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In 1989, a collaboration between the Centers for Disease Control (CDC) and a California biotechnology company identified the hepatitis C virus (HCV, formerly known as non-A, non-B hepatitis virus) as the causative agent in the epidemic of silent posttransfusion hepatitis resulting in cirrhosis. We now know that, the HCV genome is a 9.6 kb positive, single-stranded RNA. A single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which participate in posttranslational proteolytic processing and replication of HCV genetic material. Less than 25 years later, a new class of medications, known as direct-acting antivirals (DAAs) which target these proteins, were introduced to treat HCV infection. These highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes. Although tremendous scientific progress has been made, the incidence of acute HCV infections has increased by 4-fold since 2005, compounded in the last decade by a surge in opioid and intravenous drug use. Unfortunately, awareness of this deadly hepatotropic virus among members of the lay public remains limited. Patient education, advocacy, and counseling must, therefore, complement the availability of curative treatments against HCV infection if this virus is to be eradicated.

Background HCV-specific DAAs have transformed treatment of chronic HCV, but few studies have evaluated these therapies in children. Methods Patients aged 12–17 years old with chronic GT1 HCV were enrolled into an open-label study to receive 12 weeks of LDV/SOF 90 mg/400 mg once daily, and those with HCV GT2 or GT3 to receive SOF (400 mg once daily) + RBV (15 mg/kg/day) for 12 (GT2) or 24 weeks (GT3), respectively. Primary efficacy endpoint was SVR12. Safety was assessed by adverse events and clinical/laboratory data. Pharmacokinetic (PK) sampling was conducted to confirm the appropriateness of the doses. Results 150 adolescents (100 GT1, 13 GT2 and 37 GT3) were enrolled and treated. The majority were female (56%), white (90%), treatment naive (81%), and vertically infected (80%). The mean age was 15 years (range 12–17). LDV, SOF and GS-331007 (primary metabolite) exposures were within the range of adult exposures observed in the SOF and LDV/SOF phase 2/3 studies. The SVR12 rate was 98% in GT1, 100% in GT2 and 97% in GT3; all 3 patients who were considered not to have achieved SVR12 were lost to follow-up. No adverse event (AE) leading to study drug discontinuation or serious AEs have been reported. Conclusion In adolescents, LDV/SOF for 12 weeks and SOF + RBV for 12 or 24 weeks, resulted in a SVR12 rate of 97–100% with no virologic failures. These regimens were well tolerated, demonstrating their potential as an important treatment option for children with HCV infection.

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged

Background DAA regimens have been approved for CHC treatment in 12 to Methods Patients 6 to Results 102 patients 12 to 15%) were headache, fatigue, and nausea in adolescents and vomiting, cough and headache in 6 to Conclusions In patients 6 to

Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in both adults and children. In this article, we review recent developments in the screening, diagnosis, and treatment of pediatric NAFLD. Although alanine aminotransferase (ALT) remains the best screening test for NAFLD in children, and liver biopsy is still required for the diagnosis of nonalcoholic steatohepatitis (NASH), other noninvasive biomarker/imaging studies (MRI-PDFF and VCTE) have emerged as diagnostic methods for pediatric NAFLD. Two large clinical therapeutic trials testing vitamin E, metformin, and cysteamine in pediatric NAFLD yielded mostly inconclusive results. Bariatric surgery has begun to be used in adolescents with severe obesity. An adult phase 2 study using obeticholic acid (OCA) to treat NASH patients with fibrosis showed some positive results. As we continue to await the first FDA-approved therapeutic agent for NASH, lifestyle change remains the main modality of treatment. Newer diagnostic and treatment modalities for pediatric NAFLD continue to be in development under FDA guidance.

