Delayed appearance of mature ganglia in an infant with an atypical presentation of total colonic and small bowel aganglionosis: a case report.

BACKGROUND: Total colonic and small bowel aganglionosis (TCSA) occurs in less than 1% of all Hirschsprung's disease patients. Currently, the mainstay of treatment is surgery. However, in patients with TCSA, functional outcomes are often poor. A characteristic transition zone in TCSA can be difficult to identify which may complicate surgery and may often require multiple operations. CASE PRESENTATION: We present the case of a male infant who was diagnosed with biopsy-proven total colonic aganglionosis with extensive small bowel involvement as a neonate. The patient was diverted at one month of age based on leveling biopsies at 10 cm from the Ligament of Treitz. At 7 months of age, during stoma revision for a prolapsed stoma, intra-operative peristalsis was observed in nearly the entire length of the previously aganglionic bowel, and subsequent biopsies demonstrated the appearance of mature ganglion cells in a previously aganglionic segment. CONCLUSIONS: TCSA remains a major challenge for pediatric surgeons. Our case introduces new controversy to our understanding of aganglionosis. Our observations warrant further research into the possibility of post-natal ganglion maturation and encourage surgeons to consider a more conservative surgical approach.

Correction to: Delayed appearance of mature ganglia in an infant with an atypical presentation of total colonic and small bowel aganglionosis: a case report.

Following publication of the original article [1], the authors reported error on the images/figures used which also resulted in un-sequential order. The updated figures and captions are provided below.

Importance of Ileum and Colon in Children with Short Bowel Syndrome.

BACKGROUND: It is well known that small bowel length is a dominant prognostic indicator in patients with short bowel syndrome (SBS). The relative importance of jejunum, ileum, and colon is less well defined in children with SBS. Here we review the outcome of children with SBS with respect to the type of remnant intestine. METHODS: A retrospective review of 51 children with SBS was conducted at a single institution. The duration of parenteral nutrition use was the main outcome variable. The length of the remaining intestine as well as the type of intestine were recorded for each patient. Kaplan-Meier analyses were conducted to compare the subgroups. RESULTS: Children with greater than 10% expected small bowel length or more than 30 cm of small bowel achieved enteral autonomy faster than those with less. The presence of ileocecal valve enhanced the ability to wean from parenteral nutrition. The presence of ileum significantly enhanced the ability to wean from parenteral nutrition. Patients with the entire colon also achieved enteral autonomy sooner than those with partial colon. CONCLUSIONS: The preservation of ileum and colon is important in patients with SBS. Approaches to preserve or lengthen ileum and colon may be beneficial for these patients. LEVEL OF EVIDENCE: IV.

Immunophenotyping of peripheral eosinophils demonstrates activation in eosinophilic esophagitis.

BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE. METHODS: Eosinophils and CD3+ lymphocytes were identified directly from 50 µL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset. RESULTS: Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05). CONCLUSIONS: Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

Aluminum content of parenteral nutrition in neonates: measured versus calculated levels.

BACKGROUND AND OBJECTIVE: Aluminum (Al) is associated with significant central nervous system toxicity and bone and liver damage. Because Al is a contaminant of parenteral nutrition (PN) components including calcium and phosphate additives, premature infants are at potentially high risk for toxicity. The US Food and Drug Administration (FDA) has mandated PN component product labeling and recommended maximum Al daily exposure limits. The objective of this article is to determine the actual Al content of neonatal PN solutions, compare these values to the calculated amounts from manufacturers' PN product labels, and ascertain whether the actual Al exposure exceeds the FDA recommended maximum of 5 microg . kg(-1) . day(-1). MATERIALS AND METHODS: Samples from 40 neonatal patient PN solutions were selected for sampling and Al content determination. Samples were also taken from 16 manufacturer's component products used in PN formulation. All of the samples were sent to Mayo Laboratories for Al content measurement. The calculated Al concentrations in PN samples were determined from the manufacturer's labeled content. RESULTS: Both measured and calculated Al concentrations exceeded the FDA recommended safe limit of <5 microg . kg(-1) . day(-1). The actual measured Al content was significantly lower than the calculated Al content in both the patient PN solutions and the component product samples. CONCLUSIONS: Al exposure exceeded the FDA recommended maximum limit for all patient samples; however, the actual measured Al content of all the samples was significantly less than the calculated Al content based on manufacturer's labels. These findings suggest that manufacturers label their products with actual Al content at the time of product release rather than at time of expiration. Periodic monitoring of Al levels should be considered with prolonged PN therapy. Changes in manufacturing processes, including the use of better raw materials, are essential to reduce Al contamination to meet FDA mandates.

Increased number of regulatory T cells in children with eosinophilic esophagitis.

