Intestinal diffusion barrier: unstirred water layer or membrane surface mucous coat?

The dimensions of the small intestinal diffusion barrier interposed between luminal nutrients and their membrane receptors were determined from kinetic analysis of substrate hydrolysis by integral surface membrane enzymes. The calculated equivalent thickness of the unstirred water layer was too large to be compatible with the known dimensions of rat intestine. The discrepancy could be reconciled by consideration of the mucous coat overlying the intestinal surface membrane. Integral surface membrane proteins could not be labeled by an iodine-125 probe unless the surface coat was first removed. The mucoprotein surface coat appears to constitute an important diffusion barrier for nutrients seeking their digestive and transport sites on the outer intestinal membrane.

Regional distribution and alterations of lectin binding to colorectal mucin in mucosal biopsies from controls and subjects with inflammatory bowel diseases.

Glycoconjugate composition of colorectal goblet cell mucin was characterized according to the anatomical distribution of lectin-binding sites in mucosal biopsies from 35 control subjects and 55 patients with inflammatory bowel disease. 24 of the controls had mucosal inflammation on biopsy, without clinical evidence of inflammatory bowel disease. These inflamed controls showed a similar rate of presence of lectin-binding sites as the normal noninflamed group. In the controls, the frequency of binding of Ricinus communis agglutinin I to galactosyl residues was consistently higher than that found with either Ulex europaeus agglutinin I to fucosyl or Dolichus biflorus agglutinin to N-acetyl galactosyl groups. A significant proximal to distal gradient for Ulex europaeus agglutinin I binding sites was identified in the controls group. These binding sites were present four times more often in the proximal colon than in the distal colon (P less than 0.025). In the ulcerative and Crohn's colitis groups, this gradient effect was lost, predominantly as a result of decreased availability of fucosyl residues in the proximal colon. In the descending colon of Crohn's colitis tissues, there was a complete absence of Dolichus biflorus agglutinin binding sites compared with the 62.5% incidence in the control group (P less than 0.05). These results demonstrate that the expression of lectin-binding sites in human large intestinal goblet mucin is specifically altered in inflammatory bowel disease, indicating that there are changes in glycosylation of colorectal mucin consistent with alterations in goblet cell differentiation.

Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration.

The effect on intestinal carcinogenesis of feeding a 20% wheat bran dietary supplement, either during and/or after the stage of carcinogen administration with 1,2-dimethylhydrazine, was examined in 48 male Sprague-Dawley rats fed defined diets for 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. In the rats fed bran during carcinogen administration, tumor yield was significantly greater. Benign and malignant tumors increased by 3.4-fold (p less than 0.005), adenomas by 3.5-fold (p less than 0.025), and adenocarcinomas by 3.25-fold (p less than 0.05) over the yield found in the group fed a fiber-free diet. Consumption of wheat bran, after completion of carcinogen exposure, reduced the yield of benign adenomas by 71.4% when compared with the group fed the fiber-free diet (p less than 0.025). Those rats fed a wheat bran supplement during carcinogen administration and then switched to a fiber-free diet afterwards had the highest tumor yield, 4.5 times as many benign and malignant tumors as in those rats consistently fed the fiber-free diet (p less than 0.05) and at least 6 times as many adenomas as any of the other dietary groups (p less than 0.05). These results demonstrate that dietary wheat bran, a fiber which produces a hyperproliferative response in the colon, significantly increases colon carcinogenesis when fed to rats during the stage of carcinogen administration. This effect appears to be further enhanced when the wheat bran is totally removed from the diet following the stage of carcinogen administration. These data indicate that the hyperproliferative effects of wheat bran appear to outweigh any preventive actions that bran may have on colon carcinogenesis by altering the bulk of intestinal contents and their transit time through the bowel.

Stimulation of rat colonic crypt cell proliferative activity by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration.

The effect on colonic epithelial cytokinetics of feeding a 20% wheat bran dietary supplement, either during and/or after the stage of carcinogen administration with 1,2-dimethylhydrazine, was examined in 48 male Sprague-Dawley rats fed defined diets for up to 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. All subgroups of rats fed bran, either during and/or after carcinogen administration, developed colonic crypt cell hyperplasia (p less than 0.05), this being greater in the proximal than in the distal colon. Autoradiographic studies showed a significant increase in proximal colonic crypt cell-labeling index, proliferation zone size, and migration distance in those rats fed wheat bran during the period of carcinogen administration (p less than 0.05). The increase in epithelial cell proliferation activity was most marked in the upper two-thirds of the crypt. These data show that there is a greater stimulation of crypt cell proliferation activity when wheat bran is consumed during the stage of carcinogen administration as compared to the stage following carcinogen exposure. This alteration in mucosal cytokinetics appears to be the mechanism by which wheat bran consumption enhances rat colon carcinogenesis during the period of dimethylhydrazine treatment.