Hepatobiliary scintigraphy (HBS) is used to aid in the diagnosis of Biliary Atresia in full-term infants with conjugated hyperbilirubinemia. There is little information on the utility of the HBS in premature infants with conjugated hyperbilirubinemia and infants with parenteral nutrition associated cholestasis (PNAC). The purpose of this study is to assess the utility of HBS in differentiating Biliary Atresia and PNAC in premature neonates and full-term infants who received parenteral nutrition (PN).Retrospective data collection and analysis on infants who developed conjugated hyperbilirubinemia and had HBS performed during their stay at level IV neonatal intensive care unit between 2005 and 2015.A total of 20 patients with exposure to PN had HBS; two patients were confirmed to have Biliary Atresia. There were no statistically significant differences between patients with Biliary Atresia versus PNAC in demographics, days on PN, or gamma glutamyl-transferase levels. Stool color was statistically significantly different between the two groups; patients with Biliary Atresia had acholic stools more consistently than patients without Biliary Atresia. HBS had 100% sensitivity, 17% specificity, positive-predictive value of 12%, and a negative-predictive value (NPV) of 100%.These data indicate that the ability of HBS to aid in diagnosing Biliary Atresia is poor in a population of preterm neonates and full-term infants with PNAC. Although there is 100% sensitivity, the poor specificity (17%) should be acknowledged when utilizing HBS to diagnose Biliary Atresia in this vulnerable patient population. NPV of 100% is helpful in ruling out Biliary Atresia in this population.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease1. We now understand that NAFLD affects one out of every four people in the world (global prevalence 25.24%), thus in fact making it the most prevalent of all liver diseases and as such, a major public health problem2, 3. The disease is defined by abnormally increased fat (>5% steatosis) in hepatocytes, which can manifest in some with additional features of inflammation and cell damage or nonalcoholic steatohepatitis (NASH). NASH can present with progressive stages of fibrosis and even cirrhosis. NAFLD is generally asymptomatic and only 10–15% have findings on biopsy consistent with NASH, and an even a smaller number, 5% of individuals develop cirrhosis, with 1–2% requiring liver transplant2. However, because of the enormous denominator of individuals with NAFLD, this 1–2% is estimated to have resulted in nearly 20 million liver-related deaths to date2. These data clearly underscore the need of effective treatment especially for the 5% of NAFLD with NASH.

Background & Aims. Children with chronic hepatitis C virus (HCV) infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with HCV genotype 2 or 3. Methods. Fifty-two patients received sofosbuvir 400mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled, and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). Results. The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% CI, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in Phase 2 and 3 sofosbuvir studies, the AUCtau and Cmax for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. Conclusion. Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic HCV genotype 2 or 3 infection. http://ClinicalTrials.gov NCT02175758. This article is protected by copyright. All rights reserved.

No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir. Conclusion: Ledipasvir−sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir−sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371–378).

Objective: The inability of children to comply with bowel preparation regimens can result in inadequate visualization of the colon. This study compares the safety, efficacy, and patient acceptance of a prepackaged diet kit plus a magnesium citrate/bisacodyl bowel cleansing regimen with a clear liquid diet and sodium phosphate solution regimen in children undergoing colonoscopy. Methods: Children scheduled for a diagnostic colonoscopy, were randomly assigned to receive a prepackaged diet kit and a magnesium citrate/bisacodyl laxative (group 1), or clear liquids and sodium phosphate solution (group 2). The patients and their parents completed a questionnaire to evaluate acceptance of their assigned regimen before colonoscopy. The endoscopists, blinded to the type of bowel preparation, rated bowel cleansing. Results: Sixty two children (28 males, 34 females) with mean age 12.5 years participated. Thirty six and 26 patients were in groups 1 and 2 respectively. Overall cleansing was rated significantly superior in group 1 compared to group 2 as was amount of retained feces (P = .013 for both). The overall frequency of reported side-effects was lower in group 1 than (83.3%, 30/36) than in group 2 (100.0%, 26/26) (P = 0.03). The preparations were otherwise equivalent in regards to compliance and patient tolerance. Conclusions: Although both regimens were comparable in adequacy of colon visualization, preparation tolerance, side effects and compliance profile in this pilot study, the prepackaged diet kit with magnesium citrate/bisacodyl laxative resulted in superior colon cleansing.

