Effects of phenotype, sex, and diet on plasma lipids in LA/N-cp rats.

The LA/N-corpulent (cp) rat is a recently developed congenic strain which exhibits obesity. The effects of phenotype and sex on serum and lipoprotein lipid content were examined in LA/N-cp rats fed either a control or an atherogenic diet high in saturated fat and protein. Obese rats were pair-fed to equivalent lean animals. Results from this study indicate that sex, phenotype, and diet exert significant effects on plasma and lipoprotein cholesterol content. Plasma cholesterol levels were higher in obese compared with lean rats, females than in males, and rats consuming the atherogenic diet compared with the control diet. Plasma and lipoprotein triglyceride levels were significantly increased only in obese compared with lean animals. The increased plasma cholesterol and triglyceride was observed primarily in the chylomicron and very low density lipoprotein fractions. Increased levels of plasma cholesterol were not a result of increased dietary cholesterol absorption or increased liver cholesterol biosynthesis. These data suggest that LA/N-cp rats can serve as a unique rodent model for the study of the interrelationships between hyperlipidemia, obesity, and coronary heart disease.

Human selenite metabolism: a kinetic model.

A model is developed to describe the kinetics of sodium selenite metabolism in humans, based on plasma, urine, and fecal samples obtained from six subjects over a 4-wk period after a single oral 200-micrograms dose of the enriched stable isotope tracer 74Se. The model describes absorption, distributed along the gastrointestinal tract, and enterohepatic recirculation. The model includes four kinetically distinct plasma components, a subsystem consisting of the liver and pancreas, and a slowly turning-over tissue pool. For the six subjects, the ranges of mean residence times for the four plasma components are, respectively, 0.2-1.1 h, 3-8 h, 9-42 h, and 200-285 h; for the hepatopancreatic subsystem 4-41 days; and for the tissue pool 115-285 days. Approximately 84% of the administered dose was absorbed, and after 12 days approximately 65% remained in the body. The model predicts that after 90 days approximately 35% of this Se would be retained, primarily in the tissues. Separating Se metabolism into several distinct kinetic components is a first step in identifying the efficacious, nutritious, and toxic forms of the element.

Effects of selective oral antimicrobial prophylaxis and systemic antibiotics on the fecal flora and fecal beta-aspartylglycine concentration in patients with acute leukemia.

The influence of selective oral antimicrobial prophylaxis (SOAP) and systemic antibiotic treatment (SAT) on the intestinal flora of fourteen granulocytopenic patients was investigated. For SOAP, patients received Cotrimoxazole, Polymyxin and Nystatin; Gentamicin, Ticarcillin and Cefuroxime were administered for SAT. Under SOAP, a complete elimination of Enterobacteriaceae and a marked reduction of yeasts and staphylococci was found. A reduction in the number of anaerobic species was also observed; however, the concentration of anaerobic bacteria remained constant. In contrast, additional systemic antibiotic treatment caused a significant reduction of aerobic as well as anaerobic bacteria, except for microorganisms pathogenic to neutropenic patients (i.e. Staphylococcus epidermidis and Candida sp.). The fecal concentration of beta-aspartylglycine was inversely correlated with the presence of anaerobic bacteria.

Enteric protein loss in various gastrointestinal diseases determined by intestinal alpha 1-antitrypsin clearance.

Intestinal protein loss was measured by means of faecal alpha 1-antitrypsin clearance (alpha 1 ATC) in patients with various gastrointestinal diseases. In healthy controls and in patients with various gastrointestinal diseases there is a remarkable intraindividual fluctuation of the faecal protein loss from day to day. Alpha 1 AT clearance calculated from a three-day stool collection is usually sufficient to indicate enteric protein loss in Crohn's disease, ulcerative colitis, celiac sprue, and Whipple's disease. However, in two patients with intermittent diarrhea coinciding with edema and hypalbuminemia excessive enteric protein loss was observed on one day during a two week stool sampling period only. In one of these patients suction biopsies showed histologically intestinal lymphangiectasia of a 10 cm segment of the upper jejunum. The alpha 1 ATC is a suitable and cheap method to determine enteric protein loss without the use of radioactive tracers and therefore can be used in clinics without departments of nuclear medicine. In contrast to the conventional Gordon test the use of the endogenous marker alpha 1 AT facilitates the determination of faecal protein loss over long time periods, which might be of value in the diagnosis of intermittent occurring enteric protein loss. Furthermore, the endogenous marker alpha 1 AT is of use in following the course of illness and in monitoring the efficacy of therapy in patients with enteric protein loss.

Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease.

5-Aminosalicylic acid presently is believed to represent the therapeutically active moiety of the sulfasalazine molecule in the treatment of inflammatory bowel disease. The metabolism of this compound, however, has not been studied in detail. In this paper we provide evidence that 5-aminosalicylic acid is acetylated to N-acetyl-aminosalicylic acid in homogenates from colonic biopsy specimens (370 +/- 20 nmol/g wet wt or 2.9 +/- 0.9 nmol/mg.min, n = 10), whereas acetylation in fecal samples was only small (13.0 +/- 3.0 nmol/g). Mucosal N-acetylation was rapid, cofactor- and pH-dependent, and could be enriched in the cytosolic fraction. In contrast, fecal acetylation was slow and did not depend on the presence of acetyl-coenzyme A. There were neither significant differences of acetylation between patients and controls nor a significant correlation to the individual acetylation phenotype. From our results we believe that presystemic acetylation of 5-aminosalicylic acid may be mainly mediated by a colonic mucosal enzyme and only to a small extent by fecal (bacterial) processes.

[Determination of protein nitrogen utilization with (15N) yeast protein in short bowel syndrome]. / Zur Bestimmung der Eiweissstickstoff-Utilisation mit [15N]-Hefeprotein beim Kurzdarmsyndrom.

The digestive and absorptive capacity for food protein was studied in 8 infants with short bowel syndrome by means of [15N] yeast protein as a tracer substance. The extent of resection ranged from total removal of the small bowel to partial closures of the large bowel by colostomies. The tracer substance was administered as single oral pulse labeling in a dosage of 5 mg 15N/kg. The fecal losses of 15N were extremely high in cases of total and subtotal resection of the small bowel as well as after operative removal of the Bauhins valve. In the entirety they ranged between 3 and 95% of the intake. The corresponding 15N-retention in the protein pool was in the range between 0.1 and 91.6%. Operative findings, nutritional state and passage time were of limited value for the prediction of food protein assimilation. Even residual lengths of 25 cm of the small bowel turned out to be compensated, which was shown in one of the infants by an absorption of 97% and a retention rate of 84%. The oral [15N] yeast protein loading can be considered a reliable test for the evaluation of protein nitrogen absorption and utilization in short bowel syndromes.

[The effect of food supplements on the bioavailability of breast milk for premature infants--fecal fat and carbohydrate excretion]. / Der Einfluss von Nahrungssupplementen auf die Bioverfügbarkeit der Frauenmilch für Frühgeborene. Die faecale Fett und Kohlenhydratexkretion.

Faecal excretion of fat and carbohydrates was studied in 14 preterm infants fed on raw mother's milk (group I) or banked fortified human milk (group II) at days 7, 14, 21 and 28 of postnatal life: group I: n = 5; 31.0 +/- 2.0 weeks; 1954 +/- 441 g; group II: n = 9; 32.0 +/- 1.0 weeks; 1806 +/- 176 g. Mixtures of amino acids, peptides, minerals, dextrine and maltose were designed for fortifying banked human milk. There were no significant differences between faecal excretion of fat and carbohydrates in both feeding groups. The investigated human milk fortifier helps to realize the protein-energy ratio needed in preterm infants with well tolerable volumes of feeding and without stressing their limited digestive capacity.

Disposition of single oral doses of butylated hydroxyanisole in man and rat.

