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Background: The metabolic effects of diets high in vegetable protein have not been assessed despite much recent interest in the effect of soy proteins in reducing serum cholesterol., Objective: We assessed the metabolic effects of diets high in vegetable protein (specifically, wheat gluten) on serum lipids, uric acid concentrations, and renal function., Design: Twenty hyperlipidemic men and women consumed isoenergetic test (high-protein) and control metabolic diets for 1 mo in a randomized crossover design. In the high-protein diet, 11% of the total dietary energy from starch in the control bread was replaced by vegetable protein (wheat gluten), resulting in 27% of total energy from protein compared with 16% in the control diet. In other respects, the 2 diets were identical., Results: Compared with the control, the high-protein diet resulted in lower serum concentrations of triacylglycerol (by 19.2 +/- 5.6%; P = 0.003), uric acid (by 12.7 +/- 2.0%; P < 0.001), and creatinine (by 2.5 +/- 1.1%; P = 0.035) and higher serum concentrations of urea (by 42.2 +/- 5.8%; P < 0.001) and a higher 24-h urinary urea output (by 99.2 +/- 17.2%; P < 0.001). No significant differences were detected in total or HDL cholesterol or in the renal clearance of creatinine. LDL oxidation, assessed as the ratio of conjugated dienes to LDL cholesterol in the LDL fraction, was lower with the high-protein diet (by 10.6 +/- 3.6%; P = 0.009)., Conclusions: High intakes of vegetable protein from gluten may have beneficial effects on cardiovascular disease risk by reducing oxidized LDL, serum triacylglycerol, and uric acid. Further studies are required to assess the longer-term effects on renal function.

We tested the effects of feeding a diet very high in fiber from fruit and vegetables. The levels fed were those, which had originally inspired the dietary fiber hypothesis related to colon cancer and heart disease prevention and also may have been eaten early in human evolution. Ten healthy volunteers each took 3 metabolic diets of 2 weeks duration. The diets were: high-vegetable, fruit, and nut (very-high-fiber, 55 g/1,000 kcal); starch-based containing cereals and legumes (early agricultural diet); or low-fat (contemporary therapeutic diet). All diets were intended to be weight-maintaining (mean intake, 2,577 kcal/d). Compared with the starch-based and low-fat diets, the high-fiber vegetable diet resulted in the largest reduction in low-density lipoprotein (LDL) cholesterol (33% +/- 4%, P <.001) and the greatest fecal bile acid output (1.13 +/- 0.30 g/d, P =.002), fecal bulk (906 +/- 130 g/d, P <.001), and fecal short-chain fatty acid outputs (78 +/- 13 mmol/d, P <.001). Nevertheless, due to the increase in fecal bulk, the actual concentrations of fecal bile acids were lowest on the vegetable diet (1.2 mg/g wet weight, P =.002). Maximum lipid reductions occurred within 1 week. Urinary mevalonic acid excretion increased (P =.036) on the high-vegetable diet reflecting large fecal steroid losses. We conclude that very high-vegetable fiber intakes reduce risk factors for cardiovascular disease and possibly colon cancer. Vegetable and fruit fibers therefore warrant further detailed investigation., (Copyright 2001 by W.B. Saunders Company)

Background: In animals, the whole-body content and accumulation of linoleate can be measured and compared with its intake to determine linoleate beta-oxidation. This method can also provide quantitative information about the beta-oxidation of linoleate in humans., Objectives: The objectives of the study were to 1) use the wholebody fatty acid balance method to quantify whole-body concentrations of linoleate in humans, 2) estimate the distribution of linoleate between adipose and lean tissue, and 3) assess the effect of weight loss on linoleate stores and beta-oxidation in obese humans., Design: Nine healthy obese men underwent supervised weight loss for 112 d (16 wk). Magnetic resonance imaging data and fatty acid profiles from fat biopsies were both used to determine linoleate stores in adipose and lean tissue and in the whole body. Linoleate beta-oxidation was calculated as intake - (accumulation + excretion)., Results: Mean weight loss was 13 kg and linoleate intake was 24 +/- 6 mmol/d over the study period. Whole-body loss of linoleate was 37 +/- 18 mmol/d, or 28% of the level before weight loss. Combining the intake and whole-body loss of linoleate resulted in linoleate beta-oxidation exceeding intake by 2.5-fold during the weight-loss period., Conclusions: All dietary linoleate is beta-oxidized and at least an equivalent amount of linoleate is lost from the body during moderate weight loss in obese men. The method studied permits the assessment of long-term changes in linoleate homeostasis in obese humans and may be useful in determining the risk of linoleate deficiency in other conditions.

Background: Skinfold-thickness measurements are considered to have limited clinical utility., Objective: To assess whether skinfold-thickness measurements may be a useful adjunct to conventional anthropometric assessments in predicting glucose and insulin regulation, we studied responses to replicate 75-g oral-glucose-tolerance tests (OGTTs) and performed simple anthropometry in a cross section of subjects., Design: Thirty-five subjects completed the study: 11 lean [mean (+/-SEM) age: 33 +/- 3.2 y; body mass index (BMI; in kg/m(2)): 24.1 +/- 0.8; and percentage body fat (%BF): 11.5 +/- 1.5%], 12 normal-weight (age: 33 +/- 2.9 y; BMI: 23.9 +/- 0.7; and %BF: 24.3.5 +/- 1.3%), and 12 obese (age: 41 +/- 4.5 y; BMI: 34.5 +/- 1.7; and %BF: 34.2 +/- 1.5%) individuals. The lean and normal-weight groups were selected to have similar BMIs but different %BFs. We measured the participants' heights, weights, %BFs, waist circumferences, hip circumferences, and truncal and peripheral skinfold thicknesses. Subjects received nine 75-g OGTTs and blood samples were collected at 0, 15, 30, 45, 60, 90, and 120 min. Mean plasma glucose and insulin values were used to calculate the insulin sensitivity index., Results: The obese group had higher plasma glucose concentrations and areas under the curve (AUCs) than did the normal-weight or lean group and higher plasma insulin concentrations and AUCs than did the lean group (P < 0.05). Stepwise multiple regression, with adjustment for demographic and anthropometric measurements, identified the following predictors: waist circumference, peripheral skinfold thickness, and BMI for fasting plasma glucose (partial R(2) = 0.20, 0.13, and 0.13, P < 0.05); waist circumference and truncal skinfold thickness for plasma glucose AUC (partial R(2) = 0.20 and 0.13, P < 0.05); age, waist-to-hip ratio, and peripheral skinfold thickness for fasting plasma insulin (partial R(2) = 0.26, 0.22, and 0.15, P < 0.05); truncal skinfold thickness for plasma insulin AUC (partial R(2) = 0.41, P < 0.001); and peripheral skinfold thickness for both 2-h plasma glucose (partial R(2) = 0.59, P < 0.001) and the insulin sensitivity index (partial R(2) = 0.49, P < 0.001)., Conclusion: Skinfold-thickness measurements may complement other established measurements for predicting abnormal glucose and insulin regulation.