OBJECTIVES: There are limited data on the role of regulatory T cells (Treg) in the disease pathology of eosinophilic esophagitis (EoE). We tested the differences in Treg in subjects with EoE compared with those with gastroesophageal reflux disease (GERD) and healthy controls (HC). PATIENTS AND METHODS: Pediatric patients evaluated by endoscopy were recruited for our study. Participants were categorized into 3 groups: EoE, GERD, and HC. RNA purified from esophageal biopsies were used for real-time quantitative polymerase chain reaction assays and tested for forkhead box P3 (FoxP3) mRNA expression. Treg were identified as CD4+CD25hiCD127lo cells in peripheral blood and as CD3+/FoxP3+cells in esophageal tissue. RESULTS: Forty-eight subjects were analyzed by real-time quantitative polymerase chain reaction: EoE (n = 33), GERD (n = 7), and HC (n = 8). FoxP3 expression was higher by up to 1.5-fold in the EoE group compared with the GERD and HC groups (P < 0.05). Protein levels of FoxP3 in blood and tissue were then investigated in 21 subjects: EoE (n = 10), GERD (n = 6), and HC (n = 5). The percentage of Treg and their subsets in peripheral blood were not significant between groups (P > 0.05). The amount of Treg in esophageal tissue was significantly greater in the EoE group (mean 10.7 CD3+/FoxP3+cells/high power field [HPF]) compared with the other groups (GERD, mean 1.7 CD3+/FoxP3+cells/HPF and HC, mean 1.6 CD3+/FoxP3+cells/HPF) (P < 0.05). CONCLUSIONS: We show that Treg are increased in esophageal tissue of EoE subjects compared with GERD and HC subjects. The present study illustrates another possible mechanism involved in EoE that implicates impairment of immune homeostasis.

Nordihydroguaiaretic acid (NDGA), an inhibitor of the HER2 and IGF-1 receptor tyrosine kinases, blocks the growth of HER2-overexpressing human breast cancer cells.

We have reported that nordihydroguaiaretic acid (NDGA) inhibits the tyrosine kinase activities of the IGF-1 receptor (IGF-1R) and the HER2 receptor in breast cancer cells. Herein, we studied the effects of NDGA on the growth of estrogen receptor (ER) positive MCF-7 cells engineered to overexpress HER2 (MCF-7/HER2-18). These cells are an in vitro model of HER2-driven, ER positive, tamoxifen resistant breast cancer. NDGA was equally effective at inhibiting the growth of both parental MCF-7 and MCF-7/HER2-18 cells. Half maximal effects for both cell lines were in the 10-15 microM range. The growth inhibitory effects of NDGA were associated with an S phase arrest in the cell cycle and the induction of apoptosis. NDGA inhibited both IGF-1R and HER2 kinase activities in these breast cancer cells. In contrast, Gefitinib, an epidermal growth factor receptor inhibitor but not an IGF-1R inhibitor, was more effective in MCF-7/HER2-18 cells than in the parental MCF-7 cells and IGF binding protein-3 (IGFBP-3) was more effective against MCF-7 cells compared to MCF-7/HER2-18. MCF-7/HER2-18 cells are known to be resistant to the effects of the estrogen receptor inhibitor, tamoxifen. Interestingly, NDGA not only inhibited the growth of MCF-7/HER2-18 on its own, but it also demonstrated additive growth inhibitory effects when combined with tamoxifen. These studies suggest that NDGA may have therapeutic benefits in HER2-positive, tamoxifen resistant, breast cancers in humans.

Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation.

BACKGROUND: Aluminum toxicity can cause serious central nervous system and bone toxicities. Aluminum is a contaminant of parenteral nutrition (PN) solution components. Premature neonates requiring high doses of calcium and phosphate to mineralize their bones, children with impaired renal function, and children on PN therapy for prolonged duration are at the highest risk. Effective in July 2004, the U.S. Food and Drug Administration (FDA) mandated labeling requirements for aluminum content in all PN solution components. To assess the aluminum exposure in neonatal and pediatric populations, this study aims to determine patients' daily aluminum load (mug/kg/d) delivered from PN solutions. METHODS: The study included all inpatients who received PN during calendar year 2006 (13,384 PN patient days). The calculated parameters of mug/kg/d and mug/L of parentally administered aluminum were stratified according to patient age and weight. Aluminum content by product and manufacturer were tabulated. RESULTS: Forty-nine percent of the PN patient days were in patients weighing < 3 kg. These patients also received the largest amounts of aluminum (range, 30-60 mug/kg/d). Meeting the FDA regulation was possible only in patients weighing > 50 kg. CONCLUSIONS: Currently available parenteral products used to make PN solutions contain amounts of aluminum that make it impossible to meet the new FDA rule of <5 mug/kg/d of aluminum exposure. Manufacturers must identify, develop, and adopt new methods to reduce the aluminum contamination in their products. Health care professionals should calculate aluminum loads in patients and make informed decisions when choosing PN products.

Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth.

In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers.

Management of short bowel syndrome in postoperative very low birth weight infants.