The kinetics and metabolism of butylated hydroxyanisole (BHA) have been compared between man and rats. Oral doses of 2, 20 or 200 mg BHA/kg body weight were administered to male Wistar rats and a single oral dose of 0.5 mg/kg body weight was administered to human volunteers (non-smoking males). Following oral administration of 2 or 20 mg BHA/kg body weight to rats, no plasma BHA profiles were observed, whereas at the 200 mg BHA/kg body weight dose level plasma BHA peak concentrations between 100 and 400 ng/ml were detected. Plasma BHA peak levels and the area under the curve show that the application of 15% polyethylene glycol-400 as the vehicle produced significantly lower values compared with those obtained using the vehicles, salad dressing, corn oil and dimethylsulphoxide. In man, oral administration of 0.5 mg BHA/kg body weight dissolved in corn oil gave plasma BHA peak concentrations of greater value than 100 ng/ml (range 53 to 255 ng/ml). In rats, 24 hr after dosing 2, 20 or 200 mg BHA/kg body weight the mean BHA concentrations in adipose tissue ranged from 0.7 to 6.8 micrograms/g. In man and rats, BHA was O-demethylated to tert-butylhydroquinone (TBHQ). This is the first study to report that TBHQ is an in vivo metabolite of BHA in rats. Within 4 days following oral administration the total recovery of BHA in the urine and faeces of man (0.5 mg BHA/kg body weight) and rats (200 mg BHA/kg body weight) was 49 +/- 7% and 95 +/- 10% (mean +/- SD) respectively. In rats, BHA was excreted in the urine as free BHA (2%), conjugated BHA (48%) and conjugated TBHQ (9%) and in the faeces as free BHA (36%). In man, BHA was excreted in the urine mainly as conjugated BHA (39%) together with smaller amount of conjugated TBHQ (9%); no free BHA was found in the urine or faeces. In man and rats only the fraction of BHA excreted in urine as conjugates of BHA and TBHQ was qualitatively and quantitatively comparable. Results in this study indicate a considerable difference in the biological fate of BHA following oral administration of high and low doses of BHA in rat and man, respectively.

Differences in fecal excretion of cholesterol and bacterial degradation products in high- and low-responding rhesus monkeys: implications in colon cancer.

This paper reports the differences in the fecal excretion of cholesterol and its degradation products in high- and low-responding rhesus monkeys fed diets with and without extra cholesterol. The high-responding monkeys had a great increase in plasma cholesterol concentration when fed a high-cholesterol diet, whereas the low-responders had a small increase when fed the same diet. The results show that low-responding monkeys, when fed high-cholesterol diets, excrete nearly two to three times the amount of cholesterol and its bacterial degradation products in the feces than the high-responding monkeys. We suggest that these two select groups of monkeys may be useful models for the study of the role cholesterol and its bacterial degradation products play in colon cancer.

Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice.

Flavone acetic acid (FAA) is a novel antitumor agent with broad solid-tumor activity. However, this drug has shown a steep dose-response curve in preclinical trials, with a narrow sublethal window of efficacy. To investigate this threshold behavior, we studied various aspects of FAA pharmacology in mice after i.v. administration. Mice bearing advanced-stage s.c. colon 38 adenocarcinoma were treated at four dose levels (39, 65, 108 and 180 mg/kg), and only the highest dose produced significant antitumor activity, showing a steep dose-response curve. Using an HPLC assay, FAA pharmacokinetics in both plasma and tumors were found to be dose-dependent. As the dose increased, there was a decrease in both total body clearance and volume of distribution at steady state. The increase in tumor area under the curve (AUC) was more pronounced than the corresponding increase in plasma AUC, showing a better tumor exposure to FAA at high doses. The distribution of FAA in normal tissues showed a short-term retention in the liver and kidneys; low concentrations were observed in the heart, spleen, and brain, with some retention in the latter. The highest FAA concentrations were found in the gastrointestinal (GI) tract, mainly in the duodenum, suggesting an important biliary excretion of the drug. Various possible causes of FAA nonlinear pharmacokinetics were investigated. Serum protein binding was high (79%) and remained constant up to 100 micrograms/ml, but decreased thereafter at higher FAA concentrations, e.g., 76% at 500 micrograms/ml and 64% at 1,000 micrograms/ml. Urinary and biliary clearances were dose-dependent and decreased 5- and 9-fold, from the 39- to the 180-mg/kg dose levels, respectively. A direct assessment of FAA enterohepatic circulation using intercannulated mice showed that 27% of the plasma AUC was accounted for by enterohepatic circulation. FAA acyl glucuronide was identified as the major metabolite in mice and was found to contribute to the nonlinear pharmacokinetics due to its facile hydrolysis under physiological conditions, regenerating FAA. In conclusion, the steep FAA dose-response curve was found to be caused by dose-dependent pharmacokinetics in mice. The nonlinear pharmacokinetics of this drug was attributed to a dose-dependent decrease in both urinary and biliary clearances, concentration-dependent serum protein binding, enterohepatic circulation, and the instability of FAA acyl glucuronide under physiological conditions forming a futile cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Protein-losing enteropathy detected by 99mTc-labeled human serum albumin abdominal scintigraphy.