Poor reproducibility of the 75-g oral glucose tolerance test (75-g OGTT) is a major criticism. To test whether dilution might be a contributor, we studied the effect of administering it at 300, 600, and 900 ml on the coefficient of variation (CV) and overall tolerability. Each dilution was randomly repeated three times by 35 subjects: 11 lean (body fat [BF]: 11.5+/-1.5%, body mass index (BMI): 24.1+/-0.8 kg/m(2), age: 33+/-3 years), 12 normal (BF: 24.3+/-1.3%, BMI: 23.9+/-0.7 kg/m2, age: 33+/-3 years), and 12 obese (BF: 34.1+/-1.5%, BMI: 34.5+/-1.6 kg/m(2), age: 41+/-4 years). The protocol followed, the American Diabetes Association (ADA) guidelines with venous samples drawn at 0, 15, 30, 45, 60, 90, and 120 min. Scales assessing palatability, acceptability, satiety, nausea, and dizziness were also completed. No differences were detected in CV between the three dilutions at the 2 h-diagnostic-endpoint in any group. CV for glycemia, however, was lower for the 300-ml OGTT (10+/-2.1%) than either the 600 ml (17.9+/-2.1%) or 900-ml OGTT (19.9+/-4.4%) at 45 min in the lean group (P<0.05). CV for insulinemia was lower for the 300 ml (30.6+/-4.5%) and 600 ml (30.6+/-4.1%) OGTT than the 900-ml OGTT (53.7+/-7.9%) at 60 min in the obese group (P<0.05). When affective ratings were compared, the 600-ml OGTT scored highest on palatability and acceptability (P<0.05). We concluded that the dilution of the 75-g OGTT improves the overall tolerability but not reproducibility of results. Practitioners may choose to give it at the best-tolerated dilution.

Background: Insulin and insulin-like growth factors can stimulate proliferation of colorectal cells. High intake of refined carbohydrates and markers of insulin resistance are associated with colorectal cancer. To test the insulin/colon cancer hypothesis, we determined whether the dietary glycemic index and the glycemic load are associated with colorectal cancer risk., Design: A case-control study on colorectal cancer conducted in Italy. Cases included 1125 men and 828 women with histologically confirmed incident cancer of the colon or rectum. Controls were 2073 men and 2081 women hospitalized for acute conditions. We calculated average daily dietary glycemic index and glycemic load, and fiber intake from a validated food frequency questionnaire., Results: Direct associations with colorectal cancer risk emerged for glycemic index (odds ratio (OR) in highest vs. lowest quintile = 1.7; 95% confidence interval (CI): 1.4-2.0) and glycemic load (OR = 1.8; 95% CI: 1.5-2.2), after allowance for sociodemographic factors, physical activity, number of daily meals, and intakes of fiber, alcohol and energy. ORs were more elevated for cancer of the colon than rectum. Overweight and low intake of fiber from vegetables and fruit appeared to amplify the adverse consequences of high glycemic load., Conclusions: The positive associations of glycemic index and load with colorectal cancer suggest a detrimental role of refined carbohydrates in the etiology of the disease.

Syntheses of 3'-O-alpha-D-glucopyranosyl-1-beta-D-ribofuranosidoimidazole 2',3'', 4''-trisphosphate (7) and 3'-O-alpha-D-glucopyranosyl-9-beta-D-ribofuranosidopurine 2',3'',4''- trisphosphate (8), two analogues of the superpotent 1D-myo-inositol 1,4,5-trisphosphate receptor agonist adenophostin A (2), are described. 5-O-Benzyl-1, 2-O-isopropylidene-alpha-D-ribofuranose was prepared by an improved route from 1,2-O-isopropylidene-alpha-D-xylofuranose and was coupled with 3,4-di-O-acetyl-2,6-di-O-benzyl-D-glucopyranosyl dimethyl phosphite to give 3',4'-di-O-acetyl-2',5, 6'-tri-O-benzyl-3-O-alpha-D-glucopyranosyl-1, 2-O-isopropylidene-alpha-D-ribofuranose. Removal of the isopropylidene acetal and subsequent acetylation gave the central disaccharide 1,2,3',4'-tetra-O-acetyl-2',5, 6'-tri-O-benzyl-3-O-alpha-D-glucopyranosyl-D-ribofuranose. Vorbrüggen condensation with activated imidazole or purine gave the required beta-substituted derivatives which were further elaborated to 7 and 8, respectively. Radioligand binding assays to hepatic InsP(3) receptors and functional assays of Ca(2+) release from permeabilized hepatocytes gave a rank order of potency of the ligands 2 approximately 8 > 7 approximately Ins(1,4,5)P(3) indicating that the N(6)-amino group of 2 is of little importance for activity and that a minimum of a two-fused-ring nucleobase is required for activity to exceed that of Ins(1,4,5)P(3). The role of the adenine base in the activity of the adenophostins is discussed. This general method should facilitate ready access to nucleobase-modified adenophostin analogues for SAR studies.

Consumption of soy protein may reduce the risk of cardiovascular disease both through reduction in serum lipids and by the antioxidant properties of protein-associated soy isoflavones. However, the effect that processing required for the manufacture of breakfast cereals may have on the lipid lowering and antioxidant activities of soy has not been studied. We have therefore assessed the health benefits of soy incorporation into breakfast cereals. Twenty-five hyperlipidemic men and women took soy (providing 36 g/d soy protein and 168 mg/d isoflavones) and control breakfast cereals, each for 3 weeks in a randomized crossover study with a 2-week washout period between treatments. Fasting blood samples were obtained pretreatment and at weeks 2 and 3 of each treatment. No significant difference was seen in serum lipids between treatments at week 3 apart from a 3.8% +/- 1.5% higher apolipoprotein A-1 level on control versus soy (P = .021). However, oxidized low-density lipoprotein (LDL) was reduced on the test compared with the control both as total dienes in LDL and as the ratio of conjugated dienes to cholesterol in the LDL fraction by 9.2% +/- 4.3% (P = .042) and 8.7% +/- 4.2% (P = .050), respectively. High isoflavone intakes in soy breakfast cereals may decrease the risk of cardiovascular disease by reducing oxidized LDL, while having no significant effect on the absolute concentration of LDL cholesterol.

Background: Some weight-loss diets are nutritionally sound and consistent with recommendations for healthy eating while others are "fad" diets encouraging irrational and, sometimes, unsafe practices., Objective: The purpose of the study was to compare several weight loss diets and assess their potential long-term effects., Design: Eight popular weight-loss diets were selected (Atkins, Protein Power, Sugar Busters, Zone, ADA Exchange, High-Fiber Fitness, Pritikin and Omish) to be non-clinically analyzed by means of a computer to predict their relative benefits/potential harm. A summary description, menu plan and recommended snacks were developed for each diet. The nutrient composition of each diet was determined using computer software, and a Food Pyramid Score was calculated to compare diets. The Mensink, Hegsted and other formulae were applied to estimate coronary heart disease risk factors., Results: Higher fat diets are higher in saturated fats and cholesterol than current dietary guidelines and their long-term use would increase serum cholesterol levels and risk for CHD. Diets restricted in sugar intake would lower serum cholesterol levels and long-term risk for CHD; however, higher carbohydrate, higher fiber, lower fat diets would have the greatest effect in decreasing serum cholesterol concentrations and risk of CHD., Conclusions: While high fat diets may promote short-term weight loss, the potential hazards for worsening risk for progression of atherosclerosis override the short-term benefits. Individuals derive the greatest health benefits from diets low in saturated fat and high in carbohydrate and fiber: these increase sensitivity to insulin and lower risk for CHD.

