Effect of carbohydrate and corticosteroids on activity of -glucosidases in intestine of the infant rat.

The activities of intestinal sucrase and isomaltase are not detectable in rats before 15-16 days of age, but administration of corticosteroids precociously induces the activities of these two alpha-glucosidases. 9-day old rats were removed from their mothers, warmed in an incubator, and fed by constant infusion through gastrostomies. The basic diet was a soya preparation to which various sugars were added. When the diet contained 2% sucrose, diarrhea ensued for 48 hr, but subsided when intestinal sucrase and isomaltase appeared precociously. In animals fed sucrose, the activities of sucrase and isomaltase were markedly increased as compared to animals on carbohydrate-free diets (sucrase 2.41+/-0.23 vs. 0.63+/-0.13 U, isomaltase 3.43+/-0.42 vs. 0.78+/-0.18 U). Maltase activity was doubled, while lactase was not altered significantly. The mitotic index of crypt cells, the depth of crypts, and incorporation of thymidine-(3)H into DNA were increased. In adrenalectomized rats, activities of sucrase and isomaltase were not detected nor induced by sucrose. Steroids given to adrenalectomized rats caused appearance of the enzymes; but if cortisone and sucrose were given together, there was synergism evidenced by a marked increase in activities (sucrase 7.2+/-1.1 vs. 0.68+/-0.12 U). In contrast to observations in adult animals, the effect of sucrose on alpha-glucosidases in developing animals demands the participation of the adrenal gland.

Subcellular localization of enterokinase (enteropeptidase EC 3.4.21.9) in rat small intestine.

The subcellular localization of enterokinase is controversial. In this study, enterokinase was extracted from a soluble fraction and a brush border fraction of rat small intestine by differential centrifugation. The soluble fraction contained 41% of the initial enterokinase activity while the brush border fraction contained only 4.6% of the initial activity. In contrast, alkaline phosphatase monitored as a brush border marker, yielded 26.3% in the brush border fraction and only 6% in the soluble fraction. Further separation of the soluble fraction on a Sepharose 4B column revealed three peaks of enterokinase activity. One small peak (3%) of a bound enzyme (Mr, 2 - 10(6)) and two larger peaks of free enzyme (Mr, 3 - 10(5) and 9 -10). In contrast, alkaline phosphatase major fraction was in a high molecular weight peak of bound enzyme. When the brush border fraction was chromatographed only a single peak of bound enterokinase and alkaline phosphatase were found. In the lower part of the small intestine, no brush border-bound enterokinase was found, while the peak of alkaline phosphatase was the same as in the upper intestine. These data suggest that enterokinase activity in the rat intestine is mainly in a free form localized in the mucin and soluble fraction and to a negligible extent in the brush border.

Interaction of epidermal growth factor with specific binding sites of enterocytes isolated from rat small intestine during development.

Isolated enterocytes from rat small intestine were characterized for their specific binding of epidermal growth factor (EGF). Intestinal epithelial cells were isolated at 4 degrees C to minimize the loss of receptor sites during the isolation procedure. 125I-labelled EGF binding to enterocytes from adult rats was found to be specific, saturable, temperature dependent and trypsin sensitive. Binding performed in the presence of a lysosomotropic agent (NH4Cl) increased the time required to reach maximal binding at 25 degrees C. NH4Cl had no significant effect on the time-course of EGF binding at 4 degrees C and 37 degrees C. A Scatchard plot showed a curvilinear relationship indicating that EGF binds to enterocytes with more than one binding site. Developmentally, enterocytes from fetuses and pups showed characteristic temperature dependence and trypsin sensitivity, but with different levels of binding to EGF. Specific EGF binding was demonstrably higher in enterocytes from small intestine of term fetuses. EGF binding to isolated enterocytes declined rapidly after birth, and the level stayed fairly constant thereafter. Pretreatment of enterocytes from fetal intestine with mature rat milk led to a dose-dependent decrease in EGF binding. These results suggest the presence of endogenous milk factors that modify EGF binding and account for, at least partly, the observed rapid decrease of EGF binding after birth.

