Robert D. Baker

Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition.

Gastroesophageal reflux (GER), defined as passage of gastric contents into the esophagus, and GER disease (GERD), defined as symptoms or complications of GER, are common pediatric problems encountered by both primary and specialty medical providers. Clinical manifestations of GERD in children include vomiting, poor weight gain, dysphagia, abdominal or substernal pain, esophagitis and respiratory disorders. The GER Guideline Committee of the North American Society for Pediatric Gastroenterology and Nutrition has formulated a clinical practice guideline for the management of pediatric GER. The GER Guideline Committee, consisting of a primary care pediatrician, two clinical epidemiologists (who also practice primary care pediatrics) and five pediatric gastroenterologists, based its recommendations on an integration of a comprehensive and systematic review of the medical literature combined with expert opinion. Consensus was achieved through Nominal Group Technique, a structured quantitative method. The Committee examined the value of diagnostic tests and treatment modalities commonly used for the management of GERD, and how those interventions can be applied to clinical situations in the infant and older child. The guideline provides recommendations for management by the primary care provider, including evaluation, initial treatment, follow-up management and indications for consultation by a specialist. The guideline also provides recommendations for management by the pediatric gastroenterologist. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology and Nutrition on the evaluation and treatment of gastroesophageal reflux in infants and children. The American Academy of Pediatrics has also endorsed these recommendations. The recommendations are summarized in a synopsis within the article. This review and recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the management of all patients with this problem.

Consensus report on nutrition for pediatric patients with cystic fibrosis.

Laura K. Bachrach, M.D. Robert J. Beall, Ph.D. Preston W. Campbell, III, M.D. Susan C. Casey, B.S., R.D. Mitchell B. Cohen, M.D. Mary Corey, Ph.D. W. Hobart Davies, Ph.D. Judy A. Fulton, R.D. Richard J. Grand, M.D. John E. Grunow, M.D. Dana S. Hardin, M.D. Lesles Hendeles, Pharm.D. James E. Heubi, M.D. Van S. Hubbard, M.D. Hui-Chuan Kai, Ph.D. Sheila Innis, Ph.D. Elisabeth Luder, Ph.D., R.D. Karen MacGuiness, R.D. Richard K. Mathis, M.D. Annie McKenna, M.S., R.D., C.N.S. Antoinette Moran, M.D. Laurie Moyer-Mileur, Ph.D., R.D. Kimberly O. O’Brien, Ph.D. Hebe Quinton, M.S. Lynne M. Quittell, M.D. Ross W. Shepherd, M.D., FRACP Ronald J. Sokol, M.D. Lori J. Stark, Ph.D. John N. Udall, Jr., M.D., Ph.D. Babette Zemel, Ph.D. INTRODUCTION

Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH

Nonalcoholic steatohepatitis (NASH) is a serious liver disease associated with obesity. Characterized by metabolic syndrome, hepatic steatosis, and liver inflammation, NASH is believed to be under the influence of the gut microflora. Here, the composition of gut bacterial communities of NASH, obese, and healthy children was determined by 16S ribosomal RNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of patients and healthy controls. UniFrac‐based principle coordinates analysis indicated that most of the microbiome samples clustered by disease status. Each group was associated with a unique pattern of enterotypes. Differences were abundant at phylum, family, and genus levels between healthy subjects and obese patients (with or without NASH), and relatively fewer differences were observed between obese and the NASH microbiomes. Among those taxa with greater than 1% representation in any of the disease groups, Proteobacteria, Enterobacteriaceae, and Escherichia were the only phylum, family and genus types exhibiting significant difference between obese and NASH microbiomes. Similar blood‐ethanol concentrations were observed between healthy subjects and obese non‐NASH patients, but NASH patients exhibited significantly elevated blood ethanol levels. Conclusions: The increased abundance of alcohol‐producing bacteria in NASH microbiomes, elevated blood‐ethanol concentration in NASH patients, and the well‐established role of alcohol metabolism in oxidative stress and, consequently, liver inflammation suggest a role for alcohol‐producing microbiota in the pathogenesis of NASH. We postulate that the distinct composition of the gut microbiome among NASH, obese, and healthy controls could offer a target for intervention or a marker for disease. (HEPATOLOGY 2013)

Clinical Report—Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age)

This clinical report covers diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants (both breastfed and formula fed) and toddlers from birth through 3 years of age. Results of recent basic research support the concerns that iron-deficiency anemia and iron deficiency without anemia during infancy and childhood can have long-lasting detrimental effects on neurodevelopment. Therefore, pediatricians and other health care providers should strive to eliminate iron deficiency and iron-deficiency anemia. Appropriate iron intakes for infants and toddlers as well as methods for screening for iron deficiency and iron-deficiency anemia are presented.

