Site of substrate stimulation of jejunal sucrase in the rat.

To identify the site of stimulation of sucrase by a sucrose diet, changes in sucrase-specific activity of jejunal mucosa were studied after introduction of sucrose diet to carbohydrate-deprived rats. Results were correlated with simultaneous changes in villus gradients of sucrase-specific activity. Simultaneous with the introduction of sucrose diet, [(3)H]thymidine (100 muCi) was administered intravenously, and rates of cell migration measured during adaptation to the new diet. After a 72-h fast, rats fed sucrose diet for 6, 12, or 18 h showed no change in sucrase-specific activity in either whole mucosa or villus gradients. However, within 18-24 h after starting a sucrose diet, there was a marked rise in whole mucosal sucrase-specific activity above fasting values (99 +/- 14 vs. 38 +/- 4 muM glucose/min per g protein, P < 0.001) in association with the development of a region of increased activity at the lower villus (154 +/- 22 vs. 60 +/- 9 muM glucose/min per g protein, P < 0.02, but with no change in villus tip activity (56 +/- 5 vs. 46 +/- 8 muM glucose/min per g protein). Similar changes were seen in animals fed 24 h of sucrose diet after a 72-h carbohydratefree diet. Fasted animals fed sucrose diet for 36 h had increased sucrase-specific activity at the villus tip (144 +/- 11 muM glucose/min per g protein) as well as at the lower villus region, and this pattern persisted at 1 wk of sucrose diet. Maximal activity patterns for isomaltase and maltase paralleled those for sucrase, but the villus gradients for lactase were unaffected by sucrose diet. The region of maximal sucrase-specific activity always coincided with or followed the leading edge of radioactivity as determined by liquid scintillation counting. Therefore, sucrose-mediated changes in sucrase activity of the jejunal mucosa in the rat appear to be initiated at the level of the crypt epithelial cell and are expressed after a latent period of 18-24 h during which these cells mature and migrate toward the villus tip.

Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum.

Intestinal proglucagon is thought to be synthesized primarily by the distal gut, although the role of proglucagon-derived glucagon-like peptide I (GLP-I) as a major physiological incretin would seem to be associated with production in proximal small bowel. To better characterize the sites of production of proglucagon and GLP-I in the small intestine and evaluate nutrient regulation of small bowel proglucagon and derived peptides, we evaluated the effects of fasting for 72 h and subsequent refeeding or jejunal infusion of long-chain triglyceride (LCT) for 24 h on local expression of proglucagon in proximal and distal small bowel. Proglucagon mRNA abundance and cellular localization were determined and correlated with wet weight of bowel. In jejunum, proglucagon mRNA abundance decreased by 40% with fasting (P < 0.005) and increased with refeeding to levels similar to those of ad libitum-fed animals. In ileum, fasting resulted in a 20% decrease in proglucagon mRNA (P < 0.005); in contrast to jejunum, refeeding did not result in a significant rise in ileal proglucagon mRNA abundance from fasting values. In jejunum, signal intensity of proglucagon mRNA per cell, determined by in situ hybridization, decreased with fasting (P < 0.05) and increased with refeeding (P < 0.005) in proportion to changes in mRNA abundance. Plasma enteroglucagon and GLP-I levels correlated with jejunal proglucagon mRNA. Intrajejunal infusion of LCT increased expression of proglucagon to a greater extent in jejunum than in ileum. In conclusion, enteral nutrient intake stimulates small bowel proglucagon expression; this effect is greater in jejunum than ileum, consistent with greater intraluminal nutrient exposure and the role of jejunum as a source of the major incretin GLP-I.

Fasting prevents experimental murine colitis produced by dextran sulfate sodium and decreases interleukin-1 beta and insulin-like growth factor I messenger ribonucleic acid.