99mTc-labeled human serum albumin (HSA) abdominal imaging is a new way of demonstrating gastrointestinal protein loss. We present two children with hypoalbuminemia of obscure etiology in whom albumin loss was localized in the gastrointestinal tract with 99mTc-HSA scintigraphy and the loss correlated with abnormal fecal alpha 1-antitrypsin excretion. In the absence of gastrointestinal blood loss or contamination of the 99mTc-HSA with free pertechnetate, significant activity accumulating in the gastrointestinal tract and moving with its contents is thought to represent 99mTc-HSA leakage into bowel lumen. Abdominal imaging with 99mTc-HSA has a low radiation burden to the patient and is readily available, relatively inexpensive, and easily performed. It can be used as a screening test for the detection of protein-losing enteropathy. It also offers the potential of being able to localize the site of protein loss visually within the gastrointestinal tract.

Fecal alpha-1-antitrypsin excretion in acute diarrhea: relationship with causative pathogens.

Concentrations of alpha-1-antitrypsin (AT) in random fecal samples from 68 infants (92.7% outpatients) with acute diarrhea and 32 healthy controls were determined. The mean +/- s.d. for AT in infants with diarrhea was 2.07 +/- 1.88 mg/g dry stool (mg/g d.s.) compared with 1.29 +/- 0.72 mg/g d.s. (p less than 0.05) in controls. Fecal AT was significantly greater than that of the controls only for diarrhea caused by Rotavirus or Salmonella. Salmonella patients also had significantly higher fecal levels of AT than patients with diarrhea caused by Campylobacter. Fifty percent of the infants with Salmonella infections excreted more than 2.73 mg/g d.s. AT, which is above the control mean + 2 s.d. Fecal excretion of AT was highest in patients with macroscopic intestinal bleeding, but it still depended more on the causative agent than on bleeding per se. This finding of increased intestinal protein loss during acute diarrhea, even in the less severe diseases, emphasizes the necessity to rapidly restart adequate nutritional intake.

Developmental changes of lactose malabsorption in normal Chinese children: a study using breath hydrogen test with a physiological dose of lactose.

The malabsorption of a physiological dose of lactose (0.5 g/kg body weight) was studied in 726 healthy Chinese children, ranging in age from 3 to 18 years, using the breath hydrogen test. The prevalence of lactose malabsorption was found to increase with age; it occurred in less than 15% of preschool-age children and in approximately 45% of younger school-age and 60% of older school-age children. Approximately 70% of adolescents measured showed malabsorption. The critical period of change was from 6 to 7 years of age, with the lactose malabsorption rate rising abruptly from 12 to 43%. The incidence of lactose intolerance in teenagers and adolescents was 27 and 33%, respectively. The great majority of them had only dull abdominal pain. No case of lactose intolerance was seen in children less than 9 years of age. These results indicated that preschool Chinese children can absorb a physiological dose of lactose (equivalent to the average amount of milk consumed daily) without any adverse effects. In contrast, one half of school-age children and two thirds of adolescents were malabsorbers.

Physical training plasma lipoproteins and faecal steroid excretion in sedentary men.

