Pediatric gastroenterology at the Mount Sinai hospital.

The history of pediatric gastroenterology at Mount Sinai begins in 1960. Early publications by Drs. Korelitz and Gribetz on the management of inflammatory bowel disease in children served as the preface to forty years of progress in this important area. The history of pediatric gastroenterology includes important work by many individuals, including Horace Hodes, Lotte Strauss and Frederick Kopel. Early observations on the nature of inflammatory bowel disease (IBD), and its course, preceded work on nutritional therapies for IBD, mechanisms of gene-nutrient interactions, regulation of gene transcription, and molecular processes involved in bile transport in the liver and small intestine. Over the last twenty years, the division has grown in size and reputation. Today there are fourteen full-time faculty - 9 M.D.'s and 5 Ph.D.'s - who work in three funded research laboratories. There are also five advanced practice nurses (including three nurse practitioners), two social workers and two nutritionists, as well as several administrators and assistants. In addition to being recognized as a premier center for the treatment of children with general pediatric gastroenterological problems, especially inflammatory bowel disease, the division is also known as one of the nation's largest pediatric liver and liver transplant centers, and it is rapidly becoming one of the largest pediatric short gut syndrome and small bowel transplant centers.

Living related liver transplantation for acute liver failure in children.

The mortality rate among children with acute liver failure (ALF) on the waiting list for liver transplantation is high. We present our experience with living related donor liver transplantation (LRD-LT) in children who required urgent transplantation for ALF. Between December 1995 and July 1997, 6 children underwent LRD-LT for ALF. Cause of liver failure, recipient and donor demographics, clinical and laboratory data, surgical details, complications, and 6-month and 2-year graft and patient survival were recorded. Five boys and 1 girl received left lateral segment grafts from their parents. The mean age was 4 +/- 2.8 years (range, 1 to 9 years). ALF was caused by Wilson's disease in 1 patient and sickle cell intrahepatic cholestasis syndrome in 1 patient; in 4 patients, the cause was unknown. All patients had mental status changes; 2 were on life support. Mean pretransplantation liver function test values were: alanine aminotransferase, 972 +/- 565 U/L (normal, 1 to 53 U/L), total bilirubin, 31.3 +/- 12.4 mg/dL (normal, 0.1 to 1.2 mg/dL), prothrombin time, 34.3 +/- 12.4 seconds (normal, 10.8 to 13.3 seconds), international normalized ratio, 8.46 +/- 5.4 (normal < 2), and fibrinogen, 109 +/- 23.9 mg/dL (normal, 175 to 400 mg/dL). The donors were 5 mothers and 1 father. The mean donor age was 32.5 +/- 7.6 years (range, 19 to 40 years). No donor required blood transfusion, and no donor had any early or late postoperative complications. The donors' mean hospital length of stay was 5 days. In five cases, grafts were blood group-compatible; 1 child received a blood group-incompatible graft. All grafts functioned immediately. No patient had hepatic artery or portal vein thrombosis or biliary complications. The child who received a mismatched graft died of infection of the brain caused by Aspergillus spp at 22 days posttransplantation with a functioning graft. The child with ALF caused by sickle cell intrahepatic cholestasis syndrome developed outflow obstruction 3 months posttransplantation and required retransplantation; he eventually died of vascular complications related to his primary disease. Four children are alive at a mean follow-up of 27 months (range, 14 to 36 months). LRD-LT for children with ALF facilitates timely transplantation without drawing on cadaveric donor resources. The established safety record of LRD-LT made this option appealing to both physicians and parental donors.

Transcriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT displacement protein/cut homolog, is associated with histone deacetylation.

Human cystic fibrosis transmembrane conductance regulator gene (CFTR) transcription is tightly regulated by nucleotide sequences upstream of the initiator sequences. Our studies of human CFTR transcription focus on identifying transcription factors bound to an inverted CCAAT consensus or "Y-box element." The human homeodomain CCAAT displacement protein/cut homolog (CDP/cut) can bind to the Y-box element through a cut repeat and homeobox. Analysis of stably transfected cell lines with wild-type and mutant human CFTR-directed reporter genes demonstrates that human histone acetyltransferase GCN5 and transcription factor ATF-1 can potentiate CFTR transcription through the Y-box element. We have found 1) that human CDP/cut acts as a repressor of CFTR transcription through the Y-box element by competing for the sites of transactivators hGCN5 and ATF-1; 2) that the ability of CDP/cut to repress activities of hGCN5 and ATF-1 activity is contingent on the amount of CDP/cut expression; 3) that histone acetylation may have a role in the regulation of gene transcription by altering the accessibility of the CFTR Y-box for sequence-specific transcription factors; 4) that trichostatin A, an inhibitor of histone deacetylase activity, activates transcription of CFTR through the Y-box element; 5) that the inhibition of histone deacetylase activity leads to an alteration of local chromatin structure requiring an intact Y-box sequence in CFTR; 6) that immunocomplexes of CDP/cut possess an associated histone deacetylase activity; 7) that the carboxyl region of CDP/cut, responsible for the transcriptional repressor function, interacts with the histone deacetylase, HDAC1. We propose that CFTR transcription may be regulated through interactions with factors directing the modification of chromatin and requires the conservation of the inverted CCAAT (Y-box) element of the CFTR promoter.