Creationists and evolutionists acknowledge that the human diet has passed through at least four phases. The original plant food-based diet; a second phase of increasing meat consumption; a third phase of agricultural dependence on starchy foods; and, finally, the supermarket high-saturated fat, low-fibre phase with minimal energy expenditure. Our aim is to define the value of the original or 'Garden of Eden' diet and to speculate on which components should be retained in the modern supermarket diet. The original plant-based diet would have been high in vegetable proteins, plant sterols, dietary fibre and antioxidants, and low in saturated fats with no trans fatty acids. This diet would increase fecal cholesterol losses from the body as bile acids and neutral sterols, while providing little stimulus to cholesterol synthesis. To replace the bile acid losses we would have adapted to a relatively high capacity for cholesterol synthesis. Now, in the high-saturated fat, low-fibre supermarket age, this may be a disadvantage and predisposes consumers to high serum cholesterol and increased risk of cardiovascular disease. We believe part of the solution is a return to the plant-based 'Garden of Eden' diet combined with physical activity. A lipid-lowering portfolio containing vegetable proteins, especially soy, plant sterols and high fibre intakes combined with low saturated and trans fatty acids and cholesterol, would go a long way to reducing serum lipids and coronary heart disease risk seen in the modern Western diet.

Background: Legumes have reported benefits in terms of reduced risk for coronary heart disease and of colonic health. A novel legume fiber, cocoa bran, also may have favorable health effects on serum lipid levels, low-density lipoprotein (LDL) cholesterol oxidation, and fecal bulk., Methods: Twenty-five healthy normolipidemic subjects (13 men and 12 women) (mean +/- SEM age, 37 +/- 2 years; mean +/- SEM body mass index [calculated as weight in kilograms divided by the square of height in meters], 24.6 +/- 0.7) ate cocoa-bran and chocolate-flavored low-fiber breakfast cereals for 2-week periods, with 2-week washout, in a double-blind crossover study. The cocoa-bran cereal provided 25.0 g/d of total dietary fiber (TDF). The low-fiber cereal (5.6 g/d TDF) was of similar appearance and energy value. Fasting blood samples were obtained at the start and end of each period, and 4-day fecal collections were made from days 11 through 14., Results: High-density lipoprotein (HDL) cholesterol level was higher (7.6% +/- 2.9%; P =.02) and the LDL/HDL cholesterol ratio was lower (6.7% +/- 2.3%; P =.007) for cocoa-bran compared with low-fiber cereal at 2 weeks. No effect was seen on LDL cholesterol oxidation. Mean fecal output was significantly higher for cocoa-bran than for low-fiber cereal (56 +/- 14 g/d; P<.001) and equal to the increase seen in the same subjects with wheat fiber in a previous study., Conclusions: A chocolate-flavored cocoa-bran cereal increased fecal bulk similarly to wheat bran and was associated with a reduction in the LDL/HDL cholesterol ratio. In view of the low-fat, high-fiber nature of the material, these results suggest a possible role for this novel fiber source in the diets of normal, hyperlipidemic, and constipated subjects.

Soy isoflavones have been studied extensively for estrogenic and antiestrogenic properties. Other flavonoids, found in fruits, vegetables, tea and wine, have been much less tested for steroid hormone activity. We therefore assessed the estrogenic, androgenic and progestational activities of 72 flavonoids and structurally-related compounds. These compounds were tested on BT-474 human breast cancer cells at concentrations of 10(8)-10(-5) M, with estradiol (estrogen), norgestrel (progestin) and dihydrotestosterone (androgen) used as positive controls, and ethanol (solvent) as a negative control. pS2, an estrogen-regulated protein, and prostate-specific antigen (PSA), regulated by androgens and progestins, were quantified in tissue culture supernatants using ELISA-type immunofluorometric assays developed in-house. Of the 72 compounds tested, 18 showed estrogenic activity at 10(-5) M. Of this subset, seven also showed progestational activity at this concentration. The soy isoflavones, biochanin A and genistein, showed the most potent estrogenic activity, with a dose-response effect up to 10(-7) M. Of all other flavonoids, luteolin and naringenin displayed the strongest estrogenicity, while apigenin had a relatively strong progestational activity. Based on our data, we have formulated a set of structure/function relationships between the tested compounds. Flavonoids, therefore, exhibit significant steroid hormone activity, and may have an effect in the modification of cancer risk by diet, or in cancer therapeutics and prevention.

The causative agent of alveolar hydatidosis in humans, the fox tapeworm Echinococcus multilocularis, is extending its geographical range in Europe and has been found in domestic cats in some areas. A dermally applied cestocidal treatment for domestic cats has been developed and the efficacy of this treatment is reported. Thirty purpose-bred cats were experimentally infected each with 10000 protoscoleces of Echinococcus multilocularis. Ten days later one group of ten cats was treated with Droncit(R) Spot-on (Praziquantel) 4% w/v dermally in one place on the dorsal aspect of the neck at a dose of 8 mg/kg. Eleven days later (21 days p.i.) a second group of ten cats was also treated with Droncit(R) Spot-on the same way. One group of ten cats was left untreated as controls. Twenty three days after infection the cats were examined for the presence of E. multilocularis tapeworms. No E. multilocularis were recovered from any of the cats in either of the treated groups. Echinococcus multilocularis were recovered from eight of the ten cats left untreated as controls. The worm burdens in the untreated cats were 0, 0, 5, 15, 75, 110, 220, 815, 2635, and 3045 worms per cat. The worms ranged in development from the three to four segment stage. Many of the E. multilocularis with four segments contained unshelled eggs in the terminal segment. This study indicates that Droncit(R) Spot-on (Praziquantel) 4% w/v applied dermally at 8 mg/kg is highly effective in removing E. multilocularis from the small intestine of cats infected with immature and mature (prepatent) infections of E. multilocularis. In the cats with the mature infections all tapeworms were absent from the small intestine within 2 days of treatment.

Background: Dilution has been noticed to increase the glycemic response to various sugars, including glucose. This effect may contribute to the poor reproducibility of the oral glucose tolerance test (OGTT). To test this hypothesis we assessed the effect of diluting a 75-g OGTT on 2-hour postprandial blood glucose based diagnostic outcomes, incremental glycemia and area under the glucose curve., Methods: On 3 different occasions, 10 subjects (mean age 40 [and standard error of the mean (SEM) 3.2] years; mean body mass index 27.2 [and SEM 1.2] kg/m2) without previously diagnosed dysglycemia were given a 300-mL, 600-mL or 900-mL 75-g OGTT in random order. The protocol followed the American Diabetes Association's guidelines. Finger-prick capillary blood samples were obtained at fasting and then 15, 30, 45, 60, 90 and 120 minutes after the start of the test., Results: At 30, 45 and 60 minutes, incremental glycemic concentrations were significantly higher with the 900-mL meal (means [and SEMs]: 4.9 [0.4] mmol/L, 5.1 [0.6] mmol/L and 4.6 [0.8] mmol/L, respectively) than with the 600-mL (means [and SEMs]: 4.0 [0.3] mmol/L, 4.2 [0.6] mmol/L and 3.6 [0.7] mmol/L, respectively) and the 300-mL meals (means and [SEMs]: 3.8 [0.5] mmol/L, 4.0 [0.5] mmol/L and 3.2 [0.6] mmol/L, respectively) (p < 0.05). The same was true for peak incremental blood glucose, regardless of time (p < 0.05). The area under the curve for the 900-mL meal (mean [and SEM] 404 [57] min.mmol/L) was significantly higher than for the 600-mL (mean [and SEM] 331 [51] min.mmol/L) and 300-mL meals (mean [and SEM] 280 [48] min.mmol/L) (p < 0.05). No other significant differences were observed., Interpretation: Dilution of the 75-g OGTT will likely not affect current screening practices that use 2-h postprandial glucose levels as the basis for diagnosis. It may, however, bias the interpretation of older criteria that rely on intermediate time points because these midpoints appear to be sensitive to alterations in the total volume of the meal ingested.

Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = .032), even in subjects already using vitamin E supplements (400 to 800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers.

The pure antiestrogen ICI 182,780 has been shown to have antiprogestin activity in reporter gene constructs. Cell lines, naturally devoid of progesterone receptors (PR) were transfected with either the A or B forms of the human PR and a luciferase construct driven by a progesterone-response element (PRE). Because this system is an artificial one, our purpose was to determine whether these observations could be made in a human breast cancer cell line, naturally containing PR. We further evaluated the dose-response of ICI 182,780 and RU-486 (mifepristone) on PR and estrogen receptors (ER) in the presence of either progesterone, norgestrel or estradiol. These effects were measured using immunoassays for prostate-specific antigen (PSA) and human glandular kallikrein (hK2) and pS2. We found that ICI 182,780 blocked progesterone-stimulated PSA and hK2 production 100% at 10(-5) M, which decreased significantly by 10-6 M. This inhibition did not occur when norgestrel was the progestin used. RU-486 showed 100% blockade for both progestins at all concentrations used. We concluded that the antiprogestin activity of ICI 182,780 exists for progesterone only. This weak antiprogestin activity may be unlikely to have significant clinical implications.

Initially, it was hoped that resistant starches (ie, starches that enter the colon) would have clear advantages in the reduction of colon cancer risk and possibly the treatment of ulcerative colitis. Recent studies have confirmed the ability of resistant starch to increase fecal bulk, to increase the molar ratio of butyrate in relation to other short-chain fatty acids, and to dilute fecal bile acids. However, reduction in fecal ammonia, phenols, and N-nitroso compounds have not been achieved. At this point the picture from the standpoint of colon cancer risk reduction is not clear. Nevertheless, there is a fraction of what has been termed resistant starch (RS1), which enters the colon and acts as slowly digested, or lente, carbohydrate. Foods in this class are low glycemic index and have been shown to reduce the risk of chronic disease. They have been associated with systemic physiologic effects such as reduced postprandial insulin levels and higher high-density lipoprotein cholesterol levels. Consumption of low glycemic index foods has been shown to be related to a reduced risk of type 2 diabetes. Type 2 diabetes has in turn been related to a higher risk of colon cancer, especially colon cancer deaths. If carbohydrate has a protective role in colon cancer prevention, it may lie in the systemic effects of low glycemic index foods. The colonic advantages of different carbohydrates, therefore, remain to be documented. However, there is reason for optimism about the possible health advantages of so-called resistant starches that are slowly digested in the small intestine.

Several epidemiological studies link consumption of fibre-rich foods to a reduced risk of type 2 diabetes and CHD. The 'fibre hypothesis' suggested that this was a direct effect of fibre. However, fibre-rich foods contain different types of fibre as well as other potentially beneficial compounds, and many foods naturally high in fibre have low glycaemic and insulinaemic indices, possibly due to food form. The question therefore emerges as to the effect of isolated fibre per se on insulin sensitivity, lipids and other risk factors associated with the metabolic syndrome. Many beneficial effects are seen with pharmacological doses of isolated viscous soluble fibre, including improved insulin sensitivity, decreased LDL-cholesterol levels and decreased clotting factors. Similar effects are seen with low glycaemic-index foods. In contrast, insoluble non-viscous cereal fibre is not seen to act directly on risk factors when taken in refined foods such as in milled flour. Since cereal fibre, the major type of fibre in western diets, does not directly act on the risk factors for the metabolic syndrome, the question remains as to possible mechanisms. Until now, fibre and the nature and processing of the starch and particle size have been seen as the main determinants of the metabolic response to starchy foods. However, fibre-rich foods also have an increased protein-to-carbohydrate ratio. Hence we suggest that the protective effect of fibre may also be due to increased vegetable protein content, which may act directly to reduce clotting factors and oxidized LDL-cholesterol levels.

Viscous fibres such as guar, glucomannans, pectins, oat betaglucan and psyllium continue to be seen as hypocholesterolaemic. Nevertheless, in large cohort studies, ironically it is the insoluble cereal fibre that has been demonstrated to relate negatively to cardiovascular disease and diabetes, despite an absence of effect on fasting lipids or postprandial glycaemia. In general, resistant or nonabsorbable starch is lipid neutral, whereas some nonabsorbable sugars or oligosaccharides may raise serum cholesterol, possibly through providing more acetate after colonic fermentation by colonic microflora. On the other hand, fructo-oligosaccharides appear to reduce serum triglycerides for reasons that are not entirely clear. Of possibly greater recent interest have been the carbohydrates that are not so much resistant to absorption, but rather are slowly absorbed. They possess some of the features of dietary fibre in providing a substrate for colonic bacterial fermentation. In the small intestine, however, they form lente or sustained release carbohydrate. In the form of low glycaemic index foods, lente carbohydrate consumption has been shown to relate to improved blood lipid profiles in hyperlipidaemic individuals and improved glycaemic control in diabetes. In larger cohort studies, low glycaemic index foods or low glycaemic load diets have been associated with higher HDL-cholesterol levels and reduced incidence of diabetes and cardiovascular disease.

Coproparasitological and purging methods for diagnosing canids infected with the intestinal helminth Echinococcus granulosus, an important zoonotic parasite, are unreliable. Detection of coproantigens in feces of infected dogs by enzyme-linked immunosorbent assay (ELISA) is suitable for detecting patent and prepatent infections with a high degree of sensitivity and specificity. In the present study, natural and experimental infections in domestic and wild Australian canids were investigated using a coproantigen capture ELISA. Experimental infection of dogs with E. granulosus was detected at between 14 and 22 days postinfection (PI), and optical density (OD) values remained high until termination of experiments 35 days PI. After chemotherapy, coproantigen levels in infected dogs dropped rapidly, becoming negative 2-4 days after treatment. In experimentally infected red foxes (Vulpes vulpes), the coproantigen excretion profile was different, with ELISA OD levels peaking 15-17 days PI, then falling to low or undetectable levels by 30 days PI. Coproantigens were detected in the feces of naturally infected Australian wild dogs (dingoes, dingo/domestic dog hybrids) with infection levels ranging between 2 worms and 42,600. Preliminary data on the stability of coproantigen in dog feces exposed to environmental conditions indicated that there was no change in antigenicity over 6 days. The results suggest the coproantigen ELISA could be successfully used to monitor E. granulosus prevalence rates in Australian domestic dogs, foxes, and wild dogs.

Purpose: We assess whether high fiber diets influence serum prostate specific antigen (PSA) related to effects on serum sex hormone levels and fecal steroid excretion., Materials and Methods: A randomized crossover controlled trial was performed on 14 healthy men with hyperlipidemia on 2 metabolic diets 4 months in duration with each containing foods high in soluble or insoluble fiber and approximately 25 to 30 gm. dietary fiber per 1,000 kilocalories. Serum PSA, free testosterone and estradiol, and fecal bile acid and neutral sterol excretion were evaluated., Results: Mean serum PSA was lower with the soluble than the insoluble fiber diet (0.07+/-0.03 ng./ml., p = 0.035). No treatment difference was seen in free testosterone or estradiol, although the latter decreased significantly with the insoluble fiber diet (9+/-3 pmol./l., p = 0.004). After 16 weeks total fecal bile acid output was greater with the soluble (341+/-56 mg. daily) compared to the insoluble (203+/-35, p = 0.001) fiber diet but no differences were seen in fecal neutral sterol elimination. The treatment difference in fecal lithocholic acid output related to the difference in serum PSA (r = 0.57, p = 0.035)., Conclusions: A small but statistically significantly lower serum PSA was seen in healthy men consuming soluble fiber, which was not related to changes in serum sex hormones but was related to the increased lithocholic acid output as a possible marker of increased fecal steroid elimination. The effect of soluble fiber on prostatic disease may warrant further investigation.