Cytokines and insulin-like growth factors (IGFs) are involved in the induction and/or perpetuation of inflammatory bowel disease. The effect of fasting on inflammatory bowel disease was studied in a mouse experimental model of acute colitis caused by adding dextran sulfate sodium (DSS) to drinking water. Animals were either fed ad libitum or fasted (water only) for 2 days before death. Inflammation and tissue damage, measured as a colitis activity score, were markedly reduced in fasted (2.4 +/- 0.1) compared to fed (5.3 +/- 0.1) DSS animals (P < 0.0001). Colon interleukin-1 beta (IL-1 beta), IGF-I, and tumor necrosis factor-alpha messenger RNAs (mRNAs) were quantified by Northern blot hybridization and expressed as a percentage of mRNA abundance in fed controls. In DSS mice, IL-1 beta mRNA was elevated in the fed group (954 +/- 155%; P < 0.001), but was suppressed in fasted animals (71.1 +/- 11%). IGF-I mRNA also was elevated in fed DSS mice (421 +/- 71%; P < 0.01). This increase was attenuated in fasted DSS mice (202 +/- 17%; P < 0.01 compared to fed DSS mice). Tumor necrosis factor-alpha mRNA was increased in fed DSS mice (162 +/- 15%; P < 0.01), but was not significantly lower in fasted animals. By in situ hybridization, IL-1 beta mRNA was localized to the lamina propria of colonic mucosa in fed DSS animals, but was not detectable in other groups. We conclude that fasting has a protective effect on the progression of acute DSS, induced colitis. This is associated with decreased expression of IL-1 beta and IGF-I mRNAs in the colon.

Effect of removal of pancreaticobiliary secretions on adaptation to short bowel in orally nourished rats.

To evaluate the need for intraluminal pancreaticobiliary secretions for mucosal adaptation in animals with short bowel, groups of paired rats were prepared with: 1) normal bowel length, 2) 60% proximal small bowel bypass, and 3) similar bypass of distal bowel. One animal in each pair underwent operative diversion of pancreaticobiliary secretions to distal (group 1) or bypassed intestine (groups 2 and 3). Rats were fed an elemental diet and killed 1 month later. Mucosal wet weight, protein content, and DNA content were measured in comparable segments of proximal jejunum and mid-small bowel. Within each group the patterns of response of the three measures of mucosal mass were similar. Group 1: removal of secretions was associated with a 20 to 30% increase in mass in both segments. Group 2: after proximal bypass, mass doubled in mid-small bowel (in continuity) whether or not pancreaticobiliary secretions were removed. Group 3: after distal bypass, no change in mass was apparent in the jejunum even with removal of secretions. We conclude that intraluminal pancreaticobiliary secretions are not required for maintenance of mucosal mass or adaptation to short bowel in animals fed an elemental diet.

Effect of proximal transposition of the ileum on mucosal growth and enzyme activity in orally nourished rats.

To determine whether exposure to proximal intestinal contents per se is an adequate stimulus for ileal adaptation of the magnitude seen after jejunectomy, rats were prepared by transposing 30 cm of distal ileum to the duodenojejunal junction or by sham operation. One month after surgery, mucosal mass (wet weight, protein content, and DNA content) and digestive enzyme activities were measured in segments of small intestine and compared between the groups. Measurements of mucosal mass in transposed ileum more than doubled those in control jejunum (p less than 0.001). Mean enzyme activities/cm bowel length in transposed ileum approached or surpassed measurements in control jejunum. In contrast to the other enzymes studied, mean sucrase specific activities were similar in transposed ileum and control jejunum, values fivefold greater than that of control ileum (p less than 0.002). We conclude that exposure of ileum to proximal intestinal contents reproduces the adaptive response that follows jejunectomy, without requiring short bowel. Sucrase responds to this exposure in a unique fashion.

Reproducibility and variability of the rectal mucosal proliferation index using proliferating cell nuclear antigen immunohistochemistry.

Rectal mucosal proliferation has been shown to be increased in patients with neoplastic lesions of the large bowel and may serve as a marker of risk for colorectal malignancy. We conducted analyses to determine reliability and components of variability that might suggest optimal analysis strategies for studies of proliferation. Endoscopic pinch biopsies were obtained from 17 adult patients, labeled using proliferating cell nuclear antigen, scored using strict rules, and then rescored. Labeling index, defined as the proportion of labeled cells in a crypt, was calculated for each crypt, biopsy, subject, and group. There was excellent reproducibility. The technician was able to select previously scored crypts 95% of the time. The overall labeling index was identical on repeat. There was considerable variability in labeling index among crypts from a single biopsy and between biopsies of a single subject. Variance component estimates suggested that 20% of the variability of labeling index was due to subject, 30% due to the biopsy within a subject, and 50% due to crypts within a biopsy. There were substantial gains in statistical power by scoring two biopsies rather than one. There was less gain from further increases in biopsy number. There was little statistical advantage for counting more than 8 crypts/biopsy. Demonstrating a decrease of 25% in the mean labeling index with 90% power could require more than 100 subjects/group. We conclude that proliferating cell nuclear antigen is an extremely reproducible method to determine proliferation index. There is considerable variability among subjects, biopsies, and crypts.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of rectal mucosal proliferation measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and whole crypt dissection.

