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We studied the effects of sucrose or starch in the diet (460 g/kg diet) on fecal bile acid concentrations in Sprague Dawley rats after 4 wk of feeding. Total bile acid concentration in the feces was significantly lower in the rats fed the starch diet than in those fed the sucrose diet (4.56 +/- 0.47 mg/g dry weight and 8.03 +/- 0.94, respectively, SEM), due to a reduction of deoxycholic, alpha-muricholic and beta-muricholic acids. Fecal and cecal pH values were significantly lower in the rats fed the starch diet compared to those fed the sucrose diet (6.79 +/- 0.08 and 7.15 +/- 0.09 for fecal pH and 7.02 +/- 0.05 and 7.2 +/- 0.04 for cecal pH in the two diet groups, respectively). Colon proliferation was also significantly lower in the starch-fed rats compared to those fed sucrose (labeling index 3.51 +/- 0.6 and 5.69 +/- 0.74, respectively), and the reduction was apparent in the middle and upper compartments of the colon crypts. The mucosal proliferation, expressed as percentage of labeled cells in the upper compartment of the colon crypts, was positively correlated with the concentration of deoxycholic, lithocholic, alpha-muricholic, beta-muricholic, cholic and total bile acids in the feces (per gram wet weight). The results indicate a protective effect of starch versus sucrose diets on colon mucosa.

The effect of dietary starch and sucrose on colon proliferation and the growth of foci of dysplastic crypts in the colon (FDC) were studied in female Sprague-Dawley rats, treated p.o. with 1,2-dimethylhydrazine (DMH). The animals were fed for 30 and 105 days with high fat (23% w/w corn oil) diets in which carbohydrates were represented by corn starch (starch diet) or sucrose (sucrose diet) (46% w/w). After 105 days of feeding, proliferation was markedly reduced in animals fed the starch diet. The number of FDC was not significantly affected by dietary treatments. However, after 30 and 105 days the percent of small FDC (formed by one-two dysplastic crypts) was higher in the animals fed the starch diet when compared to the sucrose diet. In the cecum of the animals fed the starch diet the percent of butyrate, propionic, isovaleric, and valeric over total short-chain fatty acids (SCFA) was increased, whereas the percent of acetic acid was decreased. Cecal pH was also decreased in the animals fed starch. The results suggest that starch diets have a protective role against DMH-colon carcinogenesis in the rat, mediated by a drop in cecal pH and an increased concentration of some SCFA.

The proliferative activity was evaluated in colorectal biopsies of 39 healthy subjects living in two distinct geographical areas, Trieste in northern and Florence in central Italy. Subjects living in Trieste had a significantly higher mitotic activity compared with subjects living in Florence (mitoses/cells counted x 100 were 0.17 +/- 0.04 in Trieste and 0.089 +/- 0.02 in Florence). The results of a dietary questionnaire also showed that subjects in Trieste consumed significantly fewer starches, fibers, nitrites, and proteins. However, no correlation was evident between the consumption of these nutrients and intestinal proliferation.

Rats were fed high fat (231 g/kg diet), low calcium (1.3 g/kg diet), low cellulose (20 g/kg diet) diets in which carbohydrates were represented by sucrose or starch (460 g/kg diet). A subgroup of animals was treated with 1,2-dimethylhydrazine (DMH) twice, 4 and 8 d before the beginning of the dietary treatments. Animals fed the starch diet, compared with those fed the sucrose diet, had higher concentrations of cecal and fecal short-chain fatty acids and a significantly lower acetic acid:butyric acid ratio in the cecal contents at d 105. Ratios were 14.7 +/- 1.7 and 6.8 +/- 0.4 for rats fed the sucrose and starch diets, respectively (P less than 0.01). Cecal pH was significantly lower in animals fed the starch diet for 105 d. At d 105, rectal proliferation was lower in rats fed the starch diet (labeled cells/crypt were 7.89 +/- 0.56 and 3.57 +/- 0.40 for rats fed the sucrose and starch diets, respectively, P less than 0.01); at d 30 the effect of starch on proliferation was evident in controls but not in DMH-treated rats. Rectal proliferation data were negatively correlated with the concentration and percentage of butyric acid and positively correlated with the percentage of acetic acid, the acetic acid:butyric acid ratio and cecal pH. These results suggest that low rectal proliferation in animals fed a high fat, high starch diet might be associated with a lower relative concentration of butyric acid in the cecal contents.

