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Introduction: Our previous work demonstrated that the transforming-growth factor (TGF) β pathway plays a central role in the liver fibrosis associated with experimental biliary atresia (BA). To confirm these findings in humans, we performed an in silico analysis of publicly available microarray data from liver specimens from children with BA, with the hypothesis that the TGF-β pathway would be dysregulated., Methods: We analyzed publicly available liver gene expression microarray data from 47 infants with BA. We re-analyzed the microarray image files and clinical data to compare gene expression differences between the fibrogenic and inflammatory cohorts identified in the initial study. Targets from the microarray analysis were confirmed using the animal model of BA., Results: Analysis of variance (ANOVA) detected 6903 transcripts (2822 distinct genes) differentially regulated between groups (p < 0.01; fold change >1.2). We used a targeted approach to identified a subgroup of 24 TGF-β-related transcripts. Expressions for procollagen transcripts were increased in the fibrogenic group (1.2-fold to 1.4-fold); expression of matrix metalloproteinase (MMP)-7 was similarly increased 2-fold, while MMP-9 and plasminogen activator inhibitor-1 were decreased 2-fold and 3-fold respectively. Integrins β5 (1.18-fold) and β8 (1.84-fold) also demonstrated increased expression in the fibrogenic group. Increased expression of β5 (3-fold) and β8 (5-fold) as well as Smad-3 (4-fold) and Smad interacting protein (SIP)-1 (3.5-fold) mRNA was confirmed in experimental BA. Phosphorylated Smad-3 protein in the experimental group was also nearly twice that of the control group, further implicating the TGF-β pathway., Conclusion: Gene transcripts for known upstream and downstream TGF-β mediators are differentially expressed in liver specimens from children with BA and a fibrogenic gene signature. The same integrins that were dysregulated in the human specimens were also found to be up-regulated in our animal BA model, as were other intermediaries in the TGF-β pathway. Further investigation into whether these mediators may be attractive targets for future therapy in children with BA is warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Obesity has been identified as one of the most important public health concerns in both children and adolescents. Unfortunately, even the most comprehensive and aggressive multidisciplinary weight management programs have shown only modest weight loss results. There has been increasing enthusiasm for bariatric surgery for adolescent patients with morbid obesity. Because of the relatively high morbidity and mortality associated with gastric bypass surgery, we have begun to explore laparoscopic sleeve gastrectomy as an alternative. We hypothesized that it would be a safe and effective short-term strategy., Methods: We have prospectively collected data from all patients undergoing bariatric surgery at our institution since the inception of our adolescent weight loss surgery program in January 2010. Baseline data collected included age, gender, race/ethnicity, height, weight, body mass index, and comorbid conditions. Postoperative data collected included the type of operation, length of stay, operative morbidity, the need for reoperation, and percent excess weight loss and body mass index at 3-month intervals., Results: Twenty-three patients have undergone laparoscopic sleeve gastrectomy at our institution since January 2010. Of these, 18 were female and 5 were male. The mean age was 17.3 ± 1.5 years of age. The mean preoperative weight was 149 ± 30 kg with a body mass index of 52 ± 9 kg/m(2). There were no intraoperative complications, and the only postoperative complication has been pancreatitis in 1 patient. The mean length of stay was 2.2 ± 1.1 days. The mean follow-up was 10.9 ± 7.4 months. The percent excess weight loss at 3 months, 6 months, and 1 year postoperatively was 32%, 38%, and 40%, respectively, in those who had reached these time points., Conclusion: Laparoscopic sleeve gastrectomy is a safe operation for adolescent patients with morbid obesity and represents an effective early treatment strategy with approximately 40% excess weight loss at 6 months and 1 year of follow-up. Because of the minimal morbidity associated with laparoscopic sleeve gastrectomy, it may be the optimal non-device surgical option for this select group of adolescent patients., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: As the Fundamentals of Research and Career Development Course (FRCDC) is conducted internationally, questions have arisen regarding the cultural appropriateness of the United States (US) course. We therefore assessed the US-based teaching methodology during the FRCDC in Abuja, Nigeria. We hypothesized that the US-based instructional methods would be effective., Methods: Twenty questions were distributed to attendees of the FRCDC prior to commencement. The same 20 questions were administered at the conclusion of the course after random reordering. Differences between the pre- and post-test results were assessed for normalcy and compared using the paired t-test., Results: There were 89 attendees, of whom 60 completed the pre-test and 77 completed the post-test. The pre-test group answered 12.3 ± 2.6 questions correctly, which improved to 15.0 ± 2.6 in the post-test group (P < 0.001). On the pre-test, the least common correct answers were for questions regarding type 1 and 2 error (16.7% correct), the definition of health services and outcomes research (26.7%), and how to best address missing data (26.7%). On the post-test, the questions with the least common correct answers were regarding the definition of health services and outcomes research (35%), and the components of an NIH grant (37.7%)., Conclusions: Our results suggest that the FRCDC in Nigeria as given by US faculty has short-term efficacy. Attendees were able to improve their scores despite the cultural differences between them and the lecturers. Our next goal will be to demonstrate long-term efficacy at future courses in the region using similar questionnaire strategies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The inaugural Fundamentals of Surgical Research Course was held in Sierra Leone in conjunction with the West African College of Surgeons (WACS). We subsequently performed a formal assessment of the academic needs of West African surgeons to plan for future courses, and hypothesized that they would differ from the goals of the U.S. course., Methods: A survey was distributed via email to members of the WACS and returned by the same mechanism. It consisted of 6 questions addressing specific elements of the inaugural course, and potential new topics for future courses., Results: Over half (53%, 25/47) of the respondents had not attended the inaugural course, while 85% (40/47) planned on attending the next course. Respondents identified least useful topics from the initial course as "Molecular Biology: Tools of the Trade" (45%, 21/47) and "Getting Promoted" (23%, 11/47). The least popular potential new topics were "Use and Abuse of Administrative Databases" (9%, 4/47), "Animal Models" (21%, 10/47), and "Genomics and Proteomics" (21%, 10/47)., Conclusions: The self-reported academic needs of West African surgeons are oriented toward clinical research. Basic and translational research topics are of secondary interest to the majority of respondents. Future courses in this region must address specific local needs., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Hepatic fibrosis leading to cirrhosis is the major morbidity in patients with biliary atresia (BA). This fibrosis is due to an imbalance in extracellular matrix (ECM) breakdown and deposition. We have previously demonstrated increased mRNA expression for inhibitors of ECM breakdown without increased expression for mediators of ECM deposition in our animal model of BA by d 14. However, only a mild degree of hepatic fibrosis was seen at this time. We hypothesized that expression patterns for these proteins may change once more significant fibrosis had been established, and added resuscitation to the model to improve survival. Interestingly, we found that some mice spontaneously recovered at later time points with resuscitation, and thus compared expression for inhibitors of ECM breakdown and deposition in sick and recovered mice to determine the differences., Methods: Newborn Balb/c mice received an intraperitoneal injection 1.0 x 10(6) fluorescence forming units of rhesus rotavirus 24h after birth. Mice were monitored daily for weight gain, development of jaundice, acholic stools, and bilirubinuria. Fifty muL/g of 5% dextrose in normal saline were subcutaneously injected daily to each mouse starting on d 7 until sacrifice. Mice that survived past d 14 were sacrificed at d 21 after saline or RRV infection. Livers were then harvested post-injection d 21 for histologic and immunohistochemical analysis. RNA expression