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IEC-6 cells, an intestinal epithelial cell line, produce insulin-like growth factor (IGF)-II and IGF-binding protein-2 (IGFBP-2). Exogenous IGFs stimulate and IGFBP-2 attenuates DNA synthesis. To investigate whether endogenously secreted IGFBP-2 inhibits proliferation, IEC-6 cells were transfected with a full-length rat IGFBP-2 cDNA antisense expression construct. The steady-state level of IGFBP-2 mRNA decreased by 54% in the antisense cDNA-transfected cells (denoted revBP2) compared with vector-transfected controls. Moreover, revBP2 cells secreted less IGFBP-2 than controls (maximally a 68% decrease). In serum-containing medium, revBP2 cells exhibited a 35% increase in log-phase proliferation rate and growth-arrested at a maximum density 14% higher than controls. We conclude that endogenous IGFBP-2 inhibits proliferation of IEC-6 cells, probably by sequestering IGFs.

Cyclic vomiting syndrome (CVS) is an unusual cause of episodic emesis in children. It manifests as intermittent episodes of severe vomiting, similar in time of onset and duration, with no symptoms during the intervening period. Dehydration necessitating intravenous fluid therapy may occur. Most therapeutic maneuvers have proven unsuccessful. We report the use of erythromycin as a prokinetic agent in the treatment of cyclic vomiting in 24 children (10 boys, 14 girls). Many patients had mild associated abdominal pain with their vomiting. Fourteen patients had previously been given metoclopramide but none responded. Two patients were mildly developmentally delayed. Twenty-four patients were given oral erythromycin ethylsuccinate, approximately 20 mg/kg/day, in two to four divided doses for 7 days. This dose was repeated as needed when symptoms reappeared. Eighteen of 24 patients reported total resolution of symptoms when re-evaluated at 2 and 6 months. All males responded, eight of 18 responders were female, and all six with partial or no response to therapy were female. This uncontrolled trial suggests that erythromycin may be a useful prokinetic agent in the treatment of CVS in childhood. Because the study was uncontrolled, placebo effect cannot be excluded. Case-controlled, double-blinded prospective trials should be considered to evaluate the effectiveness of erythromycin in CVS.

The present study examined the effects of dexamethasone on mucosal adaptation after massive small bowel resection. Rats underwent 80% jejunoileal resection or a sham operation and received either vehicle or 128 micrograms.kg-1.day-1 sc dexamethasone for 7 days. Dexamethasone infusion resulted in decreased weight, DNA content, and protein content in the duodenojejunal and ileal mucosa in both sham and resected rats. Sucrase, lactase, and maltase activities (all in mumol.g protein-1.min-1) in the duodenojejunal mucosa were elevated by dexamethasone infusion. By contrast, enzyme activities were elevated only in the ileal mucosa of dexamethasone-infused sham-operated rats compared with sham-operated control rats, and dexamethasone did not elevate enzyme activities in resected rats. We further examined whether the inhibitory effects of dexamethasone on mucosal adaptation may be related to changes in either insulin-like growth factor (IGF) or IGF binding protein (BP) serum levels. Serum IGF-I and IGF-II levels were markedly decreased in dexamethasone-infused resected and sham-operated rats. IGF BP-1 serum levels were elevated by dexamethasone treatment with a concomitant depression in serum IGF BP-2 levels. IGF BP-3 levels were lowered by dexamethasone treatment in sham-operated rats and by gut resection, and serum IGF BP-4 levels did not change. These results suggest that the growth-inhibiting effects of dexamethasone in small intestinal mucosa may be partially mediated by decreased serum IGF levels or by alterations in IGF activity associated with changes in serum levels of IGF BPs.

Background/aims: Adaptive hyperplasia of the small intestine is important in the outcome of short bowel syndrome. Previous studies have shown that long-chain fats stimulate this process. In the present study, the trophic effects of dietary menhaden oil, a highly unsaturated fat source, on mucosal adaptation following small bowel resection in rats was evaluated., Methods: Thirty weanling Sprague-Dawley rats and their controls were fed diets containing fats provided primarily as menhaden oil, safflower oil, or beef tallow. After 4 weeks, animals underwent a 70% jejunoileal resection. Mucosal mass, DNA, protein, and sucrase levels were assessed 14 days after a 70% jejunoileal resection or control feeding. Serum fatty acid composition and several gastrointestinal hormone levels were measured., Results: Resected animals fed menhaden oil showed a marked increase in mucosal weight, DNA, and protein levels compared with rats fed the other fat sources. Enteroglucagon level was increased in all resected groups, but least increased in the menhaden-fed animals. In contrast, peptide YY concentrations were most increased in animals fed menhaden oil., Conclusions: Menhaden oil appears more effective in inducing intestinal adaptation than less highly unsaturated fats. Analysis of gastrointestinal hormones revealed no clear-cut explanation for this finding, other than a modest but associated increase in peptide YY levels.