Rectal mucosal proliferation has been promoted as an intermediate marker for risk of colorectal neoplasia. Proliferating cell nuclear antigen (PCNA) immunohistochemistry has become a standard method to measure cell proliferation. Whole-crypt dissection may provide a technically simpler method for determining proliferation within an entire crypt. We conducted a study to assess the reliability (reproducibility) of whole-crypt dissection in 10 subjects. Reliability of whole-crypt dissection with the subject as the unit of observation was excellent. The intraclass correlation coefficient for subjects was 0.93. Biopsy-to-biopsy reliability was lower (r=0.86) and crypt-to-crypt reliability lower still (r = 0.35). There was poor correlation between measures of proliferation index using the two techniques (Kendall's tau = 0.13; P = 0.08). Compartment analysis based on the percentage of the total number of labeled cells appearing in each crypt quartile also did not demonstrate a significant correlation between the two measures. We conclude that PCNA labeling index and whole-crypt mitotic count are not comparable measures of rectal mucosal proliferation.

Upper gastrointestinal endoscopy in infants: diagnostic usefulness and safety.

Although fiberoptic, upper gastrointestinal (UGI) endoscopy has become an accepted diagnostic technique in the older child and adult, concerns about safety have limited the use of this procedure in infants. A 1-year experience with 49 upper gastrointestinal endoscopies in infants less than 25 months of age is reported. There were varied indications for the procedures, including upper gastrointestinal hemorrhage and obstruction, but evaluation for esophagitis secondary to gastroesophageal reflux was most common. Procedures were performed without sedation in 45% of all infants studied, including 87% of infants less than 3 months of age; procedures were well tolerated. General anesthesia was used on only three occasions. A thorough examination was always possible, and biopsies were taken whenever indicated. Only one complication, transient bradycardia, occurred in a critically ill infant. This experience demonstrates that upper gastrointestinal endoscopy is a safe and effective diagnostic aid in infants, and it can often be performed with little or no sedation.

Bacterial gastroenteritis.

Acute diarrhea is a major cause of childhood morbidity. Important advances in the understanding of bacterial gastroenteritis have been made in the past two decades. This article reviews the epidemiology, pathogenesis, and methods of diagnosis of bacterial gastroenteritis. Bacterial enteric pathogens common to North America are discussed in more detail.

Refeeding during recovery from acute diarrhea.

PIP: A study of nutritional repletion during recovery from acute gastroenteritis was conducted among otherwise healthy children and infants in Lima, Peru. The children were initially given only intravenous fluids followed by oral glucose-electrolyte rehydration solution (GES) either alone or with half-strength or full-strength formula. This formula was lactose-free, and the diet was advanced every 2 days. The study concluded that lactose-free formula along with GES solution provided better therapy for acute gastroenteritis. Further, it was shown that early feeding improves the overall nutritional health of a child. It is also possible that oral nutrients accelerate the recovery process of small-bowel mucosa. The study failed, however, to allow the children to show a catch-up weight gain, and the study design itself was erroneous because the effects of early formula feeding were inevitable. Finally, it is observed that children between 3 months and 3 years of age are able to tolerate full-strength, lactose-free formula while recovering from acute gastroenteritis.^ieng

Pseudomembranous colitis presenting as mild, chronic diarrhea in childhood.

Two children presented with mild, chronic diarrheal illnesses. Investigation revealed typical pseudomembranous colitis in both cases, which responded to therapy. While variation in the severity of pseudomembranous colitis is recognized, the subtle, chronic presentation exemplified by these cases has not previously been well described.

Luminal epidermal growth factor preserves mucosal mass of small bowel in fasting rats.

1. Fasting causes atrophy of small bowel mucosa which rapidly resolves with luminal feeding. This effect of enteral nutrient may be mediated by stimulation of growth factor secretion. We therefore evaluated whether luminal administration of epidermal growth factor, a peptide hormone found in gastro-intestinal contents and trophic for small bowel mucosa, would prevent the mucosal atrophy associated with starvation. 2. Adult rats were: (i) fasted for 3 days, (ii) fasted and then refed for 1 day or (iii) fasted and then refed for 2 days. During the 2 days before study, animals in each group received infusions of epidermal growth factor (2.5 micrograms/day) or diluent alone into distal jejunum. 3. Epidermal growth factor treatment of fasted animals resulted in a tripling of mucosal ornithine decarboxylase activity (P < 0.001) and a doubling of mucosal DNA content (P < 0.001) in the jejunum, values similar to those of refed animals. Epidermal growth factor infusion in refed rats resulted in a further doubling of mucosal ornithine decarboxylase activity (P < 0.001), but no additional increase in DNA content. Effects of epidermal growth factor infusion were generally greater in jejunum than ileum. 4. In conclusion, luminal exposure to epidermal growth factor prevents starvation-induced mucosal atrophy in the small bowel, but does not enhance the mucosal growth associated with refeeding. Effects are greatest at the site of administration. Luminal epidermal growth factor is a potential mediator of the indirect effects of nutrient on mucosal growth in the small bowel. Enteral administration of epidermal growth factor holds promise for preventing atrophy and maintaining mucosal integrity in starved and post-operative patients.