An increased intake of soluble fiber and soy protein may improve the blood lipid profile. To assess any additional benefit on serum lipids of providing soy protein and soluble-fiber foods to hyperlipidemic subjects already consuming low-fat, low-cholesterol therapeutic diets, 20 hyperlipidemic men and postmenopausal women completed 8-week test and control dietary treatments in a randomized crossover design as part of an ad libitum National Cholesterol Education Program (NCEP) step 2 therapeutic diet (<7% saturated fat and <200 mg/d cholesterol). During the test phase, foods high in soy, other vegetable proteins, and soluble fiber were provided. During the control phase, low-fat dairy and low-soluble-fiber foods were provided. Fasting blood lipid and apolipoprotein levels were measured at 4 and 8 weeks of each phase. On the test diet, 12 +/- 2 g/d soy protein was selected from the foods chosen. Direct comparison of test and control treatments indicated an elevated high-density lipoprotein (HDL) cholesterol concentration on the test diet (6.4% +/- 2.4%, P = .013) and a significantly reduced total to HDL cholesterol ratio (-5.9% +/- 2.3%, P = .020). The proportion of conjugated dienes in the low-density lipoprotein (LDL) cholesterol fraction was significantly reduced (8.5% +/- 3.3%, P = .020) as a marker of oxidized LDL. A combination of acceptable amounts of soy, vegetable protein, and soluble-fiber foods as part of a conventional low-fat, low-cholesterol therapeutic diet is effective in further reducing serum lipid risk factors for cardiovascular disease.

Objective: Dietary fiber has recently received recognition for reducing the risk of developing diabetes and heart disease. The implication is that it may have therapeutic benefit in prediabetic metabolic conditions. To test this hypothesis, we investigated the effect of supplementing a high-carbohydrate diet with fiber from Konjac-mannan (KJM) on metabolic control in subjects with the insulin resistance syndrome., Research Design and Methods: We screened 278 free-living subjects between the ages of 45 and 65 years from the Canadian-Maltese Diabetes Study. A total of 11 (age 55+/-4 years, BMI 28+/-1.5 kg/m2) were recruited who satisfied the inclusion criteria: impaired glucose tolerance, reduced HDL cholesterol, elevated serum triglycerides, and moderate hypertension. After an 8-week baseline, they were randomly assigned to take either KJM fiber-enriched test biscuits (0.5 g of glucomannan per 100 kcal of dietary intake or 8-13 g/day) or wheat bran fiber (WB) control biscuits for two 3-week treatment periods separated by a 2-week washout. The diets were isoenergetic, metabolically controlled, and conformed to National Cholesterol Education Program Step 2 guidelines. Serum lipids, glycemic control, and blood pressure were the outcome measures., Results: Decreases in serum cholesterol (total, 12.4+/-3.1%, P<0.004; LDL, 22+/-3.9%, P<0.002; total/HDL ratio, 15.2+/-3.4%, P<0.003; and LDL/HDL ratio, 22.2+/-4.1%, P< 0.002), apolipoprotein (apo) B (15.1+/-4.3%, P<0.0004), apo B/A-1 ratio (13.1+/-3.4%, P< 0.0003), and serum fructosamine (5.2+/-1.4%, P<0.002) were observed during KJM treatment compared with WB-control. Fasting blood glucose, insulin, triglycerides, HDL cholesterol, and body weight remained unchanged., Conclusions: A diet rich in high-viscosity KJM improves glycemic control and lipid profile, suggesting a therapeutic potential in the treatment of the insulin resistance syndrome.

Objective: Due to perceived inferior fecal bulking ability, finely ground wheat bran is not recommended for treatment of colonic disorders, despite possible short chain fatty acid generation with potential benefits for colonic mucosal health. We therefore tested the effects of very fine particle size wheat bran on colonic function., Methods: Two studies, each with three phases, were undertaken in healthy subjects in a randomized crossover design. In one study (metabolic, n=23) subjects took three diets containing either an additional 19 g/d dietary fiber with mean particle size (MPS) 50 microm or 758 microm in bread or a control low fiber bread. In the other study where the supplement was provided as a breakfast cereal (ad libitum, n=24) the respective wheat bran MPS were 692 microm and 1158 microm and the control was low fiber. Fecal collections were obtained during the last week of each diet. In the metabolic study, fecal short chain fatty acids were measured and 12-hour breath gas collections obtained., Results: In both studies, wheat bran supplements significantly increased fecal bulk compared to the control (p<0.004), with no significant differences between brans of different particle size and no differences in fecal water content. However, higher fecal butyrate concentrations (p<0.007), butyrate output and breath CH4 levels (p=0.025) were seen on the low MPS wheat bran compared to the other two treatments, suggesting increased bacterial fermentation., Conclusions: Fine MPS wheat bran is an effective fecal bulking agent and may have added advantages if increased butyrate concentrations promote colonic mucosal integrity.

Inulin and oligofructose have attracted much attention recently as nonabsorbable carbohydrates with prebiotic properties. When inulin and oligofructose were added to a controlled diet, significant increases were noted in colonic bifidobacterial populations, and it has been proposed that these changes promote both colonic and systemic health through modification of the intestinal microflora. Inulin and oligofructose are rapidly and completely fermented by the colonic microflora with the production of acetate and other short-chain fatty acids. As with lactulose, they may also result in the growth of the fecal biomass, and in doing so, entrap ammonia for bacterial protein synthesis or conversion to the ammonium ion. As with dietary fiber and other nonabsorbable carbohydrates, there is also interest in inulin and oligofructose from the standpoint of inhibition of colonic carcinogenesis, blood cholesterol reduction, immune stimulation and enhanced vitamin synthesis. In these areas, the influence of their molecular weight is also an issue, with the longer chain length providing a more sustained fermentation pattern. More human studies are now required, including studies on the long-term effects of inulin and oligofructose consumption on colonic health, in particular on markers of cancer risk such as reduction in colonic polyp recurrence.

Objective: To examine whether Konjac-mannan (KJM) fiber improves metabolic control as measured by glycemia, lipidemia, and blood pressure in high-risk type 2 diabetic patients., Research Design and Methods: A total of 11 hyperlipidemic and hypertensive type 2 diabetic patients treated conventionally by a low-fat diet and drug therapy participated. After an 8-week baseline, all were randomly assigned to take either KJM fiber-enriched test biscuits (0.7 g/412 kJ [100 kcal] of glucomannan) or matched placebo wheat bran fiber biscuits during two 3-week treatment phases separated by a 2-week washout period. The diet in either case was metabolically controlled and conformed to National Cholesterol Education Program Step 2 guidelines, while medications were maintained constant. Efficacy measures included serum fructosamine, lipid profiles, apolipoproteins, blood pressure, body weight, and nutritional analysis., Results: Compared with placebo, KJM significantly reduced the metabolic control primary end points: serum fructosamine (5.7%, P = 0.007, adjusted alpha = 0.0167), total:HDL cholesterol ratio (10%, P = 0.03, adjusted alpha = 0.05), and systolic blood pressure (sBP) (6.9%, P = 0.02, adjusted alpha = 0.025). Secondary end points, including body weight, total, LDL, and HDL cholesterol, triglycerides, apolipoproteins A-1, B, and their ratio, glucose, insulin, and diastolic blood pressure, were not significant after adjustment by the Bonferroni-Hochberg procedure., Conclusions: KJM fiber added to conventional treatment may ameliorate glycemic control, blood lipid profile, and sBP in high-risk diabetic individuals, possibly improving the effectiveness of conventional treatment in type 2 diabetes.