Cyclic vomiting syndrome is an unusual cause of episodic emesis in children. It manifests as intermittent episodes of severe vomiting, similar in time of onset and duration, with no symptoms during the intervening period. Dehydration necessitating intravenous fluid therapy may occur. Most therapeutic maneuvers have proven unsuccessful. We report the use of erythromycin as a prokinetic agent in the treatment of cyclic vomiting in 20 children (9 boys, 11 girls). Many patients had mild associated abdominal pain with their vomiting. Thirteen patients had previously been given metoclopramide, but none responded. Two patients were mildly developmentally delayed. Twenty patients were given oral erythromycin ethylsuccinate, approximately 20 mg/kg/day, in 2-4 divided doses for 7 days. This dosage was repeated as needed when symptoms reappeared. Thirteen of 20 patients reported total resolution of symptoms when reevaluated at 2 and 6 months. All males responded, 4 of 13 responders were female, and all seven with partial or no response to therapy were female. This uncontrolled trial suggests that erythromycin may be a useful prokinetic agent in the treatment of cyclic vomiting syndrome in childhood. As the study was uncontrolled, placebo effect cannot be excluded. Case-controlled, double-blinded prospective trials should be considered to evaluate the effectiveness of erythromycin in cyclic vomiting syndrome.

The safety and efficacy of olsalazine sodium was compared to sulfasalazine over 3 months in a multicenter, randomized, double-blind study of 56 children with mild to moderate ulcerative colitis. Twenty-eight children received 30 mg/kg/day of olsalazine (maximum, 2 g/day) and 28 received 60 mg/kg/day of sulfasalazine (maximum, 4 g/day). Side effects were frequent in both groups. Eleven of 28 patients (39%) on olsalazine reported headache, nausea, vomiting, rash, pruritus, increased diarrhea, and/or fever. Thirteen of 28 on sulfasalazine (46%) reported similar side effects and/or neutropenia, and four patients had the drug stopped because of an adverse reaction. After 3 months, 11 of 28 (39%) on olsalazine were asymptomatic or clinically improved, compared to 22 of 28 (79%) on sulfasalazine (p = 0.006). In addition, 10 of 28 patients on olsalazine versus one on sulfasalazine required prednisone because of lack of response or worsening of colitis (p = 0.005). The dose of olsalazine used in this clinical trial was thought to be equivalent to a standard dose of sulfasalazine, but fewer patients on olsalazine improved and a greater number had progression of symptoms when compared to sulfasalazine. Although side effects were slightly less frequent for olsalazine, the number of patients was too small to detect a clinically significant difference.

Concentrations of cholecystokinin (CCK) and secretin from neonatal guinea pig plasma were evaluated in relation to pancreatic growth, and secretion from dispersed pancreatic acini. Plasma CCK was low at birth (3.1 +/- 0.8 pmol/L) but rose markedly by day 15 (11.0 +/- 0.8 pmol/L, p < 0.001). Plasma secretin was also low at birth (3.8 +/- 0.8 pmol/L) but peaked on day 4 (17.0 +/- 1.4 pmol/L, p < 0.001) and remained elevated through d 15. Adult nonfasting plasma CCK and secretin levels were 12.3 +/- 0.8 and 8.9 +/- 1.5 pmol/L, respectively. Pancreatic weight more than doubled during the first week of life, with the greatest increase during the first 4 d (156 +/- 4 to 262 +/- 10 mg/100g body wt, p < 0.001). Body weight increased most dramatically during the second week (126 +/- 9 to 190 +/- 7 g p < 0.001). Amylase secretion from isolated acini stimulated by CCK-8, carbachol, phorbol ester, forskolin, and calcium ionophore (A23187) was present at birth. The percentage of total amylase content secreted in response to CCK, carbamylcholine, and secretin did not change during the first 2 wk of neonatal life, and was independent of surges in circulating CCK and secretin. These results indicate that functional maturity of the guinea pig pancreas for amylase secretion occurs early and is different from the rat, mouse, pig, and human. Since results can readily be compared between animals of different postnatal ages, the neonatal guinea pig is ideally suited for the study of hormonal effects on acinar cell function.

