Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels.

BACKGROUND: Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. METHODS: Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. RESULTS: Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, -40.1%, P < 0.0001; diet, -27.1%, P < 0.0001; exercise, -12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001). CONCLUSION: Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.

Day