Dietary treatment of hyperlipidemia focuses on reducing saturated fat and dietary cholesterol. Other aspects of diet are not emphasized at present, despite growing evidence that a number of plant components decrease serum cholesterol. We therefore determined whether a combination of two plant components, vegetable protein and soluble fiber, further reduce serum lipids when incorporated into the currently advocated low-saturated-fat diet. Thirty-one hyperlipidemic men and women ate two 1-month low-fat (<7% of total energy from saturated fat), low-cholesterol (<80 mg cholesterol/d) metabolic diets in a randomized crossover study. The major differences between test and control diets were an increased amount of vegetable protein (93% v 23% of total protein), of which 33 g/d was soy, and a doubling of soluble fiber. Fasting blood samples were obtained at the start and end of each phase. On the last 3 days of each phase, fecal collections were obtained. Compared with the low-fat control diet, the test diet decreased total cholesterol (6.2% +/- 1.2%, P < .001), low-density lipoprotein (LDL) cholesterol (6.7% +/- 1.7%, P < .001), apolipoprotein B (8.2% +/- 1.2%, P < .001), and the ratios of LDL to high-density lipoprotein (HDL) cholesterol (6.3% +/- 2.0%, P = .004) and apolipoprotein B to A-I (5.4% +/- 1.5%, P = .001). A combination of vegetable protein and soluble fiber significantly improved the lipid-lowering effect of a low-saturated-fat diet. The results support expanding the current dietary advice to include increased vegetable protein and soluble fiber intake so that the gap in effectiveness between a good diet and drug therapy is reduced.

Objective: Wheat fiber appears to protect from cardiovascular disease despite its lack of consistent effect on serum lipids. We therefore wished to determine whether reported inconsistencies in the effect of wheat bran resulted from differences in particle size or its high gluten content., Methods: Two studies were conducted. In one-month metabolic diets, 24 hyperlipidemic subjects consumed breads providing an additional 19 g/d dietary fiber as medium or ultra-fine wheat bran and extra protein (10% of energy as wheat gluten). In two-week ad libitum diets, 24 predominantly normolipidemic subjects consumed breakfast cereals providing an additional 19 g/d of dietary fiber as coarse or a mixture of ultra-fine and coarse wheat bran with no change in gluten intake. Both studies followed a randomized crossover design with control periods when subjects ate low-fiber breads and cereals respectively with no added gluten. Fasting blood lipids were measured on day zero and at the end of each phase., Results: Wheat bran had no effect on total, LDL or HDL cholesterol irrespective of particle size or level of gluten in the diet. However, consumption of increased gluten in the metabolic study was associated with a 13+/-4% reduction in serum triglycerides (p = 0.005) which was not seen in the normal-gluten ad libitum study., Conclusions: The protective effect of wheat fiber in cardiovascular disease cannot be explained by an effect of wheat bran in reducing serum cholesterol although in hyperlipidemic subjects displacement of carbohydrate by gluten on the high-fiber phases was associated with lower serum triglycerides.

Experimental vaccine trials against hydatid disease have been undertaken in sheep using the EG95 recombinant vaccine. Challenge infection was with viable Echinococcus granulosus eggs obtained from a New Zealand isolate (dog/sheep cycle), an Australian isolate (dingo/wallaby cycle) and an Argentine isolate (dog/sheep cycle). Vaccination with EG95 conferred a high degree of protection against challenge with all three parasite isolates (protection range 96-100%). Taken together, the trials demonstrated that 86% of vaccinated sheep were completely free of viable hydatid cysts when examined approximately 1 year after challenge infection. Vaccination reduced the number of viable cysts by 99.3% compared with unvaccinated controls. These results suggest that the EG95 vaccine could have wide applicability as a new tool for use in hydatid control campaigns.

Background: Currently there is considerable interest in the potential health benefits of oil seeds, such as soy and flaxseed, especially in relation to cardiovascular disease and cancer., Objective: We therefore evaluated health aspects of partially defatted flaxseed in relation to serum lipids, indicators of oxidative stress, and ex vivo sex hormone activities., Design: Twenty-nine hyperlipidemic subjects (22 men and 7 postmenopausal women) completed two 3-wk treatment periods in a randomized, crossover trial. Subjects were given muffins that contributed approximately 20 g fiber/d from either flaxseed (approximately 50 g partially defatted flaxseed/d) or wheat bran (control) while they consumed self-selected National Cholesterol Education Program Step II diets. Both muffins had similar macronutrient profiles. Treatment phases were separated by > or = 2 wk., Results: Partially defatted flaxseed reduced total cholesterol (4.6+/-1.2%; P = 0.001), LDL cholesterol (7.6+/-1.8%; P < 0.001), apolipoprotein B (5.4+/-1.4%; P = 0.001), and apolipoprotein A-I (5.8+/-1.9%; P = 0.005), but had no effect on serum lipoprotein ratios at week 3 compared with the control. There were no significant effects on serum HDL cholesterol, serum protein carbonyl content, or ex vivo androgen or progestin activity after either treatment. Unexpectedly, serum protein thiol groups were significantly lower (10.8+/-3.6%; P = 0.007) at week 3 after the flaxseed treatment than after the control, suggesting increased oxidation., Conclusions: These data indicate that partially defatted flaxseed is effective in lowering LDL cholesterol. No effects on lipoprotein ratios, ex vivo serum androgen or progestin activity, or protein carbonyl content were observed. The significance of increased oxidation of protein thiol groups with flaxseed consumption requires further investigation.

Antibiotics are being proposed for the treatment of cardiovascular disease. In the past, antibiotics were advocated for the control of hypercholesterolemia. We have therefore investigated the relation between colonic bacterial activity and serum lipids. In a four-phase randomized crossover study, we fed a different starch supplement during each 2-week phase to 24 healthy subjects. In two phases, supplements containing resistant starches were fed that reach the colon and are largely fermented by colonic bacteria. Fecal starch recovery therefore reflects the metabolic activity of colonic microflora. The control treatments were conventional starches. Blood lipid levels were obtained at the start and 4-day fecal collections at the end of each phase. Resistant starch supplements increased fecal starch excretion by 3.8 +/- 1.2 g/d more than conventional starches (P = .006). Mean starch excretion was related positively to pretreatment serum high-density lipoprotein (HDL) cholesterol (r = -.57, P = .003) and negatively to low-density lipoprotein (LDL) cholesterol (r = -.57, P = .004), apolipoprotein B:AI (r = -.56, P = .005), and fecal output of fusobacteria (r = -.73, P = .003) and bacteroides (r = -.72, P = .003). The ratio of fusobacteria to total anaerobes was also related to pretreatment LDL cholesterol (r = .56, P = .037). Differences in starch excretion between healthy subjects, as a measure of bacterial activity, accounted for 32% of the variation in pretreatment LDL cholesterol. The activity of colonic microflora therefore appears to influence serum lipid levels. Alterations of bacterial number and activity may provide an additional strategy to control serum lipid risk factors for cardiovascular disease.

