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Nitric oxide has been shown to be an important factor in the regulation of apoptosis in mesangial cells. The following studies were conducted to determine whether L-arginine, the metabolic precursor of nitric oxide synthesis, directly modulates programmed cell death in response to a variety of stimuli. Cultured rat mesangial cells were exposed for 24-48 h to one of the following four experimental conditions known to induce apoptosis: i) a cytokine combination consisting of interferon-gamma (50 U/ml), interleukin-1 (5 ng/ml), and LPS (10 microg/ml); ii) 0.75 mM hydrogen peroxide; iii) etoposide, 150 microg/ml; and iv) cis-platinum, 100 microg/ml. Addition of L-arginine resulted in a dose-dependent decrease in apoptosis in cytokine-treated RMC. This effect was demonstrable by gel electrophoresis, diphenylamine assay of DNA fragmentation, and an ELISA to detect DNA oligonucleosomes. The effect was not related to increased osmolality of the test media and was not reproduced by the addition of equimolar D-arginine. L-Arginine also reduced apoptosis and necrosis in RMC that were incubated with etoposide and cis-platinum. In contrast, the amino acid had no beneficial effect on RMC survival following exposure to hydrogen peroxide. These findings indicate that several components of the nitric oxide biosynthetic pathway including the precursor and the enzymatic product independently exert direct effects on apoptosis in cultured rat mesangial cells.

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As pediatric liver transplantation has become relatively common since the early 1980s, most long-term follow-up care has shifted from transplant centers to the pediatric gastroenterologists at referring institutions. We reviewed our experience with 16 patients who have undergone liver transplantation at eight institutions from 1987 to 1996. Our initial follow-up visit took place at an average 4.1 months after the transplant. The mean duration of follow-up was 41 months. During this period 11 hospitalizations at the transplant center occured, including five that were to rule out lymphoma or post-transplant lymphoproliferative disease. At the Schneider Children's Hospital, NY, USA, 158 outpatient visits were recorded. Forty-two hospitalizations occurred. Twenty of the hospital admissions were accounted for by two patients. Forty-nine outpatient/inpatient surgical or diagnostic procedures were performed, including 15 percutaneous liver biopsies. In only one biopsy was there a disagreement in the histologic diagnosis between our pathologist and the pathologist at the transplant center. In conclusion, comprehensive follow-up care can be provided by an academic hospital-based gastroenterology group in conjunction with a transplant center.

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OBJECTIVES: To determine the frequency of performance of digital rectal examination by primary care practitioners on children with chronic constipation and to assess its effect on therapy. PATIENTS AND METHODS: One hundred twenty-eight children referred for chronic constipation to the Division of Pediatric Gastroenterology at Schneider Children's Hospital, New Hyde Park, NY, as well as their parents were questioned as to whether a digital rectal examination was ever performed prior to referral. All children underwent subsequent digital rectal examination by a pediatric gastroenterologist and recommended treatment regimens were compared with pretreatment regimens. The patients evaluated were a mix of private-insurance and Medicaid patients referred by pediatricians in the general community. RESULTS: Ninety-eight (77%) of the children referred for chronic constipation were found to have never had a digital rectal examination performed prior to referral. Fifty-three (54%) of these children were found to have fecal impaction. Only 19 (21%) were found to have minimal to no stool retention on digital examination. Enema therapy had been infrequently used to "clean out" the colon in referred children. Seventy percent were treated with multiple enema therapy following digital rectal examination. Organic causes of constipation were identified in 3 patients. CONCLUSIONS: Digital rectal examination is often not performed in the examination of the child with chronic constipation. The digital examination can help differentiate functional constipation from an organic process and may alter the course of therapy.

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BACKGROUND: Active colitis in patients with inflammatory bowel disease is associated with mucosal vasodilation, increased intestinal permeability and abnormal colonic motility. Nitric oxide is a messenger molecule with many functions, including regulation of local blood flow, vasomotor tone, and inflammation. Increased nitric oxide production and inducible nitric oxide synthase activity have been demonstrated in experimental models of colitis. This study was designed to determine the relationship between nitric oxide production and colonic inflammation in children with active colitis and in control subjects and whether expression of inducible nitric oxide synthase protein is demonstrable in the intestinal epithelium of these patients. METHODS: Nitrate + nitrite were measured in urine, stool, and plasma using the Griess assay. Expression of inducible nitric oxide synthase protein in intestinal tissue was determined by immunohistochemical localization. RESULTS: Urinary nitrate + nitrite levels were not significantly different in patients and control subjects. In contrast, stool and plasma nitrate + nitrite concentrations were significantly higher in children with inflammatory bowel disease compared with levels in control children (stool: 162.4 +/- 31.0 mumol/l versus 77.2 +/- 22.1 mumol/l; plasma: 65.2 +/- 9.9 mumol/l versus 38.1 +/- 6.6 mumol/L; p < 0.05). Stool nitrate + nitrite levels significantly correlated with plasma values. Immunohistochemical staining of colonic tissue from children with inflammatory bowel disease demonstrated inducible nitric oxide synthase protein located exclusively in epithelial cells. CONCLUSION: Increased nitric oxide production and enhanced intestinal epithelial cell expression of inducible nitric oxide synthase protein are associated with active colonic inflammation.