Oxidant-induced disruption of intestinal epithelial barrier function: role of protein tyrosine phosphorylation

The effect of hydrogen peroxide (H2O2) on intestinal epithelial barrier function was examined in Caco-2 and T84 cell monolayers. H2O2 reduced transepithelial electrical resistance (TER) of Caco-2 and T84 cell monolayers. This decrease in TER was associated with a decrease in dilution potential and an increase in [3H]mannitol permeability, suggesting an H2O2-induced disruption of the paracellular junctional complexes. H2O2 administration also induced tyrosine phosphorylation of several proteins (at the molecular mass ranges of 50-90, 100-130, and 150-180 kDa) in Caco-2 cell monolayers. Phenylarsine oxide and sodium orthovanadate, inhibitors of protein tyrosine phosphatase, decreased TER and increased mannitol permeability and protein tyrosine phosphorylation (PTP). A low concentration of sodium orthovanadate also potentiated the effect of H2O2 on TER, dilution potential, mannitol permeability, and PTP. Pretreatment with genistein (30-300 microM) and tyrphostin (100 microM) inhibited the effect of H2O2 on TER, dilution potential, mannitol permeability, and PTP. These studies show that H2O2 increases the epithelial permeability by disrupting paracellular junctional complexes, most likely by a PTP-dependent mechanism.The effect of hydrogen peroxide (H2O2) on intestinal epithelial barrier function was examined in Caco-2 and T84 cell monolayers. H2O2reduced transepithelial electrical resistance (TER) of Caco-2 and T84 cell monolayers. This decrease in TER was associated with a decrease in dilution potential and an increase in [3H]mannitol permeability, suggesting an H2O2-induced disruption of the paracellular junctional complexes. H2O2administration also induced tyrosine phosphorylation of several proteins (at the molecular mass ranges of 50-90, 100-130, and 150-180 kDa) in Caco-2 cell monolayers. Phenylarsine oxide and sodium orthovanadate, inhibitors of protein tyrosine phosphatase, decreased TER and increased mannitol permeability and protein tyrosine phosphorylation (PTP). A low concentration of sodium orthovanadate also potentiated the effect of H2O2on TER, dilution potential, mannitol permeability, and PTP. Pretreatment with genistein (30-300 μM) and tyrphostin (100 μM) inhibited the effect of H2O2on TER, dilution potential, mannitol permeability, and PTP. These studies show that H2O2increases the epithelial permeability by disrupting paracellular junctional complexes, most likely by a PTP-dependent mechanism.

Treatment With High-dose Proton Pump Inhibitors Helps Distinguish Eosinophilic Esophagitis From Noneosinophilic Esophagitis

Background: Eosinophilic esophagitis (EE) is a clinical entity that is recognized increasingly in children. The treatment of EE has been debated since its identification as a clinical entity separate from reflux esophagitis. We hypothesize that the treatment with a high-dose proton pump inhibitor (HDPPI) helps differentiate EE from noneosinophilic esophagitis (NEE). Patients and Methods: Retrospective review of 2221 patients who underwent esophagogastroduodenoscopy (EGD) with biopsies was undertaken. Sixty-nine patients had more than or equal to 15 eosinophils/high-power field (eos/HPF) in 1 or more esophageal levels. Of those, 36 were initially treated with HDPPI for 3 months followed by repeat EGD. Patients who demonstrated histologic response were classified as NEE. Patients with no histologic response were diagnosed as having EE and treated with HDPPI + swallowed fluticasone for 3 months followed by repeat EGD. Results: Of the 36 patients, histologic response was seen in 14 (39%) after treatment with HDPPI; 95% confidence interval (0.23–0.54). Swallowed fluticasone was added to the treatment of the 22 patients who did not show histologic response to HDPPI alone. Of those, 15 patients underwent repeat endoscopies. Seven patients were lost to follow-up or did not have repeated EGDs. Histologic response was observed in 9 of 15 (60%) patients. Of the nonresponders (6 of 15), 5 of 6 (83%) self-reported noncompliance with the swallowed fluticasone. Patients with more than or equal to 15 eos/HPF at all 3 levels (25 of 36) were less likely to respond to HDPPI alone and more likely to be categorized as EE (18 of 25), P = <0.043. Symptomatically, 28 of 36 patients reported resolution of symptoms after HDPPI therapy alone, P = <0.0001, regardless of histology. Visual endoscopic findings during the first and second EGDs did not show any significance in differentiating EE from NEE, P = 0.625 and P = 0.2405, respectively. Conclusions: The study demonstrates that HDPPI can be used to help differentiate EE from NEE histologically. Moreover, patients with more than or equal to 15 eos/HPF at all 3 levels are less likely to respond to HDPPI than patients with more than or equal to 15 eos/HPF at fewer than 3 levels. Therefore, having more than or equal to 15 eos/HPF at 1 or 2 biopsy levels does not necessarily establish the diagnosis of EE. Symptomatic response to HDPPI does not correlate with histologic findings. Clinical management guided by EGD with biopsy helps distinguish patients with EE from those with NEE.