Immature stimulus-secretion coupling in the developing exocrine pancreas and ontogenic changes of protein kinase C.

Previous observations have shown unresponsiveness of pancreatic acini to cholecystokinin C-terminal octapeptide (CCK-8) and cholinergic agents in newborn rats. In this study, the possibility that a lack of protein kinase C may be one factor limiting the responsiveness of the acini was examined. In the term fetus and in newborns cytosolic protein kinase C activity was low. Shortly after birth, the activity increased rapidly and by 2 days of age reached adult levels which were 5-fold higher than that in the newborn. No differences in subcellular distribution of protein kinase C activity between the particulate and the cytosol fractions were found at any age studied. Developmental profiles of phorbol dibutyrate binding, an alternative method for measuring protein kinase C, were similar to those of protein kinase C activity measurements. Using stimulation of amylase secretion as an index of responsiveness, dispersed pancreatic acini of newborn rats were found to be unresponsive to TPA (a potent activator of protein kinase C) and CCK-8, but were responsive to dibutyryl cAMP and calcium ionophore A23187 (agents not dependent on protein kinase C activity). These results suggest that the low levels of pancreatic protein kinase C in newborn rats are at least in part responsible for the unresponsiveness of pancreatic acini to 12-O-tetradecanoylphorbol 13-acetate and CCK-8.

The role of carbohydrate moieties of cholecystokinin receptors in cholecystokinin octapeptide binding: alteration of binding data by specific lectins.

Cholecystokinin (CCK) receptors on rat pancreatic acini have been demonstrated to be glycoproteins. In order to study whether their carbohydrate moieties play a role in ligand binding, membrane preparations (adjusted to 0.2 mg protein me) were incubated with 20 pM 125-I-CCK octapeptide (125I-CCK8) for 4 h at 30 degrees C in the presence of lectins with different sugar specificities. Concanavalin A, soy-bean agglutinin, and peanut agglutinin in concentrations up to 1 mM did not alter specific 125I-CCK8 binding. Ulex europeus lectin I showed a dose-dependent enhancement of CCK binding up to 150% of controls at a concentration of 1 mM. Wheat-germ agglutinin (WGA) was the only lectin found to have an inhibitory effect. Inhibition was dose-dependent, with maximal reduction attained at 42 nM, but CCK binding was only partially inhibited to 66.2 +/- 4.4%. Inhibition by WGA was prevented by the presence of N-acetyl-D-glucosamine or N,N',N"-triacetylchitotriose, sugars that are specific for WGA. The inhibitory effect of WGA was not due to an increase in non-specific binding, increased CCK degradation, or CCK binding to WGA. Binding data indicated that the presence of WGA resulted in a decrease in receptor affinity (Kd = 567 +/- 191 v. 299 +/- 50 pM). No significant change in the number of available binding sites was observed. This suggests that WGA is not binding to the active binding site. It is conceivable that binding of WGA to N-acetyl-D-glucosamine or its polymers can lead to a conformational change in the receptor protein, and that this carbohydrate moiety is essential for optimal receptor-ligand interaction.

Essential role for polyamine biosynthesis in thyroxine stimulated pancreatic development in neonatal rats.

Administration of thyroxine to rat pups leads to precocious development of the pancreas. The role of ornithine decarboxylase (ODC) and polyamines in thyroxine-induced pancreatic maturation was examined. Rat pups (aged 5 days) were given daily subcutaneous injection of thyroxine (0.1 micrograms/g body wt.) until the day before death. Serial ODC activities were measured in pancreatic homogenates after 1, 2, 3, 4, 5, 6, 7 and 10 days of thyroxine treatment. There was a biphasic induction of ODC activities by thyroxine: an early peak appeared on day 2 of treatment followed by a decrease on day 4; a second peak was evident on day 5 and then a decrease to control values by day 7. Significant increases in tissue concentrations of putrescine and spermidine were observed concomitant with two peaks of ODC activity. Pancreatic amylase concentration, DNA and protein also showed a significant increase after thyroxine treatment. Difluoromethyl ornithine (DFMO), a specific ODC inhibitor, given orally (8% in drinking water) to nursing dams at postnatal day 5 for 5 days caused an 83% inhibition of pancreatic ODC activity in thyroxine-treated pups when compared to thyroxine-treated pups not exposed to DFMO. Concomitantly, the thyroxine-induced increases in pancreatic weight, protein and amylase activity were suppressed. Our results suggest that increases in ODC activities and polyamine levels are critical intermediary steps in the precocious induction of pancreatic development by thyroxine.