To identify the factors regulating the proliferation of intestinal epithelium, we examined the effects of various growth factors on [3H] thymidine incorporation into the DNA of IEC-6 cells, an intestinal epithelial cell line derived from rat jejunal crypts. Insulin-like growth factor-I (IGF-I), IGF-II, and insulin stimulated the DNA and protein synthesis of IEC-6 cells in serum-free medium supplemented with transferrin, dexamethasone, and BSA (basal medium). Concentration-response experiments demonstrated that IGF-I is approximately 10 times more potent than IGF-II or insulin in producing 2- to 3-fold stimulations of DNA and protein synthesis by IEC-6 cells. In addition, IEC-6 cells proliferated slowly in the basal medium without any added growth factors. Analysis of medium conditioned by IEC-6 cells by gel filtration chromatography, RIA, HPLC, and N-terminal sequencing revealed that IEC-6 cells synthesize and secrete mature, 7,500 mo wt (M(r)) IGF-II as well as high M(r) forms of IGF-II. In addition, ligand blot, immunoblot, and N-terminal sequence analyses showed that IEC-6 cells produce the 34,000 M(r) IGF-binding protein-2 (IGFBP-2). To determine if IGFBP-2 modulates IGF responses in IEC-6 cells, the IGF-I analogs, Des-(1-3)-IGF-I and [Gln3,Ala4,Tyr15,Leu16]IGF-I, both of which have a reduced affinity for IGFBPs, were tested for their effects on IEC-6 cell proliferation. Both analogs exhibited 10-fold greater potency than IGF-I, presumably because endogenously secreted IGFBPs depress IGF-I binding to cell surface receptors. Finally, purified IGFBP-2 attenuated the DNA synthesis of IEC-6 cells in a dose-dependent manner. We conclude that IGFBP-2 secreted by intestinal epithelial cells is capable of limiting the mitogenic activity of both exogenous and endogenous IGFs by blocking the association of the growth factors with cell surface binding sites. These results further suggest that the growth of IEC-6 cells is modulated by autocrine mechanisms involving IGF-II and IGFBP-2.

It has been shown previously that insulinlike growth factors (IGFs) stimulate the proliferation of intestinal crypt cells in vitro. To examine the in vivo effects of IGF-I on mucosal adaptation, three groups of Sprague-Dawley rats underwent 80% jejunoileal resection. Miniosmotic pumps were then inserted under the skin immediately after resection to deliver vehicle (resected control), 1.5 mg/kg per day of IGF-I, or 1.5 mg/kg per day of des-(1-3)-IGF-I (des-IGF-I). Des-IGF-I is a truncated form of IGF-I that binds as well to type I IGF receptors but less tightly to several forms of IGF-binding proteins (IGFBPs) than IGF-I. Ad libitum food intake did not differ among the three resected groups. Body weight gains were greater in animals receiving des-IGF-I than in those receiving IGF-I, which were greater than resected controls. All animals were killed 7 days postoperatively, and the remaining small intestine was removed and divided at the anastomotic site. Both IGF-I and des-IGF-I induced hyperplasia (increased DNA and protein content) in the duodenojejunum but not in the ileum. IGF-I and des-IGF-I were equally active. In contrast, sucrase, maltase, and leucine aminopeptidase activities were greater only in the ileum of animals receiving IGF-I and des-IGF-I than in resected controls. Although more potent in stimulating overall body weight gain, des-IGF-I was not more potent than IGF-I when duodenal and ileal responses were determined. IGF infusion (IGF-I greater than des-IGF-I) increased the levels of circulating IGFBP-3 and IGFBP-2, which may act to modulate the biological effectiveness of the infused peptides. These results suggest that both IGF-I and des-IGF-I may have potential as therapeutic agents for short bowel patients.

With utilization of the techniques discussed in this review, patients with short bowel syndrome can be expected to live prolonged lives, even after fairly massive resection. Advances in parenteral and home parenteral nutrition and changes in the long-term management of chronic complications have altered the lifestyles of patients with short bowel syndrome. Intestinal transplantation may become an effective mode of therapy within a short period of time. Many surgeons faced with the possibility of leaving a child with only 10-15 cm of bowel in the past have closed the abdomen with the dead bowel and let the child die. These recent advances raise interesting ethical dilemmas. Research into the process of intestinal adaptation as well as greater experience with intestinal transplantation and other modes of therapy may further improve prognosis.

Following massive small bowel resection, the remaining small bowel increases in mucosal weight, protein, deoxyribonucleic acid (DNA) content and absorptive function. Enteral nutrients are known to be important in stimulating this response. Recently, glutamine has been described as an essential fuel for the small intestinal mucosa and is thought to be trophic to the small bowel. We investigated if glutamine, when added to the diet in large quantities, might stimulate mucosal adaptation beyond that which normally occurs following physiologic feedings. Male Sprague-Dawley rats were placed on powdered rat chow supplemented with either 5% glutamine, 5% glycine or 5% glucose. After 4 days rats underwent 70% jejunoileal resection. Fourteen days after resection, protein, DNA and sucrase activity in the duodenum of the glutaminefed animals were all significantly lower than results from both the glycine and glucose groups. Duodenal mucosal weight was lower in the glutamine group than in the glycine group. In the ileum, DNA content was significantly lower for the glutamine group than the glycine group. These results suggest that high concentrations of glutamine in the diet can have negative effects on intestinal adaptation.

Jejunoileal bypass operation was originally done to promote weight loss for treatment of morbid obesity. We used such a model to determine if dietary vitamin absorption is compromised by such an operation. Six rats were subjected to a jejunoileal bypass, 6 control rats were pair-fed to bypassed rats; and 6 were fed ad libitum. Vitamin content of folic, B6, riboflavin, nicotinate, pantothenate, thiamin, biotin, B12, vitamins A, E, and carotene in blood and liver was determined after 8 postoperative weeks. Aside from riboflavin, blood vitamin levels were significantly depressed in bypassed rats. The deepest depression was seen for B12, carotene and vitamin E. Liver vitamin stores of folate, riboflavin, thiamin, B12, clearly were significantly depressed in the bypassed animals compared to the pair-fed and ad libitum-fed controls. This model can serve for rapidly studying micronutrient depletion due to malabsorption without dietary manipulation or antibiotics for gut sterilization.