Background/Aims: Early weaning has been shown to induce intestinal ornithine decarboxylase (ODC) activities and cell proliferation in rats. No information is available about the effect of early weaning on ODC activity in the stomach. Methods: Suckling rats were prematurely weaned on postnatal day 15 and followed through day 21. Oxyntic gland mucosa of stomach was obtained on postnatal days 15, 16, 18 and 21 (days 0, 1, 3 and 6 after early weaning) and assayed for ODC activity, DNA, protein and pepsinogen activity. α-Difluoromethyl ornithine (DFMO), a specific ODC inhibitor, was given orally to early-weaned pups and its resultant effects were assessed on days 1 and 6 after early weaning. Results: Stomach mucosal wet weight, DNA, protein and pepsinogen activities significantly increased on day 6 after early weaning. ODC activity increased on days 1, 3, and 6 after early weaning, with the highest increase (3-fold) on day 1 when compared to controls. The increases of ODC activity, DNA and protein contents as induced by early weaning were significantly suppressed when pups were exposed to DFMO. However, no suppression of pepsinogen activity was observed. Conclusions: Our study shows that early weaning induces ODC activity and functional growth in the stomach. Gastric ODC activity is essential in gastric mucosal growth processes but not in differentiation. The induction of stomach ODC may act as an early marker in the growth of stomach mucosa induced by early weaning in rats.

Background: Triple therapy with a proton-pump inhibitor and two antibiotics is widely used in the treatment of Helicobacter pylori infection in adults. Experience with such therapy in the pediatric population is limited. This was a prospective, nonran-domized, open-label trial to evaluate safety and efficacy of a combination of lansoprazole, clarithromycin, and amoxicillin in symptomatic children with H. pylori infection. Methods: Children with H. pylori gastritis diagnosed by endoscopy performed for persistent nausea, vomiting, recurrent abdominal pain, and diarrhea with consistent histology were treated with the regimen of 0.45 mg/kg per day lansoprazole divided into two doses (maximum dose, 15 mg twice daily), amoxicillin 40 mg/kg per day in two doses (maximum dose, 1.0 g twice daily), and 250 mg clarithromycin twice daily ( 10 years old) for 2 weeks. Pre- and posttreatment endoscopic biopsy specimens were graded for the severity of gastritis and H. pylori density by a blinded pathologist. A questionnaire for assessing the severity of symptoms at the time of initial and second endoscopy were completed by patient and/or parent. Results: Thirty-two children (age range, 1-25 years; mean age, 11 years; 19 females, 13 males) were treated with this regimen during an 18-month period. H. pylori organisms with varying grades of gastritis were present in tissue specimens of all patients. Only 28 children had follow-up endoscopy, which showed eradication of H. pylori in 15 (54%) children. Histologic symptoms of gastritis improved after therapy in the whole group. Overall, symptoms of vomiting, abdominal pain, diarrhea, anorexia, and halitosis significantly improved (P < 0.05). Minor adverse effects of therapy occurred in 25% of patients. Conclusions: Symptoms, histologic, and endoscopic findings improved after triple therapy in children with H. pylori gastritis; however, eradication of bacteria was achieved in only 56% of children.

The risk of colorectal carcinoma is increased inpediatric-onset inflammatory bowel disease (IBD). Thereis little information available regarding the colonicmucosal proliferative state in children with IBD. The aim of this study was to assesscolonic ornithine decarboxylase (ODC) activity, a markerof cell proliferation, in pediatric IBD patients. ODCactivity was assessed in colonic mucosa from 23 children (7 with ulcerative colitis, 9 with Crohn'sdisease, and 7 controls) undergoing colonoscopicexamination. ODC activities were then compared withdegree of inflammation of biopsied samples. ODCactivities in patients with and without corticosteroidtreatment were also analyzed. The mucosal ODC activitiesof sigmoid colon and rectum were significantly higher(2.5- to 4-fold) in both ulcerative colitis and Crohn's disease. The higher ODC activity wasassociated with increased mucosal inflammation.Moreover, treatment with corticosteroids decreased theODC activity. In conclusion, using ODC activities as a marker of cell proliferation, our resultssuggest that there is a higher colonic mucosalproliferative state in children with IBD. The increasedODC activities were associated with increased colonicmucosal inflammation. Colonic mucosal ODC activity mayprovide an additional parameter to access thetherapeutic efficacy of corticosteroid treatment inpediatric IBD patients.