of known mediators of fibrosis was evaluated using quantitative real-time PCR. Protein expression was assessed using ELISA. Weights and normally distributed data were compared using Student's t test. Histologic findings were compared using Fisher's exact test. Comparisons of gene expression and skewed data were performed by the Mann-Whitney U test. Statistical significance was assigned to any P value less than 0.05., Results: Daily resuscitation resulted in a 35% (24/68) survival rate to d 21 in our model. Mice that recovered were significantly heavier than those that remained ill on d 14 (6.15 +/- 1.16 versus 4.94 +/- 0.82, P = 0.02) and 21 (7.31 +/- 1.41 versus 4.14 +/- 0.53, P < 0.001) despite the fact that there was no difference between the groups with respect to weight on d 7 (4.29 +/- 0.90 versus 3.89 +/- 0.81, P = 0.32). We found that all (10/10) animals that displayed clinical signs of biliary atresia on d 21 had moderate or severe histologic findings, while only one (1/9) of the recovered animals had liver abnormalities at sacrifice (P < 0.001 versus sick group). We also found that the sick mice had statistically significant median fold-increases of mRNA expression for TIMP-1 (31.9 versus 9.1, P = 0.041), TIMP-4 (88.1 versus 1.8, P = 0.022), and MMP-7 (51.8 versus 11.9, P = 0.006) compared with those that recovered. There was a trend toward decreased mRNA expression for PAI-1, which did not reach statistical significance (median 27.7 versus 2.19, P = 0.066). Increased protein expression for TIMP-1 and PAI-1 were also found in the sick group. The mRNA expression for the fibrillar collagens, fibronectin-1, connective tissue growth factor, snail-1, TIMP-2 and -3, and MMP-2 and MMP-9 was not different in the sick and recovered groups 21 d after RRV infection, and was not elevated from baseline gene expression., Conclusions: With resuscitation added to the animal model of BA, some mice spontaneously recover while others progress to more significant hepatic fibrosis. Mice with hepatic fibrosis have a continued increase in mRNA expression of TIMP-1, TIMP-4, and MMP-7, with a trend toward increased mRNA expression of PAI-1 on d 21. Protein levels for TIMP-1 and PAI-1 were also increased in the sick mice. Recovered mice display mild to no hepatic parenchymal disease and a normal pattern of mRNA expression for the mediators of fibrosis tested. No increase in mRNA expression for the mediators of ECM deposition was found in either group. These data further support the notion that inhibition of ECM breakdown alone is sufficient to induce hepatic fibrosis. Modulation of this process may be a putative target for preventing liver injury in patients with BA.

Background: The distribution of weight loss and its impact on metabolic health has not been documented for laparoscopic adjustable gastric banding (LAGB) in the adolescent population. We hypothesized that LAGB in obese adolescents would result in loss of android fat mass, resolution of comorbidities, and improvement in metabolic status., Study Design: Adolescents ages 14 to 17 who met criteria for bariatric surgery were enrolled in our FDA-approved LAGB trial. Demographic data, body mass index, body composition and bone density, laboratory evaluations, and comorbid conditions were assessed pre- and postoperatively., Results: Forty-five patients had complete 1-year followup and 41 patients had complete 2-year followup. Mean preoperative weight was 299 + or - 57 lb and body mass index was 48 + or - 6.4 kg/m(2). The percent excess weight losses at 6 months, 1 year, and 2 years were 31 + or - 16, 46 + or - 21, and 47 + or - 22, respectively. At 1-year followup, patients after LAGB had a significant decrease in their total and android fat mass. In addition, 47 of 85 identified comorbidities (55%) were completely resolved and 25 (29%) were improved in comparison with baseline. Improvements in alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, hemoglobin A1c, fasting insulin, triglycerides, and high density lipoprotein, were also seen., Conclusions: The percent excess weight loss after LAGB in morbidly obese adolescents is approximately 45% at 1- and 2-year followup, with the majority of weight loss consisting of android fat mass. Resolution or improvement of comorbidities is seen, and improved metabolic status, as demonstrated by liver function tests, lipid levels, and measures of glucose homeostasis, may be expected. These data support LAGB as an appropriate surgical option for morbidly obese adolescents.