Short-term effect of epidermal growth factor (EGF) on sodium and glucose cotransport of isolated jejunal epithelial cells.

This study was undertaken to assess the short-term effects of EGF on sodium and glucose uptake, glucose metabolism and Na+/K(+)-ATPase activity in isolated enterocytes of rats. Jejunal cells exposed to EGF had a significantly greater total uptake of sodium compared to controls after 6 min. Kinetic analysis of glucose transport across BBMV's demonstrated similar Km values but a significant increase of the Vmax in vesicles prepared from cells first exposed to EGF as compared to controls. EGF was also associated with a significant increase in glucose metabolism of jejunal enterocytes after 15 min. The activity of Na+/K(+)-ATPase increased in jejunal enterocytes exposed to EGF. The increase in Na+/K(+)-ATPase activity of the cells following EGF exposure was not accompanied by an increase in immunodetectable total or assembled Na+/K(+)-ATPase protein. EGF's effect on enzyme activity was abolished by removing NaCl from the incubation solution, and by preincubating the enterocytes with phlorizin prior to addition of EGF. Preincubation with amiloride did not inhibit the effect of EGF on Na+/K(+)-ATPase. The results confirm that EGF promotes uptake of both sodium and glucose by the jejunal mucosal cells, and suggest the effect of EGF on glucose and sodium is mediated through the brush-border membrane glucose-sodium transporter. The increase in Na+/K(+)-ATPase activity that occurs with EGF appears to be secondary to a rise in intracellular Na+ concentration. The short-term effects of EGF on glucose and sodium transport by the small intestine may have potential therapeutic implications.

Thyroidal regulation of rat pancreatic nuclear triiodothyronine receptor during postnatal development.

We have shown previously that the rat pancreas contains nuclear T3 receptors which exhibit a characteristic maturation pattern during development. To investigate whether these receptors are subjected to autologous regulation by thyroid hormones, the effect of T4 on the binding capacity (Bmax), dissociation constant (Kd), and receptor occupancy were followed in intact rat pups at various ages. Hyperthyroidism (by daily injection of T4 0.1 micrograms/g body wt to intact pups starting 4 days before death at 5, 10, 15, and 20 days of age) increased while hypothyroidism (by propylthiouracil feeding) decreased the total T3 binding capacity during preweaning ages (mean maximal binding capacities as estimated by Scatchard analysis, at 30 C for 14-20 days old eu-, hyper-, and hypothyroid pups: 186, 229, and 129 fmol/mg non-histone protein (NHP). The thyroid conditions also affected the percentage of T3 receptor occupancy but not the affinity of binding (as measured by Kd). Concomitantly, these conditions also caused corresponding changes in pancreatic weights, DNA and protein contents, and the concentrations of amylase, trypsinogen, and lipase. The postnatal developmental retardation induced by 6-n-propyl-2-thiouracil treatment was reversed by T4 replacement. The results suggest that rat pancreatic T3 nuclear receptors during postnatal ages are modulated by T4, and such modulation apparently in turn affects the development of the exocrine enzymes.

Regulation of rat pancreatic glucocorticoid receptors by thyroxine during development.

