objective: Necrotizing enterocolitis (NEC), a serious multisystemic inflammatory disease most commonly seen in premature neonates, is often associated with thrombocytopenia. Infants with severe forms of NEC commonly have platelet counts of less than 50,000/mm(3), occasionally less than 10,000/mm(3). Despite an absence of data to support the practice, platelet transfusions are commonly used to maintain a certain arbitrary platelet count in an effort to prevent bleeding. As platelet transfusions contain a variety of bioactive factors including pro-inflammatory cytokines, we hypothesized that a higher number and volume of platelet transfusions would not be associated with an improvement in mortality or morbidity., Study Design: A retrospective cohort analysis was conducted of the medical records of all infants between 1997 and 2001 with Bell's Stage 2 or 3 NEC associated with platelet counts of <100,000/mm(3). The medical records were evaluated for the following variables: platelet counts, number and volume of platelet transfusions, symptoms of bleeding, and hospital course. Mortality and development of short bowel syndrome and/or cholestasis were correlated to the total number and volume (total ml and ml/kg) of platelet transfusions. Differences between the outcome groups were compared using the independent t-test, Fisher's exact test and Mann-Whitney tests., Results: A total of 46 infants met the study criteria (gestational age 28+/-4 weeks and birth weight 1166+/-756 g, mean+/-SD). There were a total of 406 platelet transfusions administered to the study population. Of these, 151 (37.2%) were given in the presence of active bleeding, with 62% of these resulting in the cessation of bleeding within 24 hours. Other listed indications for platelet transfusions were hypovolemia and severe thrombocytopenia. On analysis of the entire cohort, there was no statistical improvement in either mortality or morbidity (short bowel syndrome and cholestasis) with greater number and/or volume of platelet transfusions. Furthermore, we found that infants who developed short bowel syndrome and/or cholestasis had been given a significantly higher number and volume of platelet transfusions when compared to those who did not have these adverse outcomes [median (minimum - maximum) - number of transfusions : 9 (0 to 33) vs 1.5 (0 to 20), p=0.010; volume of transfusions (ml/kg): 121.5 (0 to 476.6) vs 33.2 (0 to 224.3), p=0.013]., Conclusion: This retrospective analysis suggests that greater number and volume of platelet transfusions in infants with necrotizing enterocolitis are associated with greater morbidity in the form of short bowel syndrome and/or cholestasis without the benefit of lower mortality.

Objective: Necrotizing enterocolitis (NEC) is a common and serious gastrointestinal disorder that predominately affects premature infants. Few prognostic indices are available to guide physicians through the expected course of the disease. We hypothesized that the degree and timing of onset of severe thrombocytopenia (platelet count <100,000/mm(3)) would be a predictor of adverse outcome and an indication for surgical intervention in infants with NEC., Study Design: The clinical presentation and outcome of all infants with Bell stage II or III NEC treated at Texas Children's Hospital between 1997 and 2001 were retrospectively reviewed. Patients were stratified into two groups based on the presence (Group1) or absence (Group 2) of severe thrombocytopenia (platelet count <100,000/mm(3)) within 3 days of a diagnosis of NEC. Differences between groups were compared using logistic regression to estimate adjusted odds ratios., Results: A total of 91 infants met inclusion criteria (average birth weight 1288+/-135 g; average gestational age 29.0+/-3.0 weeks). Compared to infants in Group 2, infants in Group 1 were more premature (28.0+/-4.1 vs 30.0+/-4.2 weeks; p=0.02), more likely to have received postnatal steroids (42.5% vs 20.4%; p=0.02), and more likely to require laparotomy for gangrenous bowel (adjusted OR 16.33; p<0. 001). The presence of severe thrombocytopenia was also a predictor of mortality (adjusted OR 6.39; p=0.002) and NEC-related gastrointestinal complications including cholestatic liver disease and short bowel syndrome (adjusted OR 5.47; p=0.006)., Conclusion: Severe thrombocytopenia within the first 3 days after a diagnosis of NEC suggests a higher likelihood of bowel gangrene, morbidity, and mortality. Prospective studies of infants with early and severe thrombocytopenia may help determine the optimal timing of laparotomy in infants with NEC.

As the prevalence of obesity and obesity-related disease among adolescents in the United States continues to increase, physicians are increasingly faced with the dilemma of determining the best treatment strategies for affected patients. This report offers an approach for the evaluation of adolescent patients' candidacy for bariatric surgery. In addition to anthropometric measurements and comorbidity assessments, a number of unique factors must be critically assessed among overweight youths. In an effort to reduce the risk of adverse medical and psychosocial outcomes and increase compliance and follow-up monitoring after bariatric surgery, principles of adolescent growth and development, the decisional capacity of the patient, family structure, and barriers to adherence must be considered. Consideration for bariatric surgery is generally warranted only when adolescents have experienced failure of 6 months of organized weight loss attempts and have met certain anthropometric, medical, and psychologic criteria. Adolescent candidates for bariatric surgery should be very severely obese (defined by the World Health Organization as a body mass index of > or =40), have attained a majority of skeletal maturity (generally > or =13 years of age for girls and > or =15 years of age for boys), and have comorbidities related to obesity that might be remedied with durable weight loss. Potential candidates for bariatric surgery should be referred to centers with multidisciplinary weight management teams that have expertise in meeting the unique needs of overweight adolescents. Surgery should be performed in institutions that are equipped to meet the tertiary care needs of severely obese patients and to collect long-term data on the clinical outcomes of these patients.