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Previous studies have demonstrated enhanced intestinal trypsin uptake and decreased liver clearance of trypsin in newborn rats compared to adults. In order to examine the effectiveness of the reticuloendothelial system (RES) in clearing trypsin, bovine trypsin (1.25 mg/100 g body weight) plus trace 125I-trypsin were injected into the portal vein of 2-week-old (n = 57) and adult (n = 44) control rats or following RES stimulation using intraperitoneally injected lipopolysaccharide or RES suppression with intraperitoneally injected oleic acid emulsion. Plasma, liver and spleen 125I activities were assessed at 1, 5 or 15 min following infusion in control, stimulated and suppressed animals. Newborn control rats had significantly increased 125I plasma levels with decreased liver and spleen 125I activity compared to control adults. RES stimulation in the newborns did not lead to any change in liver or plasma levels although splenic values increased while adults had a decrease in liver 125I activity. RES suppression in the newborns led to increased plasma and decreased spleen 125I-trypsin values while adult rat levels were unchanged. The immature reticuloendothelial system in newborns is poorly responsive to RES stimulation although it can be made even further inefficient by RES suppression. The combination of RES immaturity and lack of response to stimulation may make newborns susceptible to proteolytic damage, especially during times of increased systemic levels of proteolytic enzymes.

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SUMMARY: : Esophageal involvement in patients with Crohn's disease, initially thought to be rare, has been documented with increasing frequency in both retrospective and prospective studies. However, there is no documented standardized medical regimen for treatment of these patients. We report five cases of esophageal Crohn's disease as well as a review of the literature emphasizing therapeutic approach and increased incidence of corticosteroid dependence in these patients. In the past, patients with significant esophageal disease and symptoms have been surgical candidates. We recommend that all patients with symptoms of dysphagia, odynophagia, chest pain, or dyspepsia with documented esophageal Crohn's disease should receive H2 receptor antagonists as part of their medical regimen. In addition, immunosuppressant agents should be considered as adjuvant therapy in steroid-dependent patients with esophageal disease involvement.

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Our aims were to determine the long-term clinical and manometric follow-up of 11 children with previously documented esophageal dysmotility, who had been breast-fed by mothers with silicone breast implants, their response to prokinetic agents, and to analyze changes in macrophage activation. Seven of 11 children had subjective clinical improvement. Weight/ height ratios remained the same or improved in 9/11. Biopsies at follow-up endoscopy were either normal or demonstrated mild esophagitis in 8/10. LES and UES pressures and percent propagation were not significantly different at follow-up, while wave amplitude significantly increased. Following intravenous metoclopramide, LES pressure, percent propagation, and wave amplitude significantly increased while UES pressure was unchanged. Urinary neopterin significantly decreased at follow-up, while urinary nitrates were unchanged. Esophageal dysmotility is chronic in this group of children, suggesting persistent autonomic nervous system dysfunction. Prokinetic agents may be useful in long-term management. The decreasing urinary neopterin levels suggest that, ultimately, there may be improvement in esophageal motility.

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OBJECTIVE: To determine whether children breast fed by mothers with silicone implants (BFSI) have increased urinary excretion of nitric oxide (NO) metabolites and neopterin, whether these are associated with esophageal dysmotility, and whether in vitro incubation of macrophages with silicone increases NO synthesis. METHODS: In a case-control study based on laboratory investigation, 38 BFSI children (17 male, 21 female, mean age 7.1 +/- 3.6 years, range 0.5-16.5) were compared with 30 controls (14 male, 16 female, mean age 8.4 +/- 3.5 years, range 2.5-17). Urinary NO was quantitated using the Griess reaction. Urinary neopterin was determined by radioimmunoassay. Murine macrophages were cultured with or without silicone and NO production assayed. RESULTS: Urinary NO and neopterin were significantly increased in BFSI children compared with controls. There was a significant inverse relationship between urinary neopterin excretion and the severity of esophageal dysfunction. In vitro nitrite production was nearly 60% higher in macrophages grown on silicone compared to other growth conditions. CONCLUSION: BFSI children have evidence of macrophage activation and this is associated with esophageal dysmotility. In vitro data support the proposal that silicone exposure causes macrophage activation.