Foveolar hyperplastic changes have been recently considered to be the most distinctive histological findings following partial gastrectomy, and their relationship to bile reflux has been proven. The present study was undertaken in order to determine whether an increase in 3H-thymidine uptake, which is an expression of increased gastric mucosal proliferative activity, might correspond to these hyperplastic changes. Histology and thymidine uptake values were assessed and compared in nineteen rats operated upon either with a Polya gastrectomy (11) or with a Roux-en-Y biliary diversion (8). Thymidine uptake values and the extent of gastric hyperplastic changes were greater in the Polya than in the Roux-en-Y group. Moreover, a significant correlation was found between thymidine uptake values and the extent of hyperplastic changes. Therefore, the relationship between hyperplastic changes and increased mucosal proliferative activity post-gastrectomy would seem to have been proven. Since bile acids have been shown to be able to stimulate cell proliferation in ileal and colonic mucosa, a role for bile reflux in the increased cell proliferation activity in the gastric stump can be hypothesized.

The effect of dietary starch and sucrose on the growth of foci of dysplastic crypts in the colon (FDC) was studied in female Sprague Dawley rats treated twice p.o. with 25 mg/kg of 1,2-dimethylhydrazine (DMH). After DMH administration, the animals were fed high-fat (23% corn oil, w/w)/low-calcium (0.1%, w/w)/low-cellulose (2%, w/w) diets in which carbohydrates were represented by corn starch (starch diet) or sucrose (sucrose diet) (46%, w/w). The animals were fed for either 30 or 105 days with the experimental diets. The number of FDC was not significantly affected by diet. However, after 30 days the percentage of small FDC (formed by 1-2 dysplastic crypts) was higher in the animals fed the starch diet compared to the animals fed the sucrose diet [90.3 +/- 1.1% (SE) and 82.6 +/- 3.1%, respectively; P less than 0.05]. In contrast, foci formed by 3-4 dysplastic crypts were decreased by the starch diet (P less than 0.05). After 105 days of feeding, the starch diet induced a number of dysplastic crypts/focus lower than that induced by the sucrose diet (2.6 +/- 0.1 and 2.9 +/- 0.1, respectively; P less than 0.05). The percentage of small FDC was also higher in the animals fed the starch diet compared to animals fed the sucrose diet (P less than 0.01). After 30 days of feeding, DMH treatment increased colon proliferative activity in both dietary groups (P less than 0.05). But after 105 days of feeding, proliferation was similar in controls and DMH-treated rats and markedly reduced in animals fed the starch diet (mean labeling index values for both controls and DMH-treated rats were 10.4 +/- 0.8 and 4.4 +/- 0.5 in the sucrose and starch diets, respectively; P less than 0.001). The overall results suggest that starch in high-fat/low-calcium/low-cellulose diets has a protective role against DMH-colon carcinogensis in the rat.

The proliferative activity and polyamine levels of the rectal epithelium in unoperated ulcerative colitis patients and in ulcerative colitis patients after total colectomy and ileorectal anastomosis were determined and compared with control subjects. Cell proliferation was evaluated in rectal biopsies by in vitro 3H thymidine incorporation by measuring the labeling index and the position of labeled cells along the crypt; polyamines were determined with a chromatographic method. In ulcerative colitis patients the labeling index was significantly increased, and labeled cells were shifted toward the upper part of the crypt when compared with controls. Ileorectal anastomosis patients showed a normalization of the labeling index and a distribution of labeled cells similar to controls. Polyamine levels were also increased in ulcerative colitis patients; in ileorectal anastomosis patients, the level of polyamines was decreased in respect to unoperated patients and return to normal values except for spermine. Because the increased proliferation and higher polyamine levels are related to increased colon cancer risk, our results confirm that ulcerative colitis is a risk factor for the development of carcinoma. Ileorectal anastomosis may reduce this risk through a normalization of mucosal cell proliferative activity and of some polyamine levels.