Increased ornithine decarboxylase (ODC) activity is associated with rapid cell proliferation in many cell types. The cellular effects of early weaning on intestinal development are not well established. To investigate whether ODC is involved in intestinal growth after early weaning, we precociously weaned suckling rats on postnatal d 15 and followed through d 21 (6 d after early weaning). Age-matched suckling pups served as controls. Rat pups were killed 1, 2, 3 and 6 d after early weaning and jejunal mucosa was assayed for ODC and sucrase activities, and protein and DNA contents. Jejunal cell proliferation was monitored by bromodeoxyuridine immunohistochemistry. Elevated jejunal ODC activity 1 d after early weaning was the earliest cellular event that was detected in the current study. ODC activity peaked at d 3 (about 15-fold greater than age-matched unweaned suckling controls). Sucrase activity was elevated at d 2 after weaning and peaked at d 3 (about 10-fold greater than controls). Greater bromodeoxyuridine immunostaining in early weaned rats occurred on d 3. Protein and DNA contents were greater in jejunal mucosa of early weaned rats at d 6. Serum corticosterone levels were elevated on d 1 and d 2 after early weaning compared to controls. To explore whether the intake of nonpurified diet played a role, we also compared the induction of jejunal ODC activity in early weaned pups and pups that were food-deprived for 1 d. ODC activity was not greater in the food-deprived group compared to suckling controls while the early weaned group had 6-fold greater activity 1 d after early weaning. Early weaning stimulates jejunal cell proliferation and differentiation. The temporal sequence of increased ODC activity followed by increases in other growth variables suggests that the induction of ODC activity may act as an early marker of intestinal growth during early weaning.

Multi-center evaluations of pediatric patients with juvenile systemic sclerosis (jSSc) have suggested that the pathogenesis of jSSc may differ from that of systemic sclerosis (SSc) in adult patients. Therefore, we undertook to identify abnormalities in the T lymphocytes of jSSc patients and to determine if they differed from the abnormalities reported in the T lymphocytes of adult SSc patients. We identified decreases in the frequency of resting regulatory T lymphocytes and an increased frequency of CD45RA expressing effector memory (EMRA) CD4 T lymphocytes, which were characterized by an increased frequency of CCR7 protein expressing cells. Neither the increases in the EMRA subpopulation nor the increased CCR7 protein expression have been reported in adult SSc patients. The decrease in resting regulatory T lymphocytes in jSSc patients may permit the expansion of the disease initiating CD4 T lymphocytes present in the CCR7 expressing EMRA CD4 T lymphocyte subpopulation.

Reflux esophagitis is a common disease in infants and can be diagnosed largely by esophageal biopsy. In adults, chronic esophagitis may lead to Barrett's esophagus, a premalignant condition for esophageal cancer development. Ornithine decarboxylase (ODC) is used as an early marker for colon cancer development. No data are available on the role of ODC in reflux esophagitis in the pediatric population. In this study we retrospectively analyzed ODC activity in esophageal biopsies of children who underwent upper endoscopy. According to the esophageal histology, patients were divided into three groups: normal mucosa, mild, and moderate/severe esophagitis. None of our patients had esophageal metaplasia or cancer. ODC level was significantly higher in the moderate/severe esophagitis group compared to mild and normal mucosa group. We conclude that ODC activity is directly proportional to the severity of the esophageal inflammation/regenerative process in children with reflux esophagitis.

Background: Patients with short bowel syndrome and renal dysfunction with TPN dependence are at high risk for developing hyperammonemia if the TPN does not contain sufficient quantities of arginine. Providing proper nutrition support is essential in the management of these patients. Methods: We report on a patient with short bowel syndrome, TPN dependence, and normal renal function who developed hyperammonemic encephalopathy due to inadvertent lack of arginine in his TPN. Results: The patient was successfully treated with hemodialysis and an IV arginine infusion to resolve the hyperammonemia. His home TPN was also adjusted such that arginine was added to his subsequent solutions. Conclusions: Our patient underscores the importance of adequate and sustained arginine supplementation to avoid hyperammonemia in TPN dependent patients with short bowel syndrome. ( Journal of Parenteral and Enteral Nutrition25:286-288, 2001)