Relationship between colonic luminal pH, cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine treated rats fed high fiber diets.

The comparative effects of different fibers on colonic luminal pH, crypt cell proliferation, and colon carcinogenesis were studied in 120 male Sprague-Dawley rats. The animals were divided into five equal groups and fed either a basal fiber free diet or the basal diet supplemented with 10% pectin, cellulose or guar, or 20% oat bran for up to 30 weeks. 1,2-Dimethylhydrazine was given at 20 mg/kg body weight as a weekly s.c. injection for 12 weeks. Food intake and weight gain were similar in all diet groups. At sacrifice, in vivo pH measurements showed that compared to fiber free rats, all fibers significantly acidified large bowel luminal contents (P less than 0.05). In the guar group 62.5% of rats developed colonic tumors compared to 33.4% of the fiber free rats (P less than 0.05). The yield of proximal colonic adenocarcinomas in the oat bran, pectin, and guar groups was increased by 4.5 to 5 times over the fiber free level (P less than 0.05-0.025). Pectin and guar provided the greatest stimulus to cell proliferation. A lower luminal pH was associated with a higher tumor yield and increased epithelial cell proliferation. Thus, acidification of colonic contents by high fiber diets failed to inhibit rat colon carcinogenesis, while the consumption of soluble fibers, such as oat bran, pectin, and guar, was associated with enhancement of proximal colon carcinogenesis.

Alterations in labeling of cell-surface glycoproteins from normal and diabetic rat intestinal microvillous membranes.

The effect of chronic streptozotocin-induced diabetes was studied on intestinal microvillous membrane surface carbohydrate groups. After 7 weeks of diabetes, purified microvillous membranes were prepared from rat small intestine and surface galactoproteins identified by labeling with galactose oxidase/sodium boro[3H]hydride. Membrane surface sialic acid residues were labeled using the sodium metaperiodate/sodium boro[3H]hydride technique. Membranes were solubilized in SDS and protein labeling analyzed by acrylamide electrophoresis. Membranes from diabetic rats showed an 81% increase in galactoprotein labeling (P less than 0.02) while labeling of sialic acid residues was unchanged. The greatest increase in galactoprotein labeling occurred in protein monomers of Mr 116,000-200,000, where there was a 155% increase in labeling (P less than 0.005). These results indicate that intestinal microvillous membrane protein glycosylation is altered in chronic diabetes. This increase in surface membrane carbohydrates could explain the decreased rates of proteolytic degradation previously described for at least one microvillous protein. An increase in membrane galactose groups has also been noted in hepatocyte and kidney glomerular basement membranes, which suggests the presence of a systematic change in membrane protein glycosylation occurring as a result of the diabetic state.

Effects of dietary fiber on mucosal growth and cell proliferation in the small intestine of the rat: a comparison of oat bran, pectin, and guar with total fiber deprivation.

The effects of dietary fiber on small intestinal mucosal mass, morphology, and cytokinetics were studied by feeding three qualitatively different forms of fiber to 40 rats for 4 wk. A fiber-free diet was fed to the control group and a similar diet with either a 20% oat bran, 10% pectin, or 10% guar supplement to the other three groups. All groups of rats exhibited similar caloric intakes and weight gains. Only the guar diet produced a significant increase in mucosal mass, as demonstrated by 19.1% increase in mucosal weight (p less than 0.05), a 16.7% increase in RNA (p less than 0.05) and an increase in DNA from 38.3 +/- 1.8 (SEM) to 44.6 +/- 2.3 micrograms/cm intestine/100 g body weight (p less than 0.05) when compared to the controls. The pectin-diet produced a decrease in villus height from 102.1 +/- 2.4 to 94.3 +/- 2.4 cells but an increase in crypt column length from 25.3 +/- 0.6 to 27.4 +/- 0.4 cells when compared to the controls (p less than 0.05). The shift in labeling index distribution curves for pectin and guar to the right and for oat bran to the left indicated an increase and decrease respectively in labeling index. The higher rate of epithelial cell migration in the pectin- and guar-fed groups shortened their estimated villus cell transit times to 36.4 +/- 0.7 and 37.0 +/- 1.4 h, respectively, when compared with 42.6 +/- 1.2 h in the oat bran and 41.1 +/- 1.0 h in the control (p less than 0.05). These results show that the modulation of small intestinal mucosal structure and growth by dietary fiber appears to be mediated through alterations in cell proliferation and that these changes depend not only on the quantity but also the quality of the fiber present in the diet.