Role of alcohol metabolism in non-alcoholic steatohepatitis.

Background Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. Methodology/Principal Findings To investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4). Conclusions/Significance The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD.

Failure to Thrive as a Manifestation of Child Neglect

Failure to thrive is a common problem in infancy and childhood. It is most often multifactorial in origin. Inadequate nutrition and disturbed social interactions contribute to poor weight gain, delayed development, and abnormal behavior. The syndrome develops in a significant number of children as a consequence of child neglect. This clinical report is intended to focus the pediatrician on the consideration, evaluation, and management of failure to thrive when child neglect may be present. Child protective services agencies should be notified when the evaluation leads to a suspicion of abuse or neglect.

Inhibition of oxidant-induced barrier disruption and protein tyrosine phosphorylation in Caco-2 cell monolayers by epidermal growth factor

The effect of epidermal growth factor (EGF) on the H202-induced increase in paracellular permeability in Caco-2 and T-84 cell monolayers was evaluated to examine the role of EGF in intestinal mucosal protection from oxidative stress. Oxidative stress was induced by exposing cell monolayers to H2O2 or a mixture of xanthine oxidase + xanthine (XO + X). Paracellular permeability was assessed by measuring transepithelial electrical resistance (TER), sodium chloride dilution potential, and unidirectional flux of [3H]mannitol. H2O2 (0.1 to 5.0 mM) reduced TER and dilution potential and increased mannitol flux. Administration of EGF delayed H2O2 and XO + X-induced changes in TER, dilution potential, and [3H]mannitol flux. This protective effect of apically or basally administered EGF was concentration-related, with A50 (95% confidence limits) values of 2.1 (1.17 to 4.34) and 6.0 (4.37 to 8.34) nM, respectively. The EGF-mediated protection was prevented by treatment of cell monolayers with genistein (10 microM), a tyrosine kinase inhibitor. H2O2 and XO + X also induced tyrosine phosphorylation of a number of proteins in Caco-2 and T-84 cell monolayers. EGF treatment inhibited the oxidant-induced tyrosine phosphorylation of proteins, particularly those with a molecular mass of 110-220 kDa. Treatment of Caco-2 cells with anti-transforming growth factor-alpha antibodies potentiated the H2O2-induced changes in TER, dilution potential, and mannitol flux. These studies demonstrated that an EGF receptor-mediated mechanism delays oxidant-induced disruption of the epithelial barrier function, possibly by suppressing the oxidant-induced tyrosine phosphorylation of proteins.

Vitamin and mineral status in patients with inflammatory bowel disease.

Objectives: Patients with inflammatory bowel disease (IBD) are at risk for vitamin and mineral deficiencies because of long-term inflammation in the gut mucosa and decreased oral intake. The aim of the study is to investigate the prevalence of vitamin and zinc deficiencies in patients with newly diagnosed IBD compared with a control group. Methods: This is a retrospective chart review of all of the patients diagnosed as having IBD from 2006 to 2010, ages 1 to 18 years. Patients who had fat- and water-soluble vitamins (A, E, D 25-OH, folate, and B12) and zinc levels obtained at time of diagnosis were included in the study. A total of 61 patients with IBD and 61 age- and sex-matched controls were included. Results: None of the 61 patients with IBD had folate or vitamin B12 deficiency. Vitamin D deficiency was found in 62% of the patients, vitamin A deficiency in 16%, vitamin E deficiency in 5%, and zinc deficiency in 40%. The control group had vitamin D and E and zinc deficiency in 75%, 8%, and 19% patients, respectively. Conclusions: We conclude that vitamin B12 and folate deficiencies are rare in children with newly diagnosed IBD in the United States and we question whether routine monitoring is warranted. Vitamin A and zinc deficiency are common in patients with newly diagnosed IBD and levels should be assessed at the time of diagnosis so that enteral repletion can commence. Vitamin D deficiency is common in all of the children in the Buffalo, NY, area, and routine screening for this deficiency is warranted.