Thirty sedentary men aged 25-52 participated in a 4-month randomized and controlled study of the effects of exercise on plasma lipoproteins and faecal steroid excretion. After 4 months the aerobic training group showed a significant (P = 0.047) increase in physical work capacity (+38 watts) and a significant (P = 0.025) decrease in faecal total steroid excretion (-257 mg/day) compared to corresponding changes in the control group. The drop in faecal total steroid excretion in the men who trained was mainly due to a significant (P less than 0.05) fall in faecal neutral sterol excretion (-240 mg/day). Plasma lipoprotein lipid concentrations did not change significantly during the study although plasma levels of very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol tended to fall in the men who trained. In the aerobic training group individual changes in plasma LDL cholesterol levels were significantly correlated with decreases in faecal total steroid excretion (p = 0.615, P less than 0.05) and faecal neutral sterol excretion (p = 0.627, P less than 0.05). The results of this study show that regular exercise is associated with a drop in faecal neutral sterol excretion which, if sufficiently large, may be associated with a decrease in plasma LDL cholesterol concentration.

Relation of changes in amount and type of dietary fat to fecapentaenes in premenopausal women.

Correlation studies suggest that fecal mutagenicity is increased in groups eating high-fat diets, the same groups who are often found to have high colorectal cancer incidence and mortality. The fecapentaenes are the best characterized class of fecal mutagens, but the relationship of dietary fat intake to the excretion of these potent genotoxins is unknown. We studied the effect of changes in amount and type of dietary fat on fecapentaene levels in 31 premenopausal women 20-40 years of age who participated in a controlled feeding study. After a pre-diet free-living period lasting 1 menstrual cycle, women were placed on a high-fat (40% energy from fat) diet for 4 menstrual cycles and then switched to a low-fat (20% energy from fat) diet for an additional 4 menstrual cycles. One-half the subjects were maintained throughout the study at a ratio of polyunsaturated-to-saturated fatty acids (P/S ratio) of 1.0, the other half at 0.3; body weight was constant. All meals during the controlled diet periods were prepared at the Human Study Facility of the Beltsville Human Nutrition Research Center. Fecapentaene and fecapentaene precursor levels were measured in acetone extracts from 3-day pooled stool samples collected during the study. No differences in fecapentaene or precursor levels were observed between the high- and low-fat diets at either P/S ratio. Fecapentaene and precursor levels were higher while on controlled diets than during the pre-diet free-living period, and levels declined again in the post-diet free-living period. We conclude that dietary fat has no significant effect on fecapentaene or precursor levels in acetone extracts of stool in premenopausal women. The effect of other dietary or non-dietary factors on fecapentaenes remains unknown.

Effects of cottonseed dietary fiber on metabolic parameters in diabetic rats and non-insulin-dependent diabetic humans.

The objective of this study was to evaluate the effect of gland cottonseed dietary fiber (CSDF) containing 86% dietary fiber (mainly cellulose) on serum glucose levels in diabetic rats and in non-insulin-dependent diabetes mellitus (NIDDM) patients. A diet containing 15% CSDF given to streptozotocin-induced diabetic rats for 30 d tended to reduce the postprandial plasma glucose level curve. Alternatively, CSDF significantly increased fecal weight (15 +/- 3 vs. 5 +/- 2 g; P less than 0.01) and shortened transit time (20 +/- 2.24 vs. 11.2 +/- 0.8 h). CSDF had no effect on body weight and serum lipid levels. Twelve NIDDM subjects were given a meal tolerance test (MTT) with or without CSDF before and after daily supplementation of CSDF (16.5 g) in pita twice a day for a month. Incremental glucose levels were significantly (P less than 0.05) lower at 30, 60 and 180 min after the MTT containing CSDF than in subjects consuming a meal without CSDF. The insulin levels also tended to be lower. The NIDDM subjects tolerated the CSDF well. No flatulence or other side effects were exhibited. Plasma lipid levels remained unchanged. We therefore concluded that CSDF may have a potential benefit in the management of NIDDM.

Bioavailability of calcium and phosphorus in human milk fortifiers and formula for very low birth weight infants.