The effect of T4 on the development of pancreatic glucocorticoid receptors was studied in normal and adrenalectomized rat pups. Daily injection of T4 (0.1 microgram/g BW) to intact pups starting 3 days before death at 10, 15, and 20 days of age resulted in a precocious increase in pancreatic glucocorticoid-binding capacities. Intact pups made hypothyroid by propylthiouracil feeding exhibited lower glucocorticoid-binding capacities in their pancreata. Scatchard analysis demonstrated an increase in the number of glucocorticoid-binding sites in the pancreata of T4-treated intact rats compared to that in normal intact rats. In hypothyroid groups the number of glucocorticoid-binding sites was much lower than that in normal intact rats. The Kd values, however, were unchanged in hypothyroid, hyperthyroid, and control groups. Rat pups who underwent adrenalectomy at 12 days of age had undetectable plasma corticosterone levels and showed an increase in their pancreatic glucocorticoid-binding capacity 3 days after operation. Replacement of corticosterone resulted in a binding level similar to that in the sham-operated group. However, injection of T4 alone to adrenalectomized pups led to a further increase in pancreatic glucocorticoid-binding capacity above that due to adrenalectomy alone. When both T4 and corticosterone were given together to adrenalectomized pups their pancreatic glucocorticoid-binding capacities increased to levels above those in the adrenalectomized group, but lower than those in pups receiving T4 alone. Our results suggest that T4 modulates the development of rat pancreatic glucocorticoid receptors and, at least in part, acts via pathways independent of adrenal function.

Correlation of lactase activity, lactose tolerance and milk consumption in different age groups.

Small intestinal lactase activity in the health adult is either the same as in early infancy or may drop to very low levels. The behavior of the enzymatic state varies with the ethnic group studied. In those adults with low lactase activity little information is availalbe as to the age at which the lactase decreases. We attempted to determine a) the frequency of low intestinal lactase activity and b) the age at which the change occurs. For this purpose we reviewed in a large number of intestinal biopsies both histologically as well as for disaccharidase activities. The biopsies were obtained from a heterogeneous group of Caucasians, including patients, their siblings and parents. The patients were those with failure to thrive in whom no organic cause could be elicited, and those with the irritable colon syndrome. Patients ranged in age from 6 weeks to 50 years and out of a total of 1, 077 jejunal biopsies, 172 morphologically normal biopsies were selected. The milk drinking habits of 118 subjects and their families were elicited and 31 oral lactose tolerance tests performed. The mucosal lactase activity and sucrase-to-lactase ratio in those 172 individuals were plotted against age. In the first 3 years the mean lactase activity was 32.1 plus or minus 10.1 mumoles/g protein per min and the sucrase-to-lactase ratio was 1.7 plus or minus 0.5 with no change from year to year. However, after age 5 two separate groups emerge. A small group (24.6% of the population) with low lactase activity, and a second group possessing the same mean value for lactase activity as noted in the first 3 years. The low lactase activity group included children and adults with clinical lactose intolerance. These individuals consumed relatively small amounts of milk and when 12 of them were tested with an oral lactose tolerance test the result was a "flat" curve with a maximum rise in blood glucose of 9 plus or minus 3.2 mg/100 ml. The second group consumed more milk averaging 1 quart/day with no discomfort and when 19 were tested with oral lactose tolerance tests the values were normal. This study indicates that low lactase activity in the Caucasian population may make its appearance at the age of 5 years.

Biochemical and morphological changes in the digestive tract of rats after prenatal and postnatal malnutrition.

Six-week-old rats subjected to prenatal and postnatal dietary restriction (maternal and weanling intake = 50% that of controls) were studied. Compared with controls, malnourished rats not only had reduced body (78 +/- 12 vs 187 +/- 21 g) and organ weights (small intestine: 4.51 +/- 0.46 vs 9.89 +/- 0.61 g; colon: 0.75 +/- 0.08 vs 1.77 +/- 0.18 g; liver: 2.75 +/- 0.34 vs 9.13 +/- 1.33 g; pancreas: 0.78 +/- 0.14 vs 1.67 +/- 0.49 g) but also decreased body weight-length ratios (6.5 +/- 0.3 vs 10.8 +/- 1.4 g/cm) and serum albumin levels. The small intestinal mucosa was hypotrophic (protein-DNA ratio: 5.02 +/- 1.43 vs 8.82 +/- 0.68, malnourished vs controls, respectively) with reduced mucosal thickness, villus height, and crypt depth. Specific activities of lactase, maltase, and sucrase were diminished (53%, 66%, 54% of control values, respectively). Colonic mucosa was hypoplastic with decreased mucosal thickness and crypt depth. Liver and pancreas were both hypotrophic and hypoplastic. The findings suggest that, in contrast to colonic mucosa, pancreas, and liver, the small intestinal mucosa maintained cell number during prolonged prenatal and postnatal malnutrition.