Purpose: Some have suggested that the criteria for weight loss surgery in adolescents be stricter than those currently recommended for adults by the National Institutes of Health (NIH). The aim of the current study is to define the characteristics of adolescents who meet NIH consensus criteria for bariatric surgery in adults to determine their level of morbidity., Materials and Methods: Using the Medical Expenditure Panel Survey 2000-2004, children designated as meeting NIH criteria were 13 to 17 years of age with (1) a body mass index >or=40 or (2) a body mass index >35, and one or more comorbidity. We contrasted surgery candidates with noncandidates. We examined items that comprise a screener for identifying children with special health care needs. The Columbia Impairment Scale (CIS) was used to assess child functioning., Results: There were 134 children identified as candidates for bariatric surgery and 4736 noncandidates in the same age range. Candidates were more likely to have special health care needs (36% vs 23%) and more likely to have a CIS above 16 (34% vs 16%). Candidates for weight loss surgery were 2.36 times as likely to have a CIS score of 16 or higher and 1.87 times as likely to be identified as a child with special health care needs (P

Introduction: Biliary atresia (BA) is a progressive obliteration of the extrahepatic bile ducts resulting in hepatic fibrosis. The underlying mechanisms have not been defined. We used an animal model of BA to evaluate mediators of extracellular matrix (ECM) processing to determine which factors may be involved., Methods: Newborn BALB/c mice received an intraperitoneal injection with rhesus rotavirus or saline within 24 h of birth. Livers were harvested on days 7 and 14 for histology and immunohistochemistry (IHC). RNA expression was determined using quantitative real-time PCR. Human liver from patients with BA and those having a resection for nonfibrosing diseases was also evaluated., Results: In experimental mice, mRNA expression for tissue inhibitor of metalloproteinase (TIMP)-1 and matrix metalloproteinase (MMP)-7 was increased 18-fold and 69-fold, respectively on day 7, with further increases on day 14. On day 14, mRNA expression for plasminogen activator inhibitor (PAI)-1 (38-fold), TIMP-4 (9.5-fold), and MMP-9 (5.5-fold) mRNA was also observed. Furthermore, integrin alpha(v) beta(6) mRNA expression was increased on days 7 (11-fold) and 14 (6-fold). Presence of integrin alpha(v) beta(6) protein was confirmed by IHC in both mouse and human specimens in the proliferating biliary epithelium., Conclusions: Our data suggest experimental BA is associated with increased mRNA expression of ECM degradation inhibitors, TIMP-1, PAI-1, and TIMP-4. MMP-7 and MMP-9 expression is also elevated in this model. Furthermore, increased gene expression of integrin alpha(v)beta(6) was demonstrated and IHC confirmed protein expression. Integrin alpha(v)beta(6) or the inhibitors of ECM breakdown may be attractive targets for future treatment strategies.

Background: The Surgical Infection Society published their most recent recommendations for antimicrobial therapy in patients with intra-abdominal infections in 2002. These guidelines outlined several important considerations for the treatment of such infections, including which patients require antimicrobial agents, the appropriate duration of treatment, which antimicrobial regimens are appropriate, and the risk factors and indications for intensified regimens. However, the applicability of these recommendations to the pediatric population is not entirely clear., Methods: Systematic review of all literature regarding antimicrobial therapy in the most common intra-abdominal infection in children, appendicitis, with the goal of establishing guidelines for use., Results: Children with uncomplicated (acute or gangrenous), but not perforated, appendicitis can be treated with prophylactic antimicrobial agents for 24 h or less. Children with perforated appendicitis can be treated after appendectomy in the same manner as adults with established intra-abdominal infections; i.e., with therapeutic antibiotics until no clinical evidence of infection exists. This is true after both laparoscopic and open operations. Whereas "triple" antibiotic therapy has been the gold standard in pediatric patients, monotherapy with broad-spectrum agents is equally effective and possibly more cost-effective. The nonoperative management of perforated appendicitis with interval appendectomy represents a unique problem, and guidelines for therapy are less well established., Conclusions: The evidence supports using guidelines in the pediatric population similar to those suggested for the adult population for the management of acute appendicitis.