The effect of starch contained in different foods on colonic proliferation was studied in C57BL/6N mice after four weeks of feeding with 20% fat diets containing cornstarch, white bread, pasta, and rice; an equicaloric amount of sucrose was used in a control diet. Cell proliferation was evaluated in different subsites of the colon (rectal end, mid colon and cecal end) by colchicine arrest and [3H]thymidine incorporation. The following parameters were analyzed: mitotic index (MI), labeling index (LI), and the distribution of labeled cells along the crypt. Different results were obtained in the different subsites. At the rectal end of the colon, all diets containing starch lowered cell proliferation compared with the sucrose diet. The values for MI in the different diets were 2.56 +/- 0.22, 1.73 +/- 0.30, 1.37 +/- 0.19, 1.61 +/- 0.29, and 1.29 +/- 0.31 for control, cornstarch, white bread, pasta, and rice, respectively. Values are means +/- SE (n = 10). The values for LI showed a similar pattern. In the mid colon, the MI was significantly lowered only by the diet containing rice, whereas the DNA synthetic activity (LI) was lowered by cornstarch, pasta, and rice. Toward the cecal end, we observed a significant reduction in MI with diets containing pasta and rice and in the LI with diets containing pasta. The distribution of the LI along the crypt in the different subsites was not significantly affected by experimental dietary variations. The results suggest that starch from different dietary sources might reduce colon proliferation in the mouse.

The effect of dietary lipids on hepatic and intestinal monooxygenases was studied by feeding C57BL/6N mice (for 2 wks) diets containing 5% and 23.5% (wt/wt) olive oil or corn oil. At the end of the feeding period, we measured arylhydrocarbon hydroxylase (AHH) activity in S9 preparations from liver, small intestine, and colon; and, using the same S9 preparations from the liver, we observed the activation of the following three dietary promutagens: 2-amino-3-methylimidazo(4,5-f)quinoline, 2-amino-3,8-dimethylimidazo(4,5-f) quinoxaline, and 2-amino-6-methyldipyrido(1,2-a:3',2'-d)imidazole. The results showed that high-fat diets increased hepatic AHH activity both in corn oil and olive oil diets compared with the low-fat diets; also, a 5% corn oil diet had significantly higher AHH activity compared with the 5% olive oil diet. AHH activity was, respectively, 48.6 +/- 5.1 and 79.5 +/- 11.4 pmol 3OH-benzo[a]pyrene formed/mg/min in the 5% and 23.5% olive oil diets and 66.1 +/- 5.1 and 83.9 +/- 12.2 in the 5% and 23.5% corn oil diets; values are means +/- SE, n = 16. The results also showed a significant increase in the ability of hepatic S9 fractions from animals on high-fat diets to activate promutagens in the Salmonella/plate test. On the contrary, AHH activity in the small intestine and colon was not affected by the fat content of the diet.

The effect of dietary fat, starch and cellulose on individual and total fecal bile acids was studied in mice after 4 wk of feeding diets containing different levels of fat (5 and 29%), starch (3, 36 and 57-65%) and cellulose (2 and 10%). Diet affected the fecal concentration of deoxycholic acid, beta-muricholic acid and total bile acids. Increasing dietary fat from 5 to 29% significantly increased the level of deoxycholic acid and total bile acids. An increase in dietary cellulose from 2 to 10% significantly decreased the level of deoxycholic acid, beta-muricholic acid and total bile acids. High levels of dietary starch (36 and 57-65%) did not significantly affect the excretion of deoxycholic, beta-muricholic and total fecal bile acids. Starch was able to bind bile acids in vitro and to affect the level of fecal free bile acids. In high fat diets, the level of free bile acids was lower in the feces of animals fed 36% starch diets than in those fed 3% starch diets. This reduction of free bile acids was accompanied by a reduction in colon proliferative activity. We suggest that free, rather than total, bile acids are the effective damaging agents for colon mucosa, and may represent a risk factor in the development of cancer.