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: The purpose of this study was to evaluate the use of the acute-phase serum protein α1-antitrypsin (α1-AT) compared with the erythrocyte sedimentation rate (ESR), platelet count, and hemoglobin level in screening for inflammation in newly diagnosed and known patients with inflammatory bowel disease (IBD). The serum α1-AT level, ESR, platelet count, and hemoglobin values of 154 children who were initially evaluated for possible IBD, as well as of 113 children with known IBD, were compared to evaluate their value as markers of inflammatory activity. Of the 154 children evaluated for IBD, 103 did not have IBD, 28 were diagnosed with Crohn's disease (CD), and 23 were found to have ulcerative colitis (UC). The sensitivity and specificity for CD was for α1-AT, 100%, 92%; for ESR, 68%, 94%; and for UC was for α1-AT, 70%, 92%; for ESR, 61%, 94%. In the 113 children with known IBD (66 CD, 47 UC), the sensitivity and specificity for predicting disease activity was for CD for α1-AT, 94%, 59%; for ESR, 52%, 63%; and for UC was for α1-AT, 79%, 76%; and for ESR, 59%, 82%. The determination of serum α1-AT levels was more sensitive and specific than the ESR in the initial diagnosis of CD and in predicting subsequent disease activity in both CD and UC.

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OBJECTIVES: The optimal timing of surgical intervention for severe ulcerative colitis remains uncertain. Numerous reports recommend surgery within 10-14 days if clinical remission is not achieved. We undertook a study to follow the clinical course and long-term follow-up of patients with severe ulcerative colitis treated medically for longer than 14 days (n = 11). METHODS: We performed a retrospective review of all patients admitted to the hospital with a diagnosis of severe ulcerative colitis who were treated for more than 14 days. RESULTS: Nine percent of patients (n = 1) required surgery during their hospitalization. Ninety-one percent of patients (n = 10, mean age 8.6 yr, 7 M, 3 F) treated with medical and nutritional therapy for more than 14 days went into clinical remission. Of these, only 10% (n = 1) ultimately required surgery; 60% remain in clinical remission up to 83 months posthospitalization (mean follow-up, 49.5 months), whereas 30% suffer from mild to moderate colitis (mean follow-up, 26.3 months). CONCLUSIONS: These results do not support the recommendation for colectomy for refractory severe ulcerative colitis if remission is not noted within 2 wk of hospitalization.

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The caloric prescription, a key component of the nutritional therapy of anorexia nervosa (AN) and bulimia nervosa (BN), may be empirically prescribed, or based on predicted resting energy expenditure (REE), yet adaptive changes in the metabolic rate may render both methods unreliable. Indirect calorimetry measurement of fasting REE was obtained in 32 patients with AN (n = 21) or BN (n = 11). Predicted REE was calculated according to the Harris-Benedict equation, and empiric caloric prescriptions were made by experienced physicians. In the AN group, mean measured REE was significantly lower than predicted REE (p = .00). The empiric caloric prescription was, as intended, significantly higher than the measured REE, but the two methods correlated significantly (r = .53, p < .05). The predicted REE overestimated caloric needs but was also highly correlated with measured REE (r = .69, p < .001). By regression analysis, measured REE could be calculated from predicted REE as follows: measured REE (Kcal/day) = (1.84 x Harris-Benedict predicted REE) - 1,435. In the BN group, mean measured REE was not significantly different from the empiric caloric prescription (p = .09) but was significantly lower than the Harris-Benedict predicted REE (p = .022). Neither correlated with measured REE in BN. Therefore, in BN indirect calorimetry is the only reliable method for determining caloric needs. In AN indirect calorimetry remains the preferred method, but when not available, we recommend the above equation to determine resting energy requirements.

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We describe a child with cystic fibrosis who was treated with high-dose pancreatic enzyme replacement therapy and who had a prominent ascending colon stricture with submucosal fibrosis. Unlike prior reported cases, this patient's disease was more extensive, involving the entire colon, and was associated with chylous ascites.