Background: Adolescent obesity continues to present one of the most difficult and important challenges for both the pediatric and adult medical communities. Evidence is mounting that bariatric surgery is the only reliable method for substantial and sustainable weight loss; however, the debate continues with regard to the optimal surgical procedure for both adolescents and adults. Although most US adult bariatric surgeons prefer the gastric bypass, our institution has demonstrated equivalent weight loss with significantly less morbidity using laparoscopic adjustable gastric banding (LAGB) in both adults and adolescents. This analysis is an update of our results in our first 73 patients, including resolution of comorbid conditions and compliance data., Methods: All adolescents aged 13 to 17 years who have undergone LAGB at our institution have been entered into our prospectively collected database since September 2001 and were reviewed. Data collected preoperatively included age, sex, race, body mass index (BMI), and presence of comorbid conditions. Postoperatively recorded data included length of stay, operative morbidity, need for reoperation, percentage of excess weight loss (%EWL), and BMI at 3-month intervals; status of any comorbid conditions, and number of postoperative visits and band adjustments., Results: Seventy-three adolescents aged 13 to 17 years (mean, 15.8 +/- 1.2 years) have undergone LAGB at our institution since September, 2001. Of these, 54 were female and 19 were male. The mean preoperative weight was 298 lb, with a BMI of 48 kg/m(2). The %EWL at 6 months, 1 year, and 2 years postoperatively was 35% +/- 16%, 57% +/- 23%, and 61% +/- 27%, respectively. One patient experienced a gastric perforation after a reoperation for band replacement because of a slip. One additional patient requested band removal because of restriction intolerance after a slip. A total of 6 patients developed band slippage, and 3 patients developed symptomatic hiatal hernias. Nutritional complications included asymptomatic iron deficiency in 13 patients, asymptomatic vitamin D deficiency in 4 patients, and mild subjective hair loss in 14 patients. In 21 patients who entered our Food and Drug Administration-approved study and had reached 1-year follow-up, there were 51 identified comorbid conditions. Of these, 35 (68.5%) were completely resolved, 9 (17.5%) were improved, 5 (10%) were unchanged, and 2 (4%) were aggravated after 1 year. Of 50 initial patients who underwent surgery more than 1 year ago, 2 patients lived a large distance from our institution, where band maintenance is being performed locally, and thus, the patients were excluded from the analysis. Two patients were lost to follow-up in the first year, and 3 patients were lost to follow-up in the second year, for an overall compliance rate of at least 89.5%. The mean number of office visits was 10 +/- 3 in the first year, and the mean number of adjustments was 6 +/- 2., Conclusions: Laparoscopic adjustable gastric banding continues to represent an attractive treatment strategy for morbidly obese pediatric patients with a %EWL of more than 55% at both 1- and 2-year follow-up, with minimal morbidity compared with the gastric bypass. Furthermore, the weight loss associated with LAGB provides excellent resolution or improvement of comorbid conditions. Although there is a necessary commitment by the patient that involves frequent office visits and band adjustments, adolescents are entirely capable of this commitment, and noncompliance should not be a reason to dissuade adolescents from having LAGB. It remains, in our opinion, the optimal surgical option for pediatric patients with morbid obesity.

Background/purpose: Long-term follow-up of fundoplication in patients with familial dysautonomia (FD) has revealed a high rate of recurrent gastroesophageal reflux. This may be because of the unique characteristics of patients with FD which include autonomic denervation accompanied by cyclic vomiting and retching. We reviewed our results with adaptations to the Nissen fundoplication to determine which would be most effective in preventing the need for reoperation., Methods: We reviewed the records of 108 patient with FD who underwent fundoplication by a single pediatric surgeon from November 1978 to July 1, 2004. Patients were divided into 4 groups based on the operative technique: standard Nissen fundoplication, Nissen with a posterior gastropexy, Nissen with posterior gastropexy and a superior anchoring suture, and Nissen with a reinforced suture line in addition to the previous modifications. Demographic data and surgical outcomes were abstracted., Results: Patients who underwent a Nissen fundoplication with a reinforced suture line were significantly less likely to require a reoperation for recurrent reflux than any other patients (P = .05, Fisher's Exact test) despite the fact that they were younger than patients who underwent a standard Nissen alone., Conclusion: The addition of a reinforced suture line to the standard Nissen fundoplication decreases the failure rate for patients with gastroesophageal reflux and FD. A reinforced suture line may be an attractive modification for patients where the fundoplication may be under continued physical stress caused by autonomic perturbations, or other conditions such as uncontrolled seizures or progressive neurologic decline.