In attempt to elucidate the link between the nonenzymatic glycosylation of proteins and the diabetic functional nephropathy, renal handling of glycosyl albumin has been evaluated in 15 normal subjects and 29 insulin-dependent diabetic patients divided in three groups according to their urinary excretion rates of albumin (Ualb): (group A) ten diabetic patients with Ualb less than 10 micrograms/m', (group B) 12 patients with Ualb between 10 and 100 micrograms/m', and (group C) seven patients with Ualb greater than 100 micrograms/m'. Albumin was purified with Blue-Sepharose CL-6B. The carbohydrate bound to albumin was determined chemically with thiobarbituric acid after the acid hydrolysis of the protein. Serum glycosyl albumin concentration in normal subjects was 0.1256 +/- 0.009 nmoles of hydroxymethylfurfural per nanomole of albumin, in group A, 0.1900 +/- 0.0124; in group B, 0.2199 +/- 0.0177; and in group C, 0.2224 +/- 0.02732. Urinary glycosyl albumin concentration was 1.8467 + 0.2132 in normal subjects, 1.4369 +/- 0.3355 in group A, 1.008 +/- 0.1584 in group B, and 0.2614 + 0.0295 in group C. In normal subjects and patients without apparent nephropathy (groups A and B), the clearance of albumin correlated with the serum concentration of glycosyl albumin. In all patients (groups A, B, and C) the urinary-serum glycosyl albumin concentration ratio was correlated inversely with albumin clearance. These data show that in normal subjects and diabetic patients with normal excretion rates of albumin and microalbuminuric diabetic patients the passage of glycosyl albumin through the glomerular wall is facilitated in contrast to normal albumin and that glycosyl albumin plays an important role in the pathogenesis of diabetic functional nephropathy.

Intestinal damage in C57BL/6J female mice was quantified by measuring the frequency of nuclear aberrations in colonic crypts. The animals were maintained on the following diets: standard (5% lipids, 5% cellulose); low- and high-cellulose (0-20% cellulose); high lipids (20% maize oil or 20% olive oil). All groups of animals were treated by gavage either with saline or 250 mg/kg of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). After 24 h their colons were removed and stained and the nuclear aberrations scored under the microscope. The administration of IQ markedly increased the number of colon aberrations in all of the treated animals. Variations in dietary fiber did not modify the colon-damaging activity of this compound. Maize oil slightly increased the colon-damaging activity, whereas significant protection was observed in the animals on a high-lipid olive-oil diet. These results show that composition of the diet may vary the genotoxic effect of this dietary carcinogen.

Our experience with the emergency surgical treatment of 19 consecutive cases of infective endocarditis (IE) is reported. The aortic valve was always affected, either alone (n = 16) or together with the mitral valve (n = 3). All patients were male. In 10 cases it was possible to identify the infecting agent (a staphylococcus was found in 6). Congestive heart failure (CHF) was the principal indication for surgery in 14 cases (in 6 active IE was associated). Five patients (1 with CHF) underwent operative treatment because of systemic emboli. Fifteen patients were in New York Heart Association (NYHA) functional class IV, 3 in class III and 1 was in class II. Two patients (10.5%), both operated on for CHF, died in the early postoperative period. Early prosthetic valve dehiscence occurred in 2 cases, reoperation was successful in both. Follow-up of operative survivors ranges between 7 and 108 months (mean = 53.24 +/- 41.89). One patients died 10 months after operation with CHF following late prosthetic dehiscence. Out of 16 currently surviving patients 14 are in NHYA functional class I, 1 is in class II and 1 in class III. No one of them has had relapse of IE.

A case of massive epicardial lipoma in an asymptomatic patient is presented. The diagnosis of solid intrapericardial mass was achieved by two-dimensional echocardiography without cardiac catheterization. The complications of postoperative course, which included myocardial infarction, cerebral embolism, and the patient's late sudden death, suggest that the cardiopulmonary bypass should be used in similar circumstances. Lipomas of the heart should be kept in mind in patients with unexplained enlargement of the cardiac silhouette whenever pericardial effusion and heart disease may be excluded.

The mutagenic activity of some dietary mutagens, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 2-amino-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), was inhibited in the Salmonella-plate test preincubated with heat-inactivated rat intestinal preparations. A similar inhibition was observed by preincubating intestinal preparations with 2-acetylaminofluorene (AAF) and benzo[a]pyrene (B[a]P). The effect was not specific for small intestine and was also obtained with spleen, liver, lung, colon and stomach preparations. Mutagenic activity was not inhibited by beef muscle proteins. Lipids extracted from intestinal mucosa preparations were equally effective as inhibitors of the mutagenic activity. Lipid fractions from intestinal mucosa were capable of inhibiting the formation of activated IQ by mammalian S9, and other components of the intestinal preparations were able to bind the promutagens and their active metabolites. The mutagenic activity of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (metronidazole) and of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was also inhibited by intestinal preparations, but not by their lipid fractions. A binding of IQ to intestinal preparations was also demonstrated with HPLC techniques. The data indicate that tissue components may reduce the mutagenic activity of chemicals by interfering with the activation process and by reducing the concentration of the promutagens and their active metabolites at target sites.