We performed a prospective, randomized, single-blind study in children undergoing colonoscopy to evaluate the acceptance and efficacy of three different bowel preparations.Seventy patients (ages 3-20 yr, 38 males) were randomly assigned to one of the three study preparations: Magnesium citrate with X-prep and clear liquid diet for 2 days (group A); Dulcolax for 2 days and Fleet enema without dietary restriction (group B); and Golytely 20 ml/kg (up to 1 L) per hour for 4 h with clear liquid diet for 1 day (group C). Endoscopists blinded to bowel preparation graded the adequacy of colon cleansing. The preparations were rated by patients for tolerance, willingness to retake them, adverse effects, and compliance.Data analysis using Fisher exact test and trend test showed that colon cleansing in groups A and C was superior to that in group B (p0.0001) and better in group C than A (p0.075). Overall tolerance and compliance were significantly better for groups A and B than group C (p0.003), but not different between A and B. More of group B patients were willing to retake the preparation than in group C (p0.002) and group A (p0.05), but this was not different between groups A and C. Adverse effects were reported more frequently by patients in group C than in groups A and B (p0.01).Although the least well tolerated, Golytely provided the best cleansing. Dulcolax without dietary restriction provided unsatisfactory colon cleansing. Magnesium citrate with X-prep was acceptable and provided good cleansing.

Background Thyroxine has been shown to play a role in the development of exocrine pancreatic enzymes in neonatal rats. Methods To further evaluate the regulatory mechanisms for thyroxine in pancreatic development, we examined the changes in the expression of pancreatic enzymes (amylase and trypsinogen) and ornithine decarboxylase (ODC) genes following daily injection of thyroxine for 5 and 10 days to neonatal rats (5 days old). Results Total pancreatic proteins and DNA contents as well as the activity of ODC and exocrine enzymes were significantly increased after 5 and 10 days of thyroxine treatment. These increases were associated with parallel alterations (to three to fourfold rise) in steady-state mRNA levels of both amylase and trypsinogen. In contrast, thyroxine only produced a 57-68% increase in steady-state ODC mRNA levels. Conclusions These data suggest that thyroxine stimulated the express of amylase and trypsinogen genes partly due to increased transcriptional rate and/ or decreased mRNA turnover. Thyroxine also stimulated ODC gene expression. However, the stimulatory mechanisms may involve transnational or posttranslational regulation of ODC and are independent of thyroxine effects.

The role of delayed gastric emptying (GE) in the pathogenesis of gastroesophageal reflux (GER) in infants is controversial at present. GE has been shown to be altered by the composition and osmolality of the feedings. This prospective study was undertaken to assess the changes in the GE and the percentage of time GER was detected by scintigraphy using three different formulas on consecutive days in infants with GER. Twenty-eight infants under 1 year of age diagnosed to have GER by extended intraesophageal pH monitoring (pH being less than 4.0 for greater than 5% of the duration of the test), underwent scintigraphy on three consecutive days using the same volume per single feeding of a casein-predominant, soy, or a whey-hydrolysate formula in a randomized order. The formulas were isocaloric. Gastric emptying and percentage of GER into the esophagus were estimated for 60 min following these feedings. Mean GER percent during the study was 20.39, 17.68, and 16.34 on casein-predominant, soy, and whey-hydrolysate formulas, respectively, and was not significantly different. Mean values of GE were 39.7%, 44.6%, and 48.5% on casein, soy, and whey formula, respectively. No significant difference in GE was also observed between casein-predominant and soy formula. However, a significant difference was observed (p less than 0.05) on GE between casein-predominant and whey-hydrolysate feedings. Our data suggest that formula selection may be important in the treatment of conditions associated with delayed gastric emptying.

Administration of thyroxine to rat pups leads to precocious development of the pancreas. The role of ornithine decarboxylase (ODC) and polyamines in thyroxine-induced pancreatic maturation was examined. Rat pups (aged 5 days) were given daily subcutaneous injection of thyroxine (0.1 micrograms/g body wt.) until the day before death. Serial ODC activities were measured in pancreatic homogenates after 1, 2, 3, 4, 5, 6, 7 and 10 days of thyroxine treatment. There was a biphasic induction of ODC activities by thyroxine: an early peak appeared on day 2 of treatment followed by a decrease on day 4; a second peak was evident on day 5 and then a decrease to control values by day 7. Significant increases in tissue concentrations of putrescine and spermidine were observed concomitant with two peaks of ODC activity. Pancreatic amylase concentration, DNA and protein also showed a significant increase after thyroxine treatment. Difluoromethyl ornithine (DFMO), a specific ODC inhibitor, given orally (8% in drinking water) to nursing dams at postnatal day 5 for 5 days caused an 83% inhibition of pancreatic ODC activity in thyroxine-treated pups when compared to thyroxine-treated pups not exposed to DFMO. Concomitantly, the thyroxine-induced increases in pancreatic weight, protein and amylase activity were suppressed. Our results suggest that increases in ODC activities and polyamine levels are critical intermediary steps in the precocious induction of pancreatic development by thyroxine.