The in vivo absorption of 3-O-methyl-D-glucose (3MG) as a marker of intestinal function has not been studied in an animal model. We evaluated the use of 3MG as a marker of intestinal absorption when given enterally to rats recovering from small bowel mucosal injury induced by methotrexate (MTX). Radiolabeled 3MG was administered into the duodenum of control (CON) and MTX-treated rats and blood samples were obtained at specified intervals. Mucosal permeability was also assessed using radiolabeled mannitol and polyethylene glycol 900 (PEG). Concentration time points were plotted, and area under the curve was calculated as an approximation of absorbed dose. Mucosal weight, maltase activity, and protein content were determined on mucosal scrapings. During the acute phase (day 5), 3MG absorption and maltase-specific activity were significantly decreased in the MTX group when compared to the CON group (p less than 0.001). The MTX group showed a trend toward greater permeability to mannitol when compared to the CON group; however, this was not statistically significant. Mucosal permeability to PEG was similar in both groups. During a later stage in the recovery process (day 12), the area under the curve calculations for 3MG absorption were the same for both CON and MTX animals, with maltase activity in the MTX group recovering to control values. Changes in 3MG absorption paralleled total maltase activities following severe injury. These results suggest that the combined active and passive transport of 3MG in vivo could be of use as a marker of intestinal absorption in states where the small intestine has sustained major damage resulting in compromised absorption as well as brush border digestion.

Patients with the short-bowel syndrome frequently develop dilated intestinal segments that may lead to impaired motility and malabsorption. Although intestinal tapering alone improves motility, the intestine can be lengthened as well. We reviewed our experience with six children undergoing intestinal lengthening to improve intestinal absorption secondary to the short-bowel syndrome. The procedure was performed by dissecting the vessels along the mesenteric border and dividing the intestine longitudinally with a stapler. Five patients were receiving total parenteral nutrition (TPN) and one was becoming malnourished with enteral feedings alone. Bacterial overgrowth was documented in four patients and abnormal liver function in three patients. The intestinal segments were dilated up to 10 cm in diameter and remnant length ranged from 15 to 79 cm. Segments 5 to 25 cm in length were divided, resulting in an average increase in length of 52%. Necrosis of one of the divided limbs necessitated resection in one patient. Follow-up ranged from 2 to 84 months. TPN has been discontinued in four patients and avoided in another. Symptomatic improvement occurred in all patients. We feel the tapering and lengthening procedure should be considered in patients with symptomatic, dilated intestinal segments in whom the need for TPN may potentially be obviated.

Prenatally acquired cytomegalovirus infection in twins was temporally associated with a discordant development of neonatal hepatitis and extrahepatic biliary atresia. This case presents evidence suggesting an association between perinatal cytomegalovirus infection and selected extrahepatic biliary atresia and neonatal hepatitis. Congenital cytomegalovirus infections and cytomegalovirus hepatitis are also discussed.

Aluminum toxicity is a documented cause of encephalopathy, anemia, and osteomalacia. Excretion is primarily renal; therefore, patients with renal insufficiency are at risk for aluminum accumulation and toxicity. This has been demonstrated in uremic children treated with aluminum-containing antacids. The purpose of this study was to determine whether plasma aluminum levels were elevated in infants with normal renal function during prolonged aluminum-containing antacid use. Ten study infants (mean age = 5.8 months), who had been receiving antacids for at least 1 week, were compared with 16 control infants (mean age = 9.8 months) not receiving antacids. The study patients consumed 123 +/- 16 mg/kg per day (mean +/- SEM) of elemental aluminum for an average of 4.7 weeks. Their plasma aluminum level (37.2 +/- 7.13 micrograms/L) was significantly greater than that of the control group (4.13 +/- 0.66 micrograms/L) (P less than .005). It is concluded that plasma aluminum levels may become elevated in infants with normal renal function who are consuming high doses of aluminum-containing antacids. The safety of antacids containing aluminum should not be assumed and they should be used judiciously in infants, with careful monitoring of the aluminum dose and plasma level.