Background: Wheat fiber is a laxative and wheat protein may affect blood lipids., Objective: We therefore tested the effects on laxation and serum lipid metabolism of a novel source of wheat fiber and protein produced by the amylolytic digestion of starch from wheat., Design: Twenty-four healthy men and women consumed 3 different test cereals in random order, each for 2 wk. The test supplement and the positive control, American Association of Cereal Chemists wheat bran supplement, both provided the same amount of fiber (21 g/d) and the negative control supplement provided 1.7 g fiber/d., Results: The test supplement and the positive control supplement increased fecal bulk similarly (239.5+/-19 and 216.7+/-19 g/d, respectively) and significantly more than did the negative control supplement (165.6+/-16 g/d, P < 0.010). Compared with the negative and positive control supplements, the week 2 value of the test supplement for the ratio of total to HDL cholesterol was significantly reduced (P = 0.046)., Conclusion: We conclude that the product of amylolytic digestion of starch from wheat flakes, which is high in wheat fiber and protein, has a fecal bulking effect similar to that of wheat bran and may have a beneficial effect on serum lipids.

We have developed a competitive assay to measure the estrogen-regulated protein pS2. A monoclonal pS2 antibody (mAb) and a biotinylated pS2 peptide are used, with time-resolved fluorometry as a detection technique. The assay has a detection limit of 16 ng/mL and is precise (within-run and day-to-day Cvs 3-12%). We used this assay to determine steroid hormone activity of six steroids in cell culture, both in terms of time course and dose response. pS2 concentrations in the tissue culture supernatant of the BT-474 breast carcinoma cell line were significantly higher when estradiol was the stimulating steroid. There was a significant time course and dose response observed for estradiol, but not for the other steroids. The availability of a sensitive, reliable, and convenient method for quantifying pS2 will allow for many research applications including the screening of natural and synthetic compounds for putative estrogenic activity., (Copyright 1999 Wiley-Liss, Inc.)

Objective: To assess the effects on fecal bulking, fecal short chain fatty acid (SCFA) production, blood lipids and glycemic indices of two different forms of resistant starch (RS2 and RS3) from a high-amylose cornstarch., Methods: Twenty-four healthy subjects (12 men; 12 women) consumed four supplements taken for 2 weeks in random order separated by 2-week washout periods. The supplements were a low-fiber (control) and supplements providing an additional 30 g dietary fiber as wheat bran (high-fiber control) or the equivalent amount of resistant starch analyzed gravimetrically as dietary fiber from RS2 or RS3. Four-day fecal collections and 12-hour breath gas collections were obtained at the end of each period. Fasting blood was taken at the beginning and end of each period. Glycemic indices of supplements were also assessed., Results: The wheat bran supplement increased fecal bulk 96+/-14 g/day compared with the low-fiber control (p<0.001) with the mean for both resistant starches also being greater (22+/-8 g/day) than the low-fiber control (p=0.013). On the resistant starch phases, the mean fecal butyrate:SCFA ratio, which has been suggested to have positive implications for colonic health, was significantly above the low-fiber control by 31+/-14% (p=0.035). Resistant starches did not alter serum lipids, urea or breath H2 or CH4. No significant differences in glycemic index were seen between the RS and control supplements., Conclusion: The potential physiological benefits of the resistant starches studied appear to relate to colonic health in terms of effects on fecal bulk and SCFA metabolism.

Echinococcus granulosus adult worms, 35 days postinfection, were measured for dispersion in the intestines of 10 dogs, a range of morphological characters, and the excreted end products of carbohydrate catabolism following 4 hr incubation in vitro. Most worms were found in the proximal sections of the small intestine, but the pattern of dispersion differed between dogs. Worm development varied both between dogs and between different regions of the small intestine of individual dogs. Overall there was a high level of variability with no simple patterns. Worm metabolism was related to worm development and, also independently, to local population density within the intestine. Larger, more mature worms produced less lactate and, at higher densities, worms tended to produce more acetate and succinate (pathways with a higher energy yield than lactate) and less ethanol. Thus, both more developed worms and high population density are associated with a shift from cytosolic to mitochondrial metabolism. The variation between worm populations along the small intestine along with the observed variation between worm populations from sibling dogs infected with genetically identical parasites suggests that the local host environment has a significant effect on parasite development.

The syntheses of three 11 beta-aryl-19-norpregna-4,9-dien-3-one derivatives with 17-spirolactone and 17 beta-hydroxy-17 alpha-cyanoethyl substitutions are described. The progesterone agonist/antagonist activities of the new compounds are investigated using a recently developed tissue culture system that relies on the progesterone agonist up-regulation of the prostate-specific antigen (PSA) gene in female breast tumor cell lines. Two of the newly synthesized compounds exhibit mixed agonistic/antagonistic progestational activity.

We have used a tissue culture system based on breast carcinoma cell lines to investigate a large number of naturally occurring compounds and beverages for steroid hormone agonist and antagonist activity. The cell lines used, T-47D and BT-474, produce prostate specific antigen (PSA) upon stimulation with androgens, progestins, glucocorticoids and mineralocorticoids. This biomarker is secreted and can be measured in the tissue culture supernatant with very high sensitivity by an immunofluorometric procedure. Steroid hormone antagonist activity can be assessed with the same system by adding the candidate antagonist first and then stimulating the cells with a known agonist. By using this system we have identified three natural compounds, apigenin, naringenin and syringic acid which exhibited weak progestational activity and eleven other compounds which exhibited weak antiandrogenic/antiprogestational activity. Our study indicates that a significant number of natural compounds have the ability to bind to steroid hormone receptors and act as weak blockers. A fewer number of compounds not only bind to the receptors but they also mediate transcriptional activity, acting as agonists. The agonists and antagonists were active at levels around 10(-5) M, in accordance with previous reports for other phytochemicals. In comparison to synthetic and natural steroid hormones, the biological activity of these compounds is weaker by a factor of approximately 10(4)-fold.