Pancreatic amylase enzyme activity starts to increase rapidly around weaning (17–21 days) and reaches the adult level during postnatal development in the rat. To see whether the maturation of amylase involves changes in amylase gene expression, total pancreatic RNA was prepared from rats of various ages (term-fetus, 5, 10, 15, 20, 28 days and adult). Northern blots of these RNAs were probed with amylase cDNA. Levels of amylase mRNA peaked around 10 days i.e., about 1 week prior to peak amylase enzyme activity. The role of glucocorticoid in pancreatic amylase development was studied by giving rat pups at ages 5, 10 and 30 days a single injection (i.p.) of dexamethasone (DX). They and their littermates (controls) were killed 24 and 48 h after the injection. Increases in amylase mRNA levels were seen in the DX treated 5- and 10-day-old groups with corresponding increases in amylase enzyme activities. A slight decrease in amylase mRNA level was, however, observed in the DX treated 30-day-old pups which also had a slight decrease in amylase enzyme activity suggesting an age dependent differential responsiveness to DX. A time sequence study with 10-day-old pups killed after a single injection of DX at 6, 12, 24 and 48 h showed a rapid increase in mRNA levels which peaked around 12 h. Amylase enzyme activity, however, did not peak until 24 h after DX injection. These results suggest that pancreatic amylase is regulated at the level of gene expression in both normal- and DX-induced maturation. Regulation appears to occur at the transcription level as both increases to amylase activity and mRNA were blocked by actinomycin D.

Peri-nuclear anti-neutrophil cytoplasmic antibodies (pANCAs) and anti- saccharomyces cerevisiae antibodies (ASCAs) are increasingly used by clinicians for evaluation of patients with IBD. Aim: This prospective study was to assess the accuracy of these antibodies in evaluating children with confirmed or suspected IBD. Methods: Two groups of patients: one with established diagnosis with ulcerative colitis (UC) or Crohn's disease (CD) based on clinical, radiological, endoscopic and histopathologic standard criteria. Second group consisted of patients who were evaluated for possible IBD and found to have gastrointestinal non-IBD disorders and served as controls. Both groups had IBD first step serologic tests then were extended to IgG and IgA ASCAs and IgG ANCA in positive screens at Prometheus lab, San Diego, CA. Peri-nuclear location of IgG ANCA-positive samples were evaluated by indirect immunofluorescence staining and confirmed by its disappearance after deoxyribonuclease treatment. In group one there were 19 patients with UC (mean age 12.8) and 27 with CD (mean age 13.8), and in group two there were 6 controls (mean age 11.2yr). Results: See table Conclusions:IBD serological markers in children are helpful diagnostic tools to assist in the evaluation of patients with suspected IBD but should not avert the need for more definitive tests.

The cellular mechanisms of early weaning on intestinal development are not well established. To see if cell proliferation occurs in intestinal mucosa after early weaning, suckling rats were weaned precociously on postnatal day 15 and sacrificed 1, 2, 3, and 6 days after early weaning. Jejunal mucosa were assayed for ODC (ornithine decarboxylase), sucrase activities, protein and DNA contents. Jejunal cell proliferation was monitored by bromodeoxyuridine (BrdU) immunohistochemistry. The results demonstrated that increased jejunal ODC activity was the earliest cellular event to occur after early weaning. ODC increased at day 1 and peaked at day 3 (32-fold), followed by sucrase activity with increases at day 2 and peaked at day 3 (13-fold). The increase in BrdU immunostaining was seen at day 3. The increase of protein and DNA contents occurred at day 6. Serum corticosterone levels were increased on days 1 and 2 only. To explore if the intake of high carbohydrate rat chow was the causative factor, we also compared the induction of ODC activity in early weaned and fasted pups. Results showed that 1 day after early weaning ODC activity was not increased in the fasted group while the early weaned group showed 7-fold increase. These findings suggest early weaning stimulates jejunal cell proliferation as indicated by increased in both BrdU immunostaining and ODC activity. Increase in corticosteroid may be the trigger in the initial stage of the early weaning process but dietary factor also plays a role.