Insulin-like growth factors (IGFs) and insulin stimulate DNA and protein synthesis in IEC-6 cells (an intestinal epithelial cell line) grown in a chemically defined medium. IGF-I stimulates proliferation of IEC-6 cells at a lower concentration (ED50 = 1.6 nM) than either insulin or IGF-II. To gain insight into the mechanisms by which IGFs stimulate IEC-6 cell growth, we have examined the characteristics of specific IGF receptors on IEC-6 cells. Binding of 125I-IGF-I and 125I-IGF-II to IEC-6 monolayers was analyzed by incubation with various concentrations (0.2 nM to 0.5 microM) of radiolabeled IGFs for 16 h at 3 C. Scatchard plots of 125I-IGF-I binding were linear, suggesting a single class of binding sites with KD = 3.1 +/- 0.35 nM and Bmax = 50.7 +/- 6 fmol/10(6) cells. IGF-II was potent in displacing 125I-IGF-I (KI = 8.1 +/- 0.85 nM), but insulin had little effect. Affinity cross-linking with 125I-IGF-I followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed three bands with Mr of 270,000, 245,000, and 133,000, and the major band was the 133,000 species. Labeling of the 133,000 and 270,000 bands was greater than or equal to 80% inhibited by 10(-7) M unlabeled IGF-I, less potently inhibited by IGF-II and not at all by insulin. These results suggest that the 133,000 band represents the alpha-subunit of the type I IGF receptor. Scatchard plots of 125I-IGF-II binding to IEC-6 cell monolayers were curvilinear, suggesting two classes of binding sites: high affinity, low capacity sites, KD = 0.87 +/- 0.08 nM and Bmax = 28 +/- 2.5 fmol/10(6) cells; low affinity, high capacity sites, KD = 60 = +/- 8.8 nM and Bmax = 1780 +/- 230 fmol/10(6) cells. Neither IGF-I nor insulin was effective in inhibiting 125I-IGF-II binding. Affinity cross-linking with 125I-IGF-II labeled predominantly a 245,000 band, suggesting that this species is the type II receptor. A band with Mr 131,000 was barely detectable with 125I-insulin. These results indicate that IEC-6 cells have abundant quantities of the type I and II IGF receptors and few insulin receptors, suggesting that the mitogenic effect of IGFs is mediated through the type I IGF receptor.

The present studies were conducted to determine if diets containing a large amount of fat stimulate the regeneration of damaged intestinal mucosa in the presence or absence of essential fatty acid deficiency. To simulate injury, male Sprague-Dawley rats were given methotrexate, 2.5 mg/kg body wt, subcutaneously for 3 consecutive days. Twenty-four hours after the last methotrexate injection, rats were placed on diets containing either 0%, 1%, or 10% safflower oil. Mucosal weight, protein, deoxyribonucleic acid, maltase, sucrase, lactase, alkaline phosphatase, leucine aminopeptidase, and fatty acids were all determined 3 and 12 days after methotrexate. Crypt-cell production rates were also determined. Essential fatty acid deficiency was confirmed in the 0% safflower oil group, in which triene-tetraene ratios were greater than 0.4. Mucosal weight, deoxyribonucleic acid, protein content, and villus height were all greater in the 1% safflower oil group than in the 0% group at 12 days. In the ileum, 1-h thymidine incorporation was greater in the 0% safflower oil group than in the other two groups. No differences in any of the parameters studied were observed between the 1% and 10% groups. These results suggest that diets deficient in essential fatty acids may impair the recovery of intestinal mucosa from injury.

The stability of several vitamins and minerals of a new formula for premature infants, Similac Special Care, was examined following passage through a simulated continuous infusion apparatus designed to duplicate that used for continuous enteral feeding in infants. The concentrations of calcium, iron, zinc, copper, magnesium, vitamin A, vitamin C, and vitamin E were measured before and after infusion at rates appropriate for delivering 120 calories/kg to infants weighing 733 and 1,000 g. Following passage through this apparatus, significant reductions were noted for calcium (44-54%), iron (23-34%), and zinc (18-32%). Concentrations of copper, magnesium, and vitamins A, C, and E remained stable. When another formula commonly used for premature infants, Similac 24LBW, was subjected to similar analysis, the concentrations of all vitamins and minerals studied remained stable. Our study demonstrates that infants fed Similac Special Care by continuous infusion may not receive the quantity of calcium, iron, and zinc implied by the product label.

Zinc absorption was evaluated six weeks after massive small-bowel resection in rats. Forty rats were divided into four groups. Ten were subjected to proximal small-bowel resection, 10 to distal resection, and 20 served as pair-fed controls. Intestinal perfusion studies were performed using a recirculation technique. Twenty ml of a solution containing 10 microgram/ml of zinc as zinc sulfate, isotonic sodium chloride, and polyethylene glycol 5 g/liter was perfused for 2 hr through 10 cm of remaining bowel in resected animals and comparable segments in control animals. Zinc uptake was determined and expressed per 0.1 g mucosal dry weight. In control animals, zinc absorption was greatest in the ileum. Animals undergoing distal bowel resection had a compensatory increase in zinc absorption in the proximal small intestine. However, animals undergoing proximal resection did not demonstrate an increase in zinc absorption in the distal bowel. The proximal small intestine appears capable of increasing its capacity for zinc absorption in the response to distal small-bowel resection.