Background: Obesity in the adolescent population has reached epidemic proportions. Although diet and behavior modification can help a minority of teenagers, most of these patients go on to become obese adults. Recently, surgical intervention for morbid obesity has gained increasing support. To date, this has only included gastric bypass procedures. However, this procedure carries at least a 1% mortality rate even in the hands of the most experienced surgeons. Therefore, our center has been using laparoscopic adjustable gastric banding (LAGB) to treat adolescents with morbid obesity. This analysis is a report of our short-term results in our first 53 patients., Methods: All adolescents aged 13 to 17 years who had undergone LAGB at our institution and had been entered into our prospectively collected database since 2001 were reviewed. Data collected preoperatively included age, sex, race, and body mass index (BMI). Postoperatively recorded data included length of stay, operative morbidity, need for reoperation, as well as percentage of excess weight loss (%EWL) and BMI at 3-month intervals., Results: Fifty-three teenagers aged 13 to 17 years (mean, 15.9 years) underwent LAGB at our institution since September 2001. Of these, 41 were female and 12 were male. The mean preoperative weight was 297 +/- 53 lb and the mean initial BMI was 47.6 +/- 6.7 kg/m2. The %EWL was 37.5 +/- 17.0 at 6 months, 62.7 +/- 27.6 at 1 year, and 48.5 +/- 15.6 at 18 months of follow-up. There were no intraoperative complications. Two patients had band slips that required laparoscopic repositioning, and 2 patients developed a symptomatic hiatal hernia that required laparoscopic repair. All of these procedures were performed as outpatient procedures. A fifth patient developed a wound infection requiring incision and drainage. Other complications included mild hair loss in 5 patients, iron deficiency in 4 patients, nephrolithiasis and cholelithiasis in 1 patient, and gastroesophageal reflux in 1 patient., Conclusions: Laparoscopic adjustable gastric banding is not only a safe operation for morbidly obese pediatric patients, but also represents an effective treatment strategy with a %EWL of approximately 50% at both 1 year and 18 months of follow-up. Because of the minimal morbidity and complete absence of mortality of the LAGB, it is the optimal surgical option for pediatric patients with morbid obesity.

Hirschsprung's disease is characterized by aganglionosis of the distal colon and hypertonicity of the anal sphincter. Endothelin receptor type B mutant (piebald) mice phenotypically resemble infants with Hirschsprung's disease in that these mice are susceptible to developing toxic megacolon because of the absence of ganglion cells in their distal colon. Therefore, we hypothesized that newborn piebald mice would have a higher resting anal sphincter pressure than would newborn wild-type mice. To test this hypothesis, we developed a reliable and reproducible technique for measuring the resting anal sphincter pressure in mice. Heterozygote breeding pairs of endothelin receptor type B mutant mice were purchased and bred in our animal facility. Pregnant, time-dated C57BL/6J mice provided control newborn mice. One-day-old newborn mice were evaluated for resting anal sphincter pressure. Under the operating microscope, a 24-gauge open-tip epidural catheter was placed into the anus until a deflection (approximately 3 to 5 mm) was noticed on a polygraph pressure monitor. Three consecutive measurements were obtained for each mouse. Mean values for each group were determined and compared using Student's t test. The resting anal sphincter pressure (mean +/- standard deviation) in newborn C57BL/6J mice was 13.3 +/- 2.6 mmHg, whereas that in piebald mice 22.7 +/- 2.5 mmHg (P < 0.0001). Therefore, because of their increased resting anal sphincter pressure, piebald mice may provide a useful animal model for the study of Hirschsprung's disease.

Patients with Crohn's disease are at risk for developing both internal and external fistulae. These can be asymptomatic incidental radiologic findings or causes of incontinence, chronic pain, abscesses, and sepsis. They can have a devastating impact on quality of life. Careful prospective studies of therapy are few in adult medicine and entirely lacking in the pediatric age group. Assessment and management require a coordinated effort between gastroenterologist, radiologist, and surgeon. Principles of management include surgical drainage of infection combined with medical therapy. Only infliximab has been studied in prospective, double-blinded fashion and clearly shown to be of use in the short term. There is good evidence that metronidazole may be useful acutely and that 6-mercaptopurine azathioprine may help to maintain closure. Diverting ostomies are of very limited value and corticosteroids seem to make matters worse. There are many other therapies that have been reported to be helpful in small, uncontrolled studies.