Effect of short-term dietary fat on cell growth in rat gastrointestinal mucosa and pancreas.

The effects of high fat diets on gastrointestinal and pancreatic cell growth were examined in order to determine whether short-term high fat consumption leads to pancreatic and colonic cell hyperplasia. Three groups of eight rats were fed defined diets for 4 wk. The controls were fed a 5% corn oil diet (unsaturated fat) while those fed high fat diets received either 27% lard (saturated fat) plus 3% corn oil or 30% corn oil. Body weight gain and total caloric intakes were equal. Both high fat diets produced significant decreases in proximal jejunal mass (p less than 0.05), while in the distal ileum and cecum, the only change was the development of mucosal cell hypoplasia in the group fed the high unsaturated fat diet (p less than 0.05). The high fat diets produced no change in cell growth or the incorporation of [3H]thymidine into DNA of stomach, pancreas, or colon but did result in a higher level of pancreatic lipase and lower levels of amylase activity. These results show that a short-term high fat intake leads to small intestinal hypoplasia without affecting pancreatic or colonic cell growth and therefore do not support the hypothesis that dietary fat promotes pancreatic and colonic carcinogenesis by producing cell hyperplasia.

Fiber supplementation results in expanded proliferative zones in rat gastric mucosa.

The effects of three different fibers on gastric fundic mucosal morphometrics and cytokinetics were compared by feeding defined diets to 40 male Sprague-Dawley rats for 4 wk. Groups of 10 rats each were fed a fiber-free diet as a control or the same diet uniformly diluted with either 20% oat bran, 10% pectin, or 10% guar. Fiber supplementation expanded the zone of proliferating cells by 58% with the guar-supplemented diet (p less than 0.05), 101% with oat bran (p less than 0.05), and 150% with pectin (p less than 0.01) compared with controls. Expansion was due to a downward shift in proliferating cells towards the muscularis mucosa of the oat bran and pectin groups (p less than 0.01) while pectin also expanded the proliferative zone toward the mucosal surface (p less than 0.05). Because expanded proliferative zones have been shown to precede and accompany neoplastic transformation, these data suggest a potentially negative effect of dietary fiber on the gastric mucosa.

Modulation of mucosal cell proliferation in the intestine of rats fed a wheat bran diet.

The effect of a 20% wheat bran dietary supplement on intestinal mucosal growth and cell proliferation was examined in two sets of male Sprague-Dawley rats fed defined diets for 4 and 9 wk, respectively. Nutrient intake and body weight gain were equivalent in all groups of animals. In the group of rats fed the bran for 4 wk, small intestinal mucosal weight, DNA, and DNA synthesis, as measured by [3H]thymidine incorporation into DNA, did not change. This was in contrast to large intestinal mucosal DNA which increased by 59.1% in the cecum (p less than 0.001), by 28.3% in the proximal colon (p less than 0.001) and by 35.6% in the distal colon (p less than 0.02) when compared with the controls on the fiber-free diet. Measurements of DNA synthesis and cell proliferation, measured autoradiographically in those rats fed bran for 9 wk, provided evidence of decreased exfoliation in the cecum, with a 45.2% decrease in cell migration (p less than 0.05), whereas in the proximal colon cell proliferation was significantly increased with a cell migration rate 114.3% greater than in the controls (p less than 0.005). These results show that the mechanisms by which wheat bran influences large bowel mucosal growth vary according to the anatomical segment of the intestine. The possible implications of these cytokinetic changes on the development of large bowel cancer are discussed.

Human intestinal folate conjugase: adaptation after jejunoileal bypass.

During intestinal absorption, dietary polyglutamyl folates are hydrolyzed to monoglutamyl folates by pteroylpolyglutamate hydrolase (folate conjugase). This enzyme is present in the brush border and intracellular fractions of human jejunal mucosa. We compared the activities of brush border and intracellular folate conjugase (BBFC and ICFC), and other mucosal enzymes in the jejunum in continuity and bypassed loop in nine patients who underwent intestinal reconstitution operations 3 to 9 yr after jejunoileal bypass. Control jejunum was obtained from seven obese patients undergoing gastric bypass surgery. Jejunal morphometry showed mucosal hyperplasia with taller villi, larger crypts, and no change in cell size in the jejunum in continuity as compared to control or bypass jejunum. In brush border fractions, specific activities of sucrase and BBFC were significantly greater in the jejunum in continuity than in the control or bypass jejunum. In contrast, the specific activities of the other brush border and intracellular enzymes, including ICFC, were similar in all three segments. This is the first evidence that BBFC, like sucrase, adapts to luminal nutrition. The difference in response of BBFC and ICFC to diet and/or pancreato-biliary secretions provides evidence that these are distinct enzymes which are regulated by different mechanisms.