Patients undergoing massive small bowel resection for a variety of conditions develop severe nutrient malabsorption which gradually improves through mucosal hyperplasia in the remaining small intestine. Following massive small bowel resection, patients are generally fed elemental diets, often containing high concentrations of medium-chain triglycerides. We evaluated the effect of high percentage medium-chain triglyceride feeding on mucosal adaptation following massive small bowel resection in rats. Twenty 150-g Sprague-Dawley rats were subjected to 60% jejunoileal resection. Another 20 animals received sham operations. One-half of each group were fed a diet containing 83% of the fat as medium-chain triglycerides, the remainder were fed a diet containing 40% medium-chain triglycerides. Animals were pair-fed for 2 wk and subsequently killed. The remaining bowel was removed and unidirectional glucose and leucine uptake were measured using isolated sacs. Mucosal wet weight, protein, and sucrase content were determined. Animals fed medium-chain triglycerides demonstrated decreased mucosal weight in the proximal bowel, decreased mucosal sucrase activity in the proximal bowel, and decreased mucosal leucine uptake in the distal bowel. While medium-chain triglycerides offer an advantage to patients with short bowel syndrome because they are easily absorbed, they may not stimulate the same degree of mucosal adaptation following resection as long-chain triglyceride feedings.

We investigated the effects of zinc deficiency on body composition by using intragastric force-feeding to obviate decreased food intake and altered eating patterns. Weanling male Sprague-Dawley rats were fed a purified zinc-deficient diet: the ad libitum-fed control group (AL; eight rats) was given powdered diet and water containing 25 ppm zinc; the zinc-replete group (ZN; nine rats) was force-fed a diet blended with water containing zinc in an amount of equal caloric intake to the AL group and allowed access to water containing zinc. The zinc intake of ZN rats was approximately twice that of AL rats based on water intake. The zinc-deficient group (ZD; 13 rats) was fed similarly to the ZN group except deionized water was used for diet preparation and drinking water. After 8 d, body and muscle weight were lower in the ZD group than in the ZN group. Femur weights were similar in the two groups. Serum, liver and femur zinc concentrations were 85, 22 and 42% lower, respectively, in the ZD group than in the ZN group. Serum glucose, relative liver weight, liver glycogen and liver lipids were higher, but muscle and liver DNA were lower in the ZD group than in control groups.

Pancreatic secretions have been shown to be important in zinc absorption in experimental animals. Recently, complete surgical diversion of biliary and pancreatic secretions from the functioning small intestine has been utilized in Europe to treat morbid obesity. To determine the importance of pancreatic secretions in zinc absorption in the human, we measured hair and serum zinc levels in 14 patients having undergone complete biliopancreatic bypass 12-56 months earlier and compared these values with those obtained from 11 patients subjected to only partial biliopancreatic bypass as well as to six morbidly obese controls. No differences were observed in either hair or serum zinc levels between any of these groups of patients. Pancreatic secretions do not appear to be necessary for adequate zinc absorption in humans.

Postresection villus hyperplasia is a major compensatory mechanism in the short-bowel patient. Substances capable of augmenting postresection mucosal hyperplasia could have therapeutic implications. Human growth hormone (hGH) and human growth hormone releasing factor (hGHRF) stimulate growth of the gastrointestinal tract; however, the diabetogenic actions of growth hormone limit its usefulness in clinical practice. Plerocercoid larvae of the tapeworm Spirometra mansonoides produce an analog of hGH void of diabetogenic side effects. We assessed effects of plerocercoid growth factor (PGF) on mucosal adaptation following 70% proximal jejunoileal resection in young rats. Mucosal weight, DNA, protein, and total sucrase activity per centimeter of bowel were increased in resected PGF-treated animals compared to resected controls. We conclude PGF augments intrinsic postresection mucosal hyperplasia following extensive intestinal resection.

Two anorectic, emaciated infants with central nervous system (CNS) neoplasms are reported. Diagnosis in each case was delayed, because computed tomography of the head was initially falsely negative, and because primary gastroenterologic illness was suggested by the presence of mild inflammation and villous atrophy of the small intestine. This experience indicates that the diagnosis of CNS neoplasm must be aggressively pursued in cachectic infants who refuse to eat, regardless of the results of the initial radiologic studies. Mild histologic abnormalities of the small intestine that may be present in infants with brain tumors probably represent a nonspecific response to starvation and, if unassociated with malabsorption, should not be considered the cause of illness.

Several recent studies suggest that jejunoileal bypass-induced liver disease results from malabsorption of essential nutrients. However, in experimental animals, resection of the defunctionalized bowel substantially reduces bypass-induced liver injury. Such models are often used to support the theory that bacteria in the defunctionalized bowel produce toxic substances which result in liver damage. We used a rat model to first explore the effects of intestinal bypass vs resection on various parameters of liver injury, and subsequently compared these findings to the effect of both bypass and resection on mucosal adaptation in the remaining intact bowel after each procedure. Bypassed animals had lower levels of hepatic cytochrome P-450, glucose-6-phosphatase, pentobarbital hydroxylase, and serum triglycerides than did animals undergoing resection of defunctionalized bowel. Concurrently, resected animals had much greater increases in mucosal weight, DNA content, and protein content in the intact bowel than did bypassed animals. We speculate that the beneficial effects of resection of bypassed bowel on liver function may be a result of increased mucosal hyperplasia in resected animals, rather than elimination of production of toxic substances in the defunctionalized bowel.