The glyconucleotides adenophostin A and B are the most potent known agonists at type 1 inositol trisphosphate [Ins(1,4,5)P3] receptors, although their stuctures differ markedly from that of Ins(1,4,5)P3. Equilibrium competition binding with [3H]Ins(1,4,5)P3 and unidirectional 45Ca2+ flux measurements were used to examine the effects of adenophostin A in hepatocytes, which express predominantly type 2 Ins(1,4,5)P3 receptors. Both Ins(1,4,5)P3 (Kd = 8.65 +/- 0.98 nM) and adenophostin A (Kd = 0.87 +/- 0.20 nM) bound to a single class of [3H]Ins(1,4,5)P3-binding site and each fully mobilized the same intracellular Ca2+ pool; although, adenophostin A (EC50 = 10.9 +/- 0.7 nM) was more potent than Ins(1,4,5)P3 (EC50 = 153 +/- 11 nM). Working on the assumption that it is the phosphorylated glucose component of the adenophostins that mimics the critical features of Ins(1,4,5)P3, we synthesized various phosphorylated disaccharide analogs containing this structure. The novel disaccharide-based analogs, sucrose 3,4,3'-trisphosphate [Sucr(3,4,3')P3], alpha,alpha'-trehalose 3,4,3',4'-tetrakisphosphate [Trehal(3,4,3',4')P4], alpha,alpha'-trehalose 2,4,3', 4'-tetrakisphosphate [Trehal(2,4,3',4')P4], and methyl 3-O-(alpha-d-glucopyranosyl)-beta-d-ribofuranoside 2,3', 4'-trisphosphate [Rib(2,3',4')P3], were all able to mobilize the same intracellular Ca2+ pool as Ins(1,4,5)P3 and adenophostin A; although, none was as potent as adenophostin A. The rank order of potency of the analogs, adenophostin A > Ins(1,4,5)P3 approximately Rib(2,3',4')P3 > Trehal(2,4,3',4')P4 > Glc(2',3,4)P3 approximately Trehal(3,4,3',4')P4 > Sucr(3,4,3')P3, was the same in radioligand binding and functional assays of hepatic Ins(1,4,5)P3 receptors. Both Rib(2,3',4')P3, which was as potent as Ins(1,4,5)P3, and Trehal(2,4,3',4')P4 bound with significantly higher affinity ( approximately 27 and approximately 3-fold, respectively) than the only active carbohydrate agonist of Ins(1,4,5)P3 receptors previously examined [Glc(2',3,4)P3]. We conclude that phosphorylated disaccharides provide novel means of developing high-affinity ligands of Ins(1,4,5)P3 receptors.

Increased dietary fibre intake is a component of prudent dietary advice, although the mechanism of its beneficial effect is unclear. Furthermore, plasma lipoprotein response to dietary fibre seems to vary both between individuals and according to the type of fibre consumed. Two common genetic variants, A54 and T54, of the intestinal fatty acid-binding protein gene (FABP2) have different in vitro binding affinities for long-chain fatty acids. We have hypothesized that variation in FABP2 would be associated with interindividual variation in the response of plasma lipoproteins to either dietary soluble or insoluble fibre. We studied 43 subjects who participated in a year-long cross-over study of the effect of insoluble and soluble fibre on plasma lipoproteins. We tested for associations between FABP2 genotypes and the response of plasma lipoproteins to dietary fibre. When compared with subjects homozygous for FABP2 A54, we found that subjects with FABP2 T54 had significantly greater decreases in plasma total and low-density lipoprotein (LDL)-cholesterol and apoB during the period when the diet was high in soluble fibre than during the period when the diet was high in insoluble fibre. Furthermore, compared with subjects with the FABP2 A54 allele, subjects with the FABP2 T54 allele had significantly lower secretion of total fecal bile acids, but this did not increase with dietary soluble fibre. Genetic variation in FABP2 may thus contribute to interindividual variation in the response of plasma lipoproteins to different dietary fibres, but the mechanism does not appear to be related to increases in fecal bile acid secretion.

We studied the western lowland gorilla diet as a possible model for human nutrient requirements with implications for colonic function. Gorillas in the Central African Republic were identified as consuming over 200 species and varieties of plants and 100 species and varieties of fruit. Thirty-one of the most commonly consumed foods were collected and dried locally before shipping for macronutrient and fiber analysis. The mean macronutrient concentrations were (mean +/- SD, g/100 g dry basis) fat 0.5 +/- 0.4, protein 11.8 +/- 8.2, available carbohydrate 7.7 +/- 6.3 and dietary fiber 74.0 +/- 12.9. Assuming that the macronutrient profile of these foods was reflective of the whole gorilla diet and that dietary fiber contributed 6.28 kJ/g (1.5 kcal/g), then the gorilla diet would provide 810 kJ (194 kcal) metabolizable energy per 100 g dry weight. The macronutrient profile of this diet would be as follows: 2.5% energy as fat, 24.3% protein, 15.8% available carbohydrate, with potentially 57.3% of metabolizable energy from short-chain fatty acids (SCFA) derived from colonic fermentation of fiber. Gorillas would therefore obtain considerable energy through fiber fermentation. We suggest that humans also evolved consuming similar high foliage, high fiber diets, which were low in fat and dietary cholesterol. The macronutrient and fiber profile of the gorilla diet is one in which the colon is likely to play a major role in overall nutrition. Both the nutrient and fiber components of such a diet and the functional capacity of the hominoid colon may have important dietary implications for contemporary human health.

We conducted a meta-analysis to determine the effect of consumption of psyllium-enriched cereal products on blood total cholesterol (TC), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels and to estimate the magnitude of the effect among 404 adults with mild to moderate hypercholesterolemia (TC of 5.17-7.8 mmol/L) who consumed a low fat diet. Studies of psyllium cereals were identified by a computerized search of MEDLINE and Current Contents and by contacting United States-based food companies involved in psyllium research. Published and unpublished studies were reviewed by one author and considered eligible for inclusion in the meta-analysis if they were conducted in humans, were randomized, controlled experiments, and included a control group that ate cereal providing /=50 y) on blood lipids. The meta-analysis showed that subjects who consumed a psyllium cereal had lower TC and LDL-C concentrations [differences of 0.31 mmol/L (5%) and 0.35 mmol/L (9%), respectively] than subjects who ate a control cereal; HDL-C concentrations were unaffected in subjects eating psyllium cereal. There was no effect of sex, age or menopausal status on blood lipids. Results indicate that consuming a psyllium-enriched cereal as part of a low fat diet improves the blood lipid profile of hypercholesterolemic adults over that which can be achieved with a low fat diet alone.

Adenophostins A and B, which are metabolic products of the fungus Penicillium brevicompactum, are potent agonists at the D-myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] receptor. In the current study, adenophostin A was approximately 50-fold more potent than Ins(1,4,5)P3 at both releasing Ca2+ from the intracellular stores of permeabilized platelets and displacing [3H]Ins(1,4,5)P3 from its receptor on rat cerebellar membranes. Various analogues bearing structural features found in the adenophostins and/or Ins(1, 4,5)P3 were examined to elucidate the molecular basis for the observed enhanced potency. 2-AMP did not induce Ca2+ release from permeabilized platelets or have any effect on Ins(1,4,5)P3-induced Ca2+ release. Two carbohydrate-based analogues, (2-hydroxyethyl)-alpha-D-glucopyranoside-2',3,4-trisphosphate and alpha,alpha'-trehalose-3,4,3',4'-tetrakisphosphate, could induce release of Ca2+ and displace [3H]Ins(1,4,5)P3 from its binding site on rat cerebellar membranes, although both were less potent than Ins(1,4,5)P3. In common with adenophostin A, release of Ca2+ from the intracellular stores could be inhibited by heparin, and both analogues were metabolically resistant. This study is the first to demonstrate the activity of a synthetic disaccharide at the Ins(1,4, 5)P3 receptor and that the Ins(1,4,5)P3 receptor is capable of accommodating an increased steric bulk. The minimal importance of the 2-hydroxyl group of Ins(1,4,5)P3 (occupied by the pyranoside oxygen in adenophostin) was confirmed by comparing the activity of DL-scyllo-Ins(1,2,4)P3 [which differs from Ins(1,4,5)P3 solely by the orientation of this hydroxyl group] with that of Ins(1,4,5)P3. An analogue of this compound, namely, DL-6-CH2OH-scyllo-Ins(1,2,4)P3, which possesses an equatorial hydroxymethyl group analogous to the 5'-hydroxymethyl group of adenophostin, was found to be equipotent to Ins(1,4,5)P3, demonstrating the tolerance of the Ins(1,4,5)P3 receptor to additional steric bulk at this position.