Short bowel syndrome is a potentially devastating morbidity for the very low birth weight infant and family with a high risk for mortality. Prevention of injury to the intestine is the ideal, but, if and when the problem arises, it is important to have a systematic approach to manage nutrition, use pharmaceutical strategies and tools to maximize the outcome potential. Safely maximizing parenteral nutrition support by providing adequate macronutrients and micronutrients while minimizing its hepatotoxic effects is the initial postoperative strategy. As the infant stabilizes and starts to recover from that initial injury and/or surgery, a slow and closely monitored enteral nutrition approach should be initiated. Enteral feeds can be complemented with medications and supplements emerging as valuable clinical tools. Engaging a multidisciplinary team of neonatologists, gastroenterologists, pharmacists, skilled clinical nutrition support staff including registered dietitians and nutrition support nurses will facilitate optimizing each and every infant's long term result. Promoting intestinal rehabilitation and adaptation through evidence-based practice where it is found, and ongoing pursuit of research in this rare and devastating disease, is paramount in achieving optimal outcomes.

Nutritional Needs and Support for Children with Chronic Liver Disease.

Malnutrition has become a dangerously common problem in children with chronic liver disease, negatively impacting neurocognitive development and growth. Furthermore, many children with chronic liver disease will eventually require liver transplantation. Thus, this association between malnourishment and chronic liver disease in children becomes increasingly alarming as malnutrition is a predictor of poorer outcomes in liver transplantation and is often associated with increased morbidity and mortality. Malnutrition requires aggressive and appropriate management to correct nutritional deficiencies. A comprehensive review of the literature has found that infants with chronic liver disease (CLD) are particularly susceptible to malnutrition given their low reserves. Children with CLD would benefit from early intervention by a multi-disciplinary team, to try to achieve nutritional rehabilitation as well as to optimize outcomes for liver transplant. This review explains the multifactorial nature of malnutrition in children with chronic liver disease, defines the nutritional needs of these children, and discusses ways to optimize their nutritional.

Treatment of catheter occlusion in pediatric patients.

A proper initial assessment of catheter occlusion is the key to successful management. The assessment screens are for both thrombotic and nonthrombotic causes (including mechanical occlusion). If mechanical occlusion is excluded, thrombotic occlusion is treated with alteplase. Nonthrombotic occlusions are treated according to their primary etiologies: lipid occlusion is treated with 70% ethanol, mineral precipitates are treated with 0.1-N hydrochloric acid (HCl), drug precipitates are treated according to their pH-acidic drugs can be cleared with 0.1-N HCl, basic medications can be cleared with sodium bicarbonate or 0.1-N sodium hydroxide (NaOH). Prevention of occlusion of central venous access devices is also critical. To date, no data conclusively show heparin flushes to be superior to saline flushes. No prophylactic regimen, including low-dose warfarin, low-molecular-weight heparin, or 1 unit heparin/mL of parenteral nutrition has been endorsed by any major medical, nursing, or pharmacy group due to lack of scientific evidence. The most encouraging information on decreasing occlusion rate comes from experience with positive-pressure devices that attach to the hub of most catheter lumens and prevent retrograde blood flow and, consequently, decrease the risk of thrombus formation in the catheter lumen.

The use of IV fat in neonates.

IV fat emulsion (IVFE) is an integral part of the parenteral nutrition (PN) regimen in neonates. It provides a concentrated isotonic source of calories and prevents or reverses essential fatty acid deficiency. Continuous administration of IV fat with PN regimens prolongs the viability of peripheral IV lines in infants who might have limited venous access. IVFE must be administered separately from the PN solution in neonates. The acidic pH of a PN solution is necessary for maximum solubility of calcium and phosphorus. If fat emulsion is added to the PN solution, as is done in 3-in-1 (total nutrient admixture) solutions, the high amount of calcium and phosphorus needed by these infants may result in an unseen precipitate with serious consequences. Continuous fat infusion over 24 hours is the preferred method in neonates. The administration rate of 0.15 g/kg/hour for IVFE in the neonate should not be exceeded. Essential fatty acid deficiency can be prevented in neonates by providing IVFE in a dose of 0.5-1.0 g/kg/day. Carnitine is not routinely required to metabolize IVFE in the neonate. Infants should receive 20% lipid emulsion to improve clearance of triglycerides and cholesterol. Serum triglyceride levels should be maintained at <150-200 mg/dL in neonates. There are concerns about potential adverse effects of early administration of IV fat in very-low-birth-weight infants weighing <800 g. We hold the IV fat dose at 1.0-1.5 g/kg/day until the second week of life in infants <30 weeks gestation.

Parenteral nutrition-associated cholestasis related to parental care.

Parenteral nutrition-associated cholestasis (PNAC) is a complication not uncommon in the pediatric population. In severe cases, patients require a liver transplant. To our knowledge, we report the only case of PNAC with end-stage liver failure in a child with short bowel syndrome that resolved with a change in caretaker. Until his care was transferred from his abusive parents, he was frequently admitted for infection and sepsis. His liver function vastly improved from aspartate aminotransferase (AST) 3139 units/L, conjugated bilirubin 25.9 mg/dL to AST 47 units/L, direct bilirubin 0.3 mg/dL under the care of his attentive foster mother, and a liver transplant was no longer necessary. Bacterial infection and sepsis are risk factors correlated with patients with PNAC requiring liver transplant. Prevention of infection by a good caregiver may be a means to reduce the incidence of PNAC.