The effect of zinc deficiency on glucose tolerance was investigated using intragastric force feeding to obviate decreased food intake and altered eating patterns. Three groups of weanling male Sprague-Dawley rats were fed a purified zinc-deficient diet: zinc-deficient, ad libitum-fed animals (ZDA) were offered powdered zinc-deficient diet; zinc-replete, force-fed controls (ZRF) were tube fed a diet blended with water containing 25 ppm of zinc; zinc-deficient, force-fed animals (ZDF) were similarly tube fed the zinc-deficient diet. The ZRF and ZDF groups received a diet of identical amount based on the intake of ad libitum-fed, zinc-replete rats. After 8 days of feeding, the ZDF group had impaired glucose tolerance curves, yet blood insulin and glucagon levels were normal. The ZDA group had normal glucose tolerance with low insulin levels compared with the ZRF group. The islet cell morphology among the three dietary groups were similar. These results suggest that the glucose intolerance observed in ZDF rats is not due to altered blood insulin and glucagon levels but rather to peripheral resistance to insulin action.

A steerable small bowel biopsy apparatus was evaluated in 56 infants and children over a 15-mo period. A mean time of only 6 min was required to obtain small bowel biopsies. Biopsies were successfully obtained in 92% of patients on the first attempt; repeat attempts were successful in all cases. No complications were encountered. The steerable biopsy tube appears to be a safe and effective means of obtaining small bowel biopsies rapidly in infants and children.

A 17-year-old boy with immunodeficiency, elevated levels of IgM,and neutropenia developed distal esophageal ulcers and stricture. Although his lower esophageal sphincter pressure was decreased, he had normal acid reflux test results, normal findings from acid clearing studies, and absence of diffuse esophagitis at esophagoscopy. Neutropenia and hypogammaglobulinemia are postulated as pathogenic factors in his esophageal ulcers.

Little is known concerning the effects of elemental diets on bowel adaptation following massive resection. Fourteen of 28 Sprague-Dawley rats (40-45 g) were subjected to a 60% jejunoileal resection. Seven of the resected animals and seven sham-operated controls were then placed on a diet containing all protein in the form of casein hydrolysate. The remaining seven resected animals and seven sham-operated controls were placed on a comparable diet in which all the protein was casein. Each control animal was paired with a resected animal. After 2 weeks, unidirectional glucose and leucine transport was determined from intestinal sacs made from the proximal 3 cm and distal 3 cm of the remaining bowel. The midportion was used for the determination of mucosal weight and protein and sucrase content. When expressed as a percent increase over control values per centimeter of bowel, only sucrase levels were significantly elevated in the distal bowel in casein hydrolysate-versus casein-fed animals. The mucosal protein level, mucosal weight, and glucose uptake did not differ from control values when expressed as a percent change. Leucine uptake was significantly decreased in casein hydrolysate-fed animals when compared to that in casein-fed animals in both the proximal and distal bowel, again when expressed as a percent change from the control values. The administration of protein in the form of casein hydrolysate following massive bowel resection does not adversely affect mucosal hyperplasia occurring after resection but may have an adverse effect on the enhancement of amino acid absorption.

To assess the influence of diamine oxidase activity on the adaptive process of the small bowel after resection, we administered aminoguanidine, a potent diamine oxidase inhibitor, to rats for 10 days after either small bowel transection (n = 5) or 80% jejunoileal resection (n = 7). Five or more additional animals from each group received saline as controls. Ileal mucosal homogenates from the resection group receiving aminoguanidine, when compared with those from resection controls, showed no diamine oxidase activity with increased putrescine content and ornithine decarboxylase activity. Mucosal proliferation, as measured by mucosal mass, protein content, and deoxyribonucleic acid content, was greater in the resected animals receiving aminoguanidine when compared with that of resection controls. Sucrase activity per gram of mucosa was almost identical in both resection groups. These results show that the suppression of diamine oxidase during the postresection adaptive period results in enhanced mucosal proliferation with no effect on mucosal functional differentiation. Diamine oxidase may play a regulatory role in adaptive intestinal proliferation.

The ability of 16,16-dimethyl-prostaglandin-E2 (PGE) to augment mucosal adaptation 14 days after a 70% distal small bowel resection in the rat was evaluated. In resected (R) and sham operated (S) animals, subcutaneous PGE 75 mg/kg, 2 X/day, induced significant (p less than 0.05) increases in mucosal protein, DNA, and disaccharidase concentrations per centimetre of bowel. The respective per cent increases in the residual proximal small intestine compared with their respective untreated controls were: protein, R = 60%, S = 66%; DNA, R = 69%, S = 29%; maltase, R = 57%, S = 5%. The uptake of leucine by intestinal rings was significantly higher (50%) in the PGE treated group at a concentration of 2 mmol/l of substrate, while the uptake of glucose was similar in all groups. The drug appears to be an effective agent in stimulating morphological and functional adaptation after massive distal small bowel resection.