Clinical manifestations of congenital syphilitic hepatitis: implications for pathogenesis.

To study the clinical course and biochemical features of congenital syphilitic hepatitis, the records of all 22 pediatric patients admitted to North Carolina Memorial Hospital between 1969 and 1979 with a positive maternal, cord blood, or serum VDRL were reviewed. Of the seven infants identified with symptomatic congenital syphilis, five had clinical and biochemical evidence of liver dysfunction. All five were jaundiced (peak bilirubin ranged from 8.4 to 29.8 mg/dl, in each case greater than 40% conjugated). Peak transaminase elevation ranged from seven to 150 times normal. Serum glutamic-oxaloacetic transaminase exceeded serum glutamic-pyruvic transaminase in each infant, the difference ranging to 7,400 U. The onset of illness did not occur until after treatment had been initiated in two of these five cases. Liver dysfunction increased with treatment in all four infants with serial enzyme determinations. Liver dysfunction also persisted for more than 6 weeks after adequate treatment in two cases. Liver biopsy 5 weeks after treatment in another infant showed giant cell hepatitis. These observations suggest that treatment can potentiate liver dysfunction in congenital syphilis and that viable treponemes are not necessarily essential in the pathogenesis of the hepatitis.

Familial visceral myopathy.

We report on a 13-year-old white body with familial visceral myopathy. The abnormalities of the gastrointestinal and urinary tracts are described and the literature regarding urologic implications of this disorder is reviewed.

Lymphoid hyperplasia causing recurrent rectal prolapse.

An 8-year-old girl had a 5-month history of recurrent rectal prolapse. On colonoscopy, two submucosal masses were noted in the distal rectum and diagnosed by biopsy as benign lymphoid hyperplasia. These were excised by limited dissection superficial to the submucosa, and the histologic diagnosis was confirmed. The child has done well after removal of the nodules, with no subsequent prolapse for more than 2 years.

Hepatoxicity with encephalopathy associated with aspirin therapy in rheumatoid arthritis.

Encephalopathy secondary to aspirin-induced hepatoxicity developed in three patients with JRA. In each patient clinical and biochemical resolution occurred after discontinuing the drug, but toxicity appeared on rechallenge. Liver biopsies in two patients showed mild nonspecific changes. Acute hepatic decompensation and encephalopathy may occur as a consequence of aspirin hepatoxicity in JRA and justify sequential observations of liver function tests and salicylate levels in such patients.

Problems identified by secondary review of accepted manuscripts.

To test the hypothesis that no important deficits would be identified on further review of accepted manuscripts, and that such manuscripts would be recommended for publication on rereview, we sent manuscripts that had been accepted for publication, after review and revision, for rereview by new referees who were unaware of the status of the manuscripts. Each review was evaluated independently by two assistant editors to determine whether substantive criticisms were identified by the new reviewers. The majority of manuscripts were thought by the new reviewers to have defects that warranted further revision, but the problems noted were often dissimilar. However, 80% of the manuscripts were recommended for publication and others were judged suitable for publication, although not at a high priority. The assistant editors frequently differed in their judgments whether a given criticism of a reviewer warranted further revision; nevertheless, there was infrequent disagreement regarding the basic decision for acceptance or rejection.

Effect of acceptance or rejection on the author's evaluation of peer review of medical manuscripts.

To determine whether authors of rejected manuscripts would evaluate the editorial review process less favorably than would authors of manuscripts accepted for publication, a questionnaire was sent to solicit evaluations of the quality of the reviews that had led to the rejection or acceptance of manuscripts submitted to the Journal of Pediatrics. Similar evaluations of the editor's letter were also sought. Authors were more likely to respond to the questionnaire if their manuscripts had been accepted and were more likely to complete the questionnaire thoroughly. Authors of accepted manuscripts evaluated the editor's communication more favorably than did the authors of manuscripts not accepted for publication, but the evaluations of the reviews were not significantly different. Most authors utilized the reviews to modify their manuscripts before submitting them to another journal.