Growth, 96-hour balance of nutrients (nitrogen, fat, calcium (Ca), phosphorus (P), and magnesium), metabolizable energy, and serum biochemical markers of mineral status (Ca and P concentrations and alkaline phosphatase activity) were measured in 22 very low birth weight infants to investigate the bioavailability of minerals from specialized formula and from human milk fortifiers. The intakes of Ca and P were similar between group FORM ("Preemie" SMA) and group CMF (1:1 wt/wt, human milk and Similac Natural Care or Similac Special Care). The intakes of nitrogen, energy, fat, and magnesium differed between groups. Group CMF had significantly greater fecal losses and significantly lower absorption and retention of Ca and P in comparison with those of group FORM. Retention of Ca and P in both groups, however, was greater than 25% below intrauterine estimates of accretion. Retention rates of Ca, P, and magnesium were not correlated with their respective intakes. Weight gain during the balance study and during the entire study interval was significantly less in group CMF. The ratio of Ca retention to either weight gained or nitrogen retained was lower in group CMF, which suggested that the low retention of Ca was related less to the slower rate of growth in these infants than to their greater fecal losses of Ca. Although the cause of the greater fecal losses of Ca and P in this group is unclear, the data suggest an insolubility of the mineral sources. Our results indicate that sole reliance on the absolute mineral concentrations of the milk selected for very low birth weight infants may be unrealistic; the bioavailability of Ca and P from particular mineral sources should be evaluated.

Effect of low-fat, high-carbohydrate, high-fiber diet on fecal bile acids and neutral sterols.

The effect of a diet low in total fat and high in complex carbohydrates on the excretion of bile acids and neutral sterols and on serum lipids was studied in women, 46-47 years old, who were consuming a mixed Western diet. Participants kept an initial 3-day food record while consuming their normal diet (pre-diet period). During the dietary intervention period (experimental diet) which lasted for 26 days, all volunteers consumed a low-calorie, low-fat (less than 10% of total calories), high-fiber (37 g/day, high-carbohydrate diet. At the 1-year follow-up, the participants completed another 3-day food record, which indicates that these volunteers maintained their caloric and fat intake at levels slightly higher than the experimental diet, but lower than the pre-diet period. Individual 24-hr fecal samples for 2 days and blood samples were collected from the volunteers during each dietary period. Fecal samples were analyzed for neutral sterols and bile acids, and blood samples were analyzed to ascertain cholesterol and triglyceride levels. There were no significant differences in the excretion of neutral sterols between the dietary periods. Fecal secondary bile acids were significantly lower during the experimental and follow-up diet periods compared with the pre-test diet period. Serum cholesterol levels were significantly lower during the experimental and follow-up diet periods than during the pre-test diet period. These results suggest that switching from a high-fat, low-fiber diet to a low-fat, high-fiber diet can reduce the excretion of bile acids which are thought to be involved in the promotion of colon cancer.

In vitro and in vivo mutagenicity studies with airborne particulate extracts.

The contribution of nitro compounds to airborne particulate mutagenicity was studied with Salmonella typhimurium strains TA98, TA98NR, TA98/1,8DNP6. The results obtained indicate that nitropyrenes play a minor role in air particulate mutagenicity. Seasonal variations indicate a relatively greater contribution of nitro compounds to the mutagenicity of spring and summer samples. Fractionation of extracts into acidic, neutral and basic components shows that neutral compounds account for about two-thirds of the total mutagenic activity. Attempts to extract mutagens adsorbed onto particulate matter with aqueous media were almost completely negative. No significant mutagenicity was detected in urine and faecal extracts and in plasma samples of Sprague-Dawley rats treated with air particulate extracts at 80 mg/kg either per os or by i.p. injection. Negative results were obtained in the micronucleus test with Swiss mice treated at 200 and 400 mg/kg (twice by i.p. injection). A significant decrease in liver aminopyrine-N-demethylase was observed in Swiss mice injected with air particulate extracts or its basic and neutral fractions. In vitro experiments suggest a direct interaction of test materials with microsomal cytochrome P-450.