The effect of chronic ethanol ingestion on the ability of the small intestine to absorb zinc was examined in male Sprague-Dawley rats. Six rats were fed the Lieber-Decarli liquid rat diet for 1 month during which 36% of their total calories were provided as ethanol, while their pair fed controls received these calories as carbohydrate. Zinc absorption was then examined simultaneously in duodenal and ileal segments by in vivo perfusion. Net absorption of zinc in the ileum was reduced by 16% following chronic ethanol feeding. Duodenal absorption of zinc was significantly less than in the ileum and was unaffected by chronic ethanol ingestion. These results demonstrate that chronic ethanol ingestion significantly impairs net zinc absorption in the ileum of the rat, the most active area of zinc uptake as measured by in vivo perfusion, and suggest that malabsorption of zinc may contribute to the zinc deficiency seen following chronic ethanol ingestion.

Lower esophageal sphincter (LES) pressure is frequently measured to diagnose LES incompetence in adults. The multilumen perfused catheters with large diameters that are used for ths purpose are not suitable for small infants. We measured LES pressure in ten normal newborns with a small, single-lumen perfused catheter and compared our values with those obtained with the standard adult apparatus. Higher pressures were recorded with the single-lumen catheter. Chloral hydrate sedation had no effect on LES pressure. Two-day-old infants had LES pressures comparable to those of adults and older children. The technique was applied to the diagnosis of LES incompetence in 23 infants. Infants with LES incompetence (chalasia) were correctly separated from infants with chronic vomiting secondary to all other causes. Single-lumen manometric studies provide a simple, reliable, and safe method of assessing LES incompetence in small infants.

Survival following massive resection of the small intestine is often possible due to substantial hyperplasia of the mucosal surface in the remaining small intestine. While nutrients provide the major stimulus for hyperplasia in the clinical setting, the availability of drugs to augment this process would have obvious therapeutic implications. We evaluated the ability of 16,16-dimethyl-prostaglandin E2 (PGE2 to augment mucosal hyperplasia following massive small bowel resection in the rat. Three groups of 7 Sprague-Dawley rats, 160 g body weight, were subjected to 70% jejunoileal resection. One group was given 150 micrograms/kg of 16,16-dimethyl-PGE2 intragastrically twice daily, a second group 75 micrograms/kg subcutaneously, and a third group was untreated. After 17 days, segmental evaluation of mucosal mass in the remaining small intestine was determined by measuring mucosal protein, DNA, and disaccharidase levels. A significantly greater increase in mucosal mass was developed in the duodenum proximal to the anastomosis in both treatment groups, but neither the proximal nor distal ileum demonstrated significantly more adaptation. Histological examination in the duodenum confirmed the presence of a greater adaptive response in both the intragastrically and subcutaneously treated animals. 16,16-dimethyl-PGE2 appears to augment mucosal adaptation following massive small bowel resection in the rat, primarily in the very proximal small intestine.

We have studied net uptake of zinc from segments of rat duodenum, jejunum, and ileum using in vivo intestinal perfusion. We have also evaluated the effect of pancreatic and bile secretions on duodenal zinc absorption. Segments of duodenum, jejunum, and ileum and duodenum with bile and pancreatic duct obstruction, 10 cm in length, were studied in six rats each. Percentage absorption of zinc as determined by atomic absorption spectrophotomety was greater from the ileum (60.1%) when compared to duodenum (19.1%) or jejunum (20.2%). Exclusion of bile and pancreatic secretions from the lumen increased zinc absorption in the duodenum (32.0%). Postperfusion mucosal zinc content comprised 29.0% of absorbed zinc from jejunum, 7.4% from ileum, 5.2% from duodenum, and 2.7% from duodenum with bile and pancreatic duct obstructed, indicating rapid transport of zinc across epithelial cells after uptake from the duodenum and ileum. Our data indicate that the ileum has the greatest capacity for zinc absorption.

Drugs that block the assembly of microtubules inhibit protein secretion by mature hepatocytes. In this study, we ascertained the effects of these drugs on hepatic protein secretion during development. Slices prepared from adult and late-gestation (day 21) fetal rat livers were incubated with colchicine, vinblastine, or podophyllotoxin, and the secretion of [14C]leucine-labeled proteins was then determined. Colchicine (10 microM) decreased trichloroacetic acid-precipitable protein secretion by 65% in adult liver, but only by 31% in fetal liver. A higher (50 microM) concentration of colchicine caused minimal further impairment of secretion in both age groups. Colchicine (10 microM) impaired the secretion of immunoprecipitable albumin to about the same degree as trichloroacetic acid-precipitable proteins in both adult and fetus. Determinations of [3H]colchicine uptake into slices indicated that reduced hepatocellular levels of the drug were not the cause of the diminished effect on protein secretion observed in the fetus. Like colchicine, various concentrations of vinblastine and podophyllotoxin inhibited trichloroacetic acid-precipitable protein and albumin secretion consistently less from the fetal liver (30%-50%) than from the adult liver (50%-75%). These results indicate a reduced dependence on normal microtubule function for protein secretion in the developing liver.