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The only multivitamin preparation for total parenteral nutrition currently available in the United States that contains vitamin K is the pediatric formulation MVI-Pediatric. The recommended dose provides 200 micrograms of vitamin K1 per day to term infants and children up to 11 years old. This dose is well above the recommended dietary allowance of approximately 1 microgram/kg per day, but the losses of vitamin K during administration are unknown. We evaluated the stability of vitamin K1 in a standard total parenteral nutrition infusion and found that an average 72.7 +/- 4.9% of the original vitamin K1 was present after 24 hours. By using high-performance liquid chromatography with electrochemical reduction and fluorescence detection, we obtained the serum vitamin K1 concentrations in 11 pediatric patients receiving total parenteral nutrition with MVI-Pediatric (Rorer Pharmaceuticals, Fort Washington, PA) supplementation and in control children. The serum vitamin K1 concentration (19.3 +/- 12.2 ng/mL) in patients receiving MVI-Pediatric is significantly higher than that in control children 1.9 +/- 1.5 ng/mL (p < .001). Current practice results in excessive levels of vitamin K in pediatric patients.

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Serum phospholipid fatty acid patterns were determined by gas chromatography in four infants with hepatobiliary disease receiving a formula with a high content of medium-chain-triglyceride (MCT) oil. All four infants demonstrated signs of essential fatty acid deficiency, characterized by decreased arachidonic acid and increased palmitoleic and oleic acids. All had substantial concentrations of the pathologic triene 5,8,11-eicosatrienoic acid. Three of four had decreased linoleic acid concentrations and abnormal ratios of triene to tetraene (5,8,11-eicosatrienoic acid: arachidonic acid), greater than 0.38. One patient may have experienced growth failure due to abnormal essential fatty acid status. Infants with the potential for fat malabsorption should only receive MCT-oil feedings with well above the generally recommended requirements for linoleic acid (3% of total caloric intake).

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Previous studies have demonstrated increased intestinal trypsin uptake in newborn rats compared to adults. The mechanisms that protect tissues against proteolytic damage by trypsin include trypsin-inhibitor binding and subsequent liver uptake. In order to examine these mechanisms, bovine trypsin (1.25 mg/100 g body weight) plus trace 125I-trypsin were injected into the portal vein of 2-week-old and adult rats. Liver, kidney and plasma 125I activity were assessed at 1, 5 or 15 min following infusion and the different trypsin inhibitor fractions were separated and examined for 125I activity. Newborn rats had significantly increased plasma levels of 125I-trypsin and significantly decreased liver 125I levels 1 min after infusion compared to adults. In addition, the slow decline in liver 125I activity seen in the adult rats did not occur in the newborns. The pattern of trypsin-inhibitor binding was not significantly different at 1, 5 and 15 min and there were no differences at these time intervals between newborns and adults. We suggest that the newborn liver is less effective in clearing infused trypsin leading to increased plasma levels, and this increased plasma trypsin concentration subsequently leads to increased liver levels of 125I-trypsin. The increased trypsin levels in the liver may predispose newborns to protease-induced liver damage.

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We describe a case of massive propranolol overdose in a healthy 19-year-old woman associated with isolated mesenteric ischemia following shock. We postulate that endogenous catecholamine release from shock combined with massive beta-adrenergic blockade led to severe splanchnic vasoconstriction from unopposed alpha-adrenergic activity. This case supports current thinking regarding the effect of vasoactive mediators on the gastrointestinal tract in humans and might be relevant to the mechanism of action of propranolol in the prophylaxis of variceal bleeding.

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Previous studies have suggested that both newborn animals and humans absorb intact proteases from the intestine in greater amounts than do adults. Absorbed proteases are rapidly complexed in plasma by several inhibitors which inactivate free proteases. In order to confirm increased intestinal uptake in newborns, we evaluated the plasma trypsin activity in both 2-week-old and adult rats following a trypsin feed. In addition, we studied the interaction between absorbed trypsin and rat trypsin inhibitors (alpha-macroglobulin, alpha 1-inhibitor 3, and alpha 1-protease inhibitor) by determining the concentration of alpha-macroglobulin complexes both in vivo and in vitro following trypsin feeding and by evaluating the amount of trypsin activity complexed with the different inhibitors. In vivo experiments demonstrated that trypsin uptake was significantly increased in newborns compared to adult rats and that 50-70% of plasma trypsin activity was associated with alpha 1-inhibitor 3. Increased uptake was not accompanied by increased alpha-macroglobulin complexes. In vitro trypsin incubation did not lead to increased alpha-macroglobulin complexes until the other inhibitors were removed. These findings suggest that newborns have increased trypsin uptake, and the trypsin initially binds to alpha 1-inhibitor 3 before being transferred to alpha-macroglobulin for clearance. Further studies are needed in order to understand the interaction between intestinal uptake and plasma inhibition of absorbed proteases.

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