Maternal dietary restriction during pregnancy and lactation: effect on digestive organ development in suckling rats.

To examine the relative effects of maternal malnutrition during pregnancy and lactation on development of the pancreas and small intestine in suckling pups, rats were restricted to 50% of control (C) intake beginning at day 5 of pregnancy. Immediately after birth, some litters were exchanged such that some C dams were suckling pups born to 50%-restricted dams (C/50) and vice versa (50/C). Other litters were allowed to stay with their own mothers, which received a control or restricted diet as during pregnancy (C/C and 50/50). Pups nurtured by restricted dams had reduced body weights, intestinal lengths, hepatic and pancreatic weights, and specific activities of pancreatic lipase and small intestinal brush border sucrase and maltase. Small intestinal lactase levels were higher in the groups of pups from mothers restricted during lactation. In nearly all cases, the 50/C group was the most severely affected while the C/50 group was intermediate between the C/C and 50/50 groups.

Effect of postnatal malnutrition on pancreatic zymogen enzymes in the rat.

In order to characterize the response of the pancreas to undernutrition during the critical neonatal growth phase, acquired postnatal malnutrition was induced in the rat, using the expanded litter. An experimental nursing litter of 16 rats and control litters of 7 to 8 rats were formed. At 19 days of age, the pups were killed. Mean pancreatic wet weight was decreased in the malnourished rat to a greater extent than the decrease in total body weight (49 versus 60%). Decreased organ weight was predominantly the result of a decrease in DNA content and cell number. Enzyme activities expressed per total organ were all diminished; lipase to the greatest extent; trypsin and amylase to an intermediate extent; followed by chymotrypsin and the carboxypeptidases. The specific activities of lipase and trypsin were decreased with lipase, the most severely effected. The low trypsin levels can be attributed to trypsin inhibitor. It is possible therefore, that only the specific activity of lipase is significantly decreased. The decrease in enzyme activities, expressed both as specific activities and as total organ activities were decreased in a nonparallel fashion.

Impact of digestion and absorption in the weaning period on infant feeding practices.

Weaning is a transition period in which solid and table foods replace milk or formula. Such a shift involves not only a change in the texture but also the nutrient constituents in the diet of the infant. Appropriate dietary changes, although known to affect the physiologic and biochemical function of the gastrointestinal tract in adults, have not been established clearly in infants. The relationship between diet and gastrointestinal development during the weaning period is explored. New concepts such as alternate pathways for digestion and absorption during infancy and the possible effects of new feeding modalities such as total parenteral nutrition and elemental diet are discussed. The influence of exogenous factors such as malnutrition and diseases on the development of the gastrointestinal function, particularly that of the small intestinal brush border hydrolytic enzymes and exocrine pancreatic enzymes, are also reviewed because of their potential influence on the weaning process.

The interrelationship of enterokinase and trypsin activities in intractable diarrhea of infancy, celiac disease, and intravenous alimentation.