Public opinion's tilt against private enterprise.

Drawing on hundreds of identically worded questions, this DataWatch finds that Americans now feel genuine concern for the health status of other people. This is a dramatic development in a country that has encouraged individuals to isolate themselves. The second finding is that necessity has pushed Americans into grudgingly accepting government taxation and regulation as the most feasible way to provide what is by now an expected benefit: secure access to essential health care. Evidence of Americans' concerns and of the tilt away from laissez-faire commitments challenges two of the most sacred conventional assumptions about public opinion in the United States.

Bioadhesive and histotoxic properties of ethyl-2-cyanoacrylate.

Ethyl-2-cyanoacrylate was applied to the cortex of rabbits to evaluate its bioadhesive and histotoxic behavior. The animals were killed at 4 or 10 days. Half of the animals were pretreated with dexamethasone. Our results indicate that the application of ethyl-2-cyanoacrylate to brain tissue produced severe superficial cortical necrosis but not bioadhesion. Pretreatment with steroids did not provide a significant protective effect.

Modification of experimental colon carcinogenesis by dietary fibers.

The literature concerning the effect of individual dietary fibers on the experimental induction of colorectal cancer was reviewed. It has become increasingly apparent that the effect of dietary fibers on colon carcinogenesis depends on many factors, including the type and amount of fiber; the other dietary components, particularly fat; animal species, strain, and sex; and the type of carcinogen and its dose and route of administration. Despite such variations in design, most experiments with wheat bran and cellulose have shown evidence of a significant protective effect. In contrast, numerous other fiber supplements have been shown to enhance tumor development. These include pectin, corn bran, undegraded carageenan, agar, Metamucil, and alfalfa. Possible mechanisms by which fibers may inhibit colon tumorigenesis include dilution and adsorption of any carcinogens or promoters contained within the intestinal lumen and faster transit time and therefore less opportunity for carcinogen/promoter interaction with the intestinal epithelium. Modulation of colonic microbial metabolic activity by dietary fibers may also be important in the activation and detoxification of carcinogens and promoters. Dietary fibers produce structural and functional changes in the intestinal epithelium and modify rates of cell proliferation changes in the intestinal epithelium and modify rates of cell proliferation and migration. Evidence suggests that if this stimulus to cell proliferation occurs during the stage of initiation, it may lead to enhancement of the carcinogenic process. Dietary fibers bind not only carcinogens, bile acids, and other potentially toxic agents but also essential nutrients that themselves can modify the carcinogenic process. Fermentation of fibers within the large bowel results in production of volatile fatty acids, which in vitro have been shown to be antineoplastic. Fermentation also produces a lower luminal pH, which in turn affects colonic microbial populations and their metabolic activities. The presence of lignans in higher plants and their bacterial synthesis from precursors present in fiber-rich foods provide an additional source of antineoplastic agents, whose relative importance in colon carcinogenesis is unknown. Because dietary fibers differ in their physiochemical properties, it has been difficult to identify a single mechanism by which fibers prevent or inhibit colon carcinogenesis. Clearly, more investigation is needed regarding the mechanism(s) by which certain fibers inhibit while others enhance experimental colon carcinogenesis.

You got a problem with that? Exploring evaluators' disagreements about ethics.

A random sample of American Evaluation Association (AEA) members were surveyed for their reactions to three case scenarios--informed consent, impartial reporting, and stakeholder involvement--in which an evaluator acts in a way that could be deemed ethically problematic. Significant disagreement among respondents was found for each of the scenarios, in terms of respondents' views of whether the evaluator had behaved unethically. Respondents' explanations of their judgments support the notion that general guidelines for professional behavior (such as AEA's Guiding Principles for Evaluators) can encompass sharply conflicting interpretations of how evaluators should behave in specific situations. Respondents employed in private business/consulting were less likely than those in other settings to believe that the scenarios portrayed unethical behavior by the evaluator, a finding that underscores the importance of taking contextual variables into account when analyzing evaluators' ethical perceptions. The need for increased dialogue among evaluators who represent varied perspectives on ethical issues is addressed.