The effect of dietary starch, fat, and cellulose on colonic proliferation was studied in female C57Bl/6J mice after 4 weeks of feeding with diets containing various levels of starch (3, 36, and 57-65%), various levels of fat (corn oil, 5 and 29%) and various levels of cellulose (2 and 10%). Cell proliferation was measured by colchicine arrest and [3H]thymidine incorporation. The following parameters were analyzed: mitotic index, labeling index, and position of labelled cells along the crypt. Increasing starch content from 3 to 36% decreased cell proliferation both in low (5%) and high (29%) fat diets. By estimating simultaneously the effects of starch and fat with a single multiple regression model, we observed a decrease of mitotic index from 3.04 +/- 0.34 to 2.04 +/- 0.43 (means +/- SE) (P less than 0.05) when starch was increased from 3 to 36% regardless of the level of fat. Other proliferation parameters showed a similar pattern. Changes in dietary fat alone did not affect significantly cell proliferation. We also investigated the effect of starch at high levels (57-65%) and its interactions with cellulose. High starch (57-65%) increased the labeling index from 7.70 +/- 0.58 to 9.65 +/- 0.88 (P less than 0.05), when also considering the effect of cellulose in the multiple regression model. Cellulose by itself did not change the labeling index. Varying starch from 36 to 57-65% increased the number of cells/crypt column from 22.20 +/- 0.82 to 25.87 +/- 1.21 (P less than 0.05) and varying cellulose from 2 to 10% increased the number of cells/crypt column from 22.20 +/- 0.82 to 27.25 +/- 0.97 (P less than 0.01). The results indicate that either high or low fat diets, containing 36% starch, have the minimum proliferative effects in the mouse colon. However, diets containing high levels of both starch (57%) and cellulose (10%) may induce an increase in proliferation. These data suggest a potential beneficial effect of starch on colon proliferation.

Toxic effects of ferrous sulfate and of ferric chloride were determined in the gastrointestinal tract by measuring the induction of nuclear aberrations and micronuclei. In fasting animals ferric chloride induced a dose-related increase of nuclear aberrations in the stomach, whereas ferrous sulfate was not active. In normally feeding animals no increase of nuclear aberrations was observed. The effects of the iron compounds on the duodenum were minimal. In fasting animals a dose-related increase of nuclear aberrations was observed at the level of the colon, with no clear difference between ferrous and ferric compounds. A modest increase of nuclear aberrations of the colon was seen in feeding animals only with ferrous sulphate. By intrarectal administration, nuclear aberrations were induced especially by ferric chloride. An increase of the frequency of micronuclei was not observed at the level of the stomach, duodenum and colon, with the exception of ferric chloride, that induces a significant, although small increase of colon micronuclei when administered intra-rectally. The data demonstrate that iron compounds have an intrinsic cellular toxicity when not administered with food, but do not seem to carry any genotoxic potential for the gastrointestinal tract.

The activity of 2-phenylpyrazolo-4-ethyl-4,7-dihydro [1,5a]pyrimidin-7-one (FPP028), a non-acidic, analgesic, antipyretic, and anti-inflammatory compound, was investigated in a number of pharmacological tests performed in rats. The anti-inflammatory properties of FPP028 were evaluated through the carrageenan induced paw edema and the cotton pellet induced granuloma and compared with the activity of indomethacin, phenylbutazone, and isoxicam; as a result, the activity of FPP028 was shown to be similar to that of the latter compounds. To assess the analgesic properties of FPP028 in comparison with indomethacin and phenylbutazone, the Randall and Sellitto and the mouse-writhing tests were used; in both tests, FPP028 demonstrated a significant analgesic activity. FPP028 was shown to possess antipyretic properties in the test of yeast-induced pyrexia. The gastro-erosive activity of phenylbutazone and FPP028 was studied in restraint-stressed rats; in such test the ulcerogenic activity of phenylbutazone appeared to be dose-related; conversely, FPP028 demonstrated a gastro-protective effect since the number of gastric lesions induced either by stress or phenylbutazone treatment was decreased bu FPP028. Our data show that FPP028 is endowed with most of the pharmacological properties of the classic antiinflammatory drugs. Further studies are however needed to more fully elucidate its mechanism of action because our in-vivo data indicate that FPP028 is not an inhibitor of prostaglandin biosynthesis.