Enterokinase initiates digestion of protein by conversion of trypsinogen into trypsin. The interactions between enterokinase and trysin were investigated in 6 patients with intractable diarrhea of infancy and 34 children with celiac disease. The six infants between 2 and 3 months with intractable diarrhea of infancy had reduced mucosal enterokinase activity (9.5 +/- 4.8muM per gram of protein per minute) and reduced intraluminal trypsin activity (2.9 +/- 0.7muM per gram of protein per minute) as compared with healthy controls (109 +/- 34.2muM per gram of protein per minute and 14.3 +/- 5.8muM per gram of protein per minute) respectively. The activities of all enzymes returned toward normal following treatment with intravenous alimentation. The mucosal morphology of all pretreatment biopsies in all cases showed Grade III atrophy which improved. These findings suggest that enterokinase deficiency and reduced intraluminal trypsin activity in intractable diarrhea of infancy may be one of the contributing factors to protein malabsorption and consequent malnutrition. Thirty-four children with celiac disease were between the age of 9 months and 13 years. The 11 newly diagnosed patients with celiac disease demonstrated Grade III to IV atrophy of the mucosa. The 23 patients with treated celiac disease on a gluten-free diet showed a normal to Grade II atrophy. In both treated and untreated celiac disease the enterokinase activities and the intraluminal trypsin activity were within normal limits. The enterokinase activity in celiac disease is near normal in contrast to the marked reduction noted in intractable diarrhea of infancy even though the intestinal mucosa shows marked morphological alteration and the disaccharidase activities are greatly reduced in celiac disease. After a prolonged alimentary fast of up to 26 days on intravenous alimentation, two patients with intractable diarrhea of infancy showed improvement in the activities of enterokinase and trypsin. These findings demonstrate that enterokinase and trypsin activities in the gut were present and improved in the absence of oral feeding.

Development of functional responses in human exocrine pancreas.

The ability of newborns to digest proteins, fats, and carbohydrates depends, to a large extent, on their level of exocrine pancreatic function. Building on the limited published data, we studied pancreatic enzyme activities in the duodenal fluid and the response of the exocrine pancreas to secretogogues in 15 premature and full-term infants at birth and at 30 days of age. We compared these findings to those obtained from identical studies of 17 children age 2 years and above. In addition, we measured the pancreatic exopeptidase, carboxypeptidase B, in relation to other pancreatic enzymes. The duodenal fluid of newborns and infants contained no amylase and negligible lipase. Carboxypeptidase B levels were also low compared to those in the older children. In contrast, chymotrypsin activity in infants was about 50% to 60% of level found in the older children. Trypsin activity, the highest of all the enzymes measured, was about the same in both newborns and older children, with a transient increase at 30 days. Administration of pancreozymin had no effect on pancreatic enzymes in the duodenal fluid of newborns and a slight effect on 1-month-old infants. But by age 2 years, a full response of the pancreas to pancreozymin was evident. In infants and newborns, responses to secretin were poor. Thus, the secretory response of the human pancreas to secretogogues, absent or minimal at birth, is acquired during the postnatal period.

Early detection of adenomatous polyposis coli in Gardner's syndrome.

Gardner's syndrome, an autosomal dominant disorder, consists of multiple polyposis of the colon associated with various soft- and hard-tissue tumors. The appearance of adenomatous hyperplasia and polyposis in at-risk patients before adolescence has not been full appreciated. Four preadolescent children from a kindred with Gardner's syndrome were examined by use of colonoscopy and mucosal biopsy. In three children (18 months, 6 years, and 9 years old) adenomatous hyperplasia or polyposis was found. The colon of the fourth child (3 years old) was normal. The three affected children were asymptomatic. The youngest had a barium enema and results were normal. The oldest child had polyps. Biopsies revealed focal atypical hyperplasia of the glands with pseudostratification of the epithelial cells, frequent mitotic figures, and the absence of goblet cells. More severe manifestations were noted in the splenic flexure than in the sigmoid flexure or rectum. The youngest patient showed early adenomatous hyperplasia characterized by a marked reduction of the goblet cells, especially in the surface epithelium. Colonoscopy and mucosal biopsies are mandatory in at-risk children. By deferring colonic examination until adolescence, a patient is placed at risk for malignant degeneration of the adenomatous tumor.

Intestinal lymphagiectasia: a reappraisal.