Growth failure as the first expression of malnutrition in children with human immunodeficiency virus infection.

BACKGROUND: To define the onset, pattern, and earliest manifestations of malnutrition related to HIV infection. METHODS: A retrospective cross-sectional analysis of changes in weight and growth in a group of 54 children with perinatally acquired HIV infection was conducted. Eight children had asymptomatic HIV infection, 26 had symptomatic infection, and 20 had symptomatic infection and were referred for nutritional support. RESULTS: We found an early decline in the rate of linear growth with a relative preservation of the weight-for-age. Weight-for-height measurements were preserved until there was advanced HIV-related disease. CONCLUSIONS: This pattern can result in a false impression of adequate nutrition and emphasizes the importance of longitudinal growth data of the child with HIV infection. Evidence of linear growth failure before clinical wasting is apparent is an absolute indication for aggressive nutritional support.

Recurrence of autoimmune hepatitis in children after liver transplantation.

BACKGROUND: Liver transplantation is recognized as the appropriate treatment for end-stage liver disease due to chronic active autoimmune hepatitis. While it was initially thought that the disease did not recur after transplant, it is now generally accepted that adult patients may develop recurrent disease, with studies reporting a recurrence rate of < or = 25%. We have noted a higher incidence of recurrent autoimmune hepatitis in our pediatric patients undergoing liver transplant, with a high incidence of associated morbidity. METHODS: We reviewed the records of six children followed up for autoimmune hepatitis who underwent orthotopic liver transplant for complications of end-stage liver disease. RESULTS: Of the six, five developed recurrent autoimmune hepatitis at a mean time of 11.4 months after transplant. The disease was aggressive, leading to cirrhosis and retransplant in three patients, within 1 year of recurrence. A second recurrence of disease occurred in all three retransplanted patients. One patient has received a third liver transplant, one has died, and one patient is asymptomatic on medical therapy. Autoimmune hepatitis recurred in all four patients receiving tacrolimus. CONCLUSION: We conclude that liver transplant for autoimmune hepatitis is likely to be palliative for most pediatric patients. Potent immunosuppressives such as tacrolimus do not protect against the development of recurrent autoimmune hepatitis.

The role of glutamine, short-chain fatty acids, and nucleotides in intestinal adaptation to gastrointestinal disease.

Important first steps have been taken towards establishing how some nutrients interact with genes and affect intestinal adaptation. These mechanisms may be typical of how other nutrients influence cell function and turnover and help to maintain intestinal integrity. The dietary effects of nucleotides on intestinal cell mucosa act at the gene transcription level. The dietary effects of nucleotides on immune suppression also may act through similar mechanisms. The effects of the other trophic agents may interact at this level or at other levels. Scientific interest in how the various tropic factors work to maintain and repair the gastrointestinal tract is manifested by a growing body of research that demonstrates potential mechanisms for nutrient-gene interaction and how much interactions affect intestinal development and turnover. It seems clear that intestinal gene transcription and the activity of transcription factors are at least sometimes directly related to nutrition. The techniques of molecular biology now permit the exploration and explanation of how dietary factors, such as glutamine, SCFAs, and nucleotides, affect normal and pathologic intestinal mucosal development, function, adaptation, and repair.

Transcription of cystic fibrosis transmembrane conductance regulator requires a CCAAT-like element for both basal and cAMP-mediated regulation.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene in man is controlled by a tightly regulated and weak promoter. The architecture of the CFTR promoter suggests regulatory characteristics that are consistent with the absence of a TATA-like sequence, including the ability to initiate RNA transcription at numerous positions. Detailed investigation of the most proximal region of the human CFTR gene promoter through deletion and mutational analysis reveals that expression is contingent on the conservation of the inverted CCAAT sequence. Basal expression of CFTR transcription and cAMP-mediated transcriptional regulation require the presence of an imperfect and inverted CCAAT element recognized as 5'-AATTGGAAGCAAAT-3', located between 132 and 119 nucleotides upstream of the translational start site. RNA isolated from a transfected pancreatic cell line carrying integrated wild-type and mutant CFTR-directed transgenes was used to map the 5' termini of the transgenic transcripts. Analysis of the transcript termini by ribonuclease protection analysis reflects the direct association of the conserved inverted CCAAT sequence in promoting transcript initiation. Because of the requirement for the inverted CCAAT sequence for promoting transcription of CFTR, the involvement of CCAAT-binding factors is suspected in the regulation of CFTR gene transcription. To test this, we used electrophoretic mobility shift assays to demonstrate that the majority of the binding to the inverted CCAAT element, between -135 and -116, was easily competed for by binding to cognate nucleotide sequences for CCAAT-enhancer binding protein (C/EBP). An antibody specific for the C/EBP-related protein, C/EBP delta, detected C/EBP delta as part of a nuclear protein complex bound to the inverted CCAAT sequence of the CFTR gene. Also, the detection of specific activating transcription factor/cyclic-AMP response element binding protein antigens by antibody supershift analysis of nuclear complexes suggest that species of this family of transcription factors could be involved in the formation of complexes with C/EBP delta within the CFTR gene inverted CCAAT-like element. These studies raise the possibility of interactions between individual members of the C/EBP and activating transcription factor/cyclic-AMP response element binding protein families potentially contribute to the tight transcriptional control rendered by the CFTR gene promoter.

Dietary purine nucleotides and the gastrointestinal tract.

There is a growing body of research that demonstrates a role for dietary nucleotides, the building blocks of RNA and DNA, during intestinal development, turnover, and repair. There is evidence that the effects of purine nucleotides may be mediated through intestinal gene transcription and, more specifically, through the action of transcription factors that, at least sometimes, are directly related to nutrition. Some of the suggested specific roles for dietary nucleotides include the enhancement of the normal host defense system, effects on neonatal lipid metabolism, and influence on iron bioavailability. This review focuses on the potential role of dietary (purine) nucleotides in the maintenance of intestinal integrity and reviews potential mechanisms for these effects.

Energy requirements in Alzheimer's disease patients.

Weight loss in Alzheimer's patients has been observed by many clinicians and reported in the international geriatric literature. It represents a puzzling challenge for clinicians and researchers, and it is an important issue for caregivers and nursing home staff concerned with state and federal requirements for nutrition and weight monitoring. Using indirect calorimetry, we studied the resting energy expenditure of 21 elderly patients; 12 were residing in a community setting, and 9 were institutionalized. Of the 12 community-living patients studied, 5 had early to moderate Alzheimer's disease, and 7 were nondemented control subjects. Of the 9 institutionalized patients, all were severely demented, bedridden, and fed exclusively by gastric tube in a closely monitored clinical environment with daily bedside weighing. Four had Alzheimer's disease, and 5 had multi-infarct dementia (MID). Among the outpatients, the Alzheimer's group showed increased energy requirements (p = 0.028) and a significantly different pattern of fat-free mass compared with control subjects (p = 0.031). These observations on community-residing elderly were consistent with, and extended by our findings on energy requirements of, the demented institutionalized patients. The calorie intake necessary for weight maintenance of the bedridden institutionalized patients was determined during their prolonged institutionalization. The presumed maintenance level of calorie intake was then verified during a 10 wk study. During the 10 wk, we documented no significant change in weight with constant energy intake. Compared with MID patients, Alzheimer's patients tended to weigh less (52.84 vs 56.4 kg; p = 0.20) but actually required more calories (1626 vs 1341 kcal, p < 0.011).(ABSTRACT TRUNCATED AT 250 WORDS)

Gene expression in the intestine: the effect of dietary nucleotides.

There is scientific concern regarding the role of dietary nucleotides in the maintenance and repair of the gastrointestinal tract. This concern is based on a growing body of research that demonstrates potential mechanisms for dietary nucleotides to affect intestinal development and turnover. It seems clear that intestinal gene transcription as well as the activity of transcription factors is at least sometimes directly related to nutrition. Implications of this work include the potential role of dietary nucleotides in infant nutrition and in intestinal repair. The techniques of molecular biology will now allow us to explore and explain how dietary factors such as nucleotides affect intestinal mucosal development, function, adaptation, and repair.

Cyclosporine as an alternative to surgery in children with inflammatory bowel disease.

Five children with ulcerative colitis for whom surgery was recommended were treated with cyclosporine. The five had received corticosteroids for 1-24 months. The group included two patients with acute-onset ulcerative colitis and three with acute exacerbations of intractable corticosteroid-dependent chronic ulcerative colitis. The average age at initiation of cyclosporine therapy was 13.8 years (range, 11.5-16); all five patients were boys. Cyclosporine was initiated in the hospital by continuous i.v. infusion. Trough levels of 400-600 ng/dl (measured by radioimmunoassay) were achieved, at which point oral cyclosporine was given and oral dosage was adjusted to similar levels. Significant hypertension requiring medical attention was seen in one patient. Of the two recently diagnosed acute cases, one failed to respond and required subtotal colectomy after 2 weeks of treatment, and the other, despite an initial response, had a subtotal colectomy 10 months later. Of the three corticosteroid-dependent children, none was able to be weaned from corticosteroids and all underwent subtotal colectomy. Our experience emphasizes that the appropriate role of cyclosporine as therapy for children with ulcerative colitis is yet to be determined. Cyclosporine was not effective as an alternative to surgery in our patients.