Intestinal lymphangiectasia (IL) may vary widely in its manifestations and severity. Fifteen children seen between 1960 and 1974 with histologically proven IL are analyzed by clinical, laboratory, radiologic, and histologic criteria. Remissions occurred in most patients and none died. Exacerbations occurred in five children. Diarrhea was present in 14 patients and in 13 appeared before the age of 3 years. Vomiting occurred in nine patients and growth retardation in seven. Four children had associated peripheral lymphedema and two of these had a family history of lymphedema, both had affected fathers and one had affected siblings and paternal cousins. Seven had hypoproteinemic edema, and of these, four suffered from hypocalcemic seizures. Chylous effusions were present in five. Hypoproteinemia was present in 12 although five had no hypoalbuminemic edema. Six had lymphopenia which was related to the severity of the disease and was the last abnormality to disappear after clinical remission. Lymphopenia may first appear years after the protein loss begins. Upper gastrointestinal tract series were performed in 13 children and had diagnostic supportive value in seven. Six children had two or more small-intestinal biopsies done. They all showed great variation from one examination to the other, ranging from a normal appearance to severe changes. Lymphatic block may occur at different sites-in the lamina propria only, generalized (lamina propria, submucosa, serosa, and mesentery), or conversely in the mesentery alone with minimal changes in the lamina propria. In three patients intravenous hyperalimentation was necessary. Specific treatment with a high-protein, low-fat diet with added medium-chain triglyceride (MCT) is valuable. Surgical resection was of benefit in one patient, and anastomosis of mesenteric to para-aortic lymph nodes in another.

Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes.

Ten adolescent and young adults with cystic fibrosis (CF) have had well-documented recurrent attacks of acute pancreatitis. The diagnosis of CF in each patient was delayed because they did not have pancreatic insufficiency. The diagnosis of CF was documented by the typical pulmonary involvement and elevated sweat sodium and chloride levels in all cases and a positive family history in six of the ten patients. Two patients were diagnosed as having acute pancreatitis before the diagnosis of CF was made, thus indicating that acute pancreatitis may be the presenting complaint in the young adult with CF. The diagnosis of acute pancreatitis was based on the presence of severe abdominal pain, usually with vomiting, tenderness in the mid-epigastrium, elevated serum and urinary amylase and serum lipase. Attacks were precipitated by fatty meals, alcohol ingestion; postcholecystectomy and tetracycline administration. In some patients no precipitating event could be elicited. Intravenous secretin-pancreozymin stimulation tests revealed a diminished bicarbonate secretion with little effect on the secretion of the zymogen enzymes. A mild attack of pancreatitis occurred after secretin-pancreozymin stimulation. The endocrine pancreatic function tested in four patients was normal as revealed by the glucose tolerance tests and determinations of serum insulin, growth hormone and free fatty acid. Transduodenal pancreatograms were performed in three patients; one showed a normal pancreatic duct, one showed duct obstruction and in the third patient a beady type of narrowing was found. The selenomethionine Se 75 uptake of the pancreas was noted only in the head of the pancreas. This suggests that loss of function occurs initially to a greater extent in the tail and body of the pancreas. Three patients died and showed characteristic lesions of CF.

Extent and duration of small intestinal mucosal injury in intractable diarrhea of infancy.

Thirty infants with intractable diarrhea of infancy (IDI) underwent small bowel biopsies in order to determine the extent and duration of small intestinal mucosal injury. The onset of the persistent diarrhea occurred prior to 3 months of age and continued for an average of 48 days prior to investigation. In 18 cases, no associated entities were found. Mucosal injury was invariably found in all 30 infants: grade IV injury in 11, grade III in eight, grade II in nine, and grade I atrophy in one. Disaccharidase activities were diminished and corresponded to the degree of atrophy. Lactase activity was diminished to a greater extent than sucrase and maltase. Significant, persistent mucosal injury existed for an average of six months in 16 of the 23 (70%) repeat biopsies. All infants were given an elemental diet (ED). Twelve of the 30 infants required parenteral nutrition (PN). These infants were gradually advanced to an oral elemental diet and maintained on this diet until histologic findings and disaccharidase levels were normal. Eighteen infants were fed and maintained on an elemental diet by mouth from time of admission until normal histologic findings and disaccharidases were found. No mortality occurred during management and follow-up. Twenty-two of the 28 infants in whom follow-up growth data were available excelled in weight and height velocity. The data suggest that prolonged injury to the small intestinal mucosa is a common finding in many cases of intractable diarrhea of infancy. Elemental diets should be started early in the course of protracted diarrhea in young infants, and may need to be continued for several months since histologic and enzymatic changes of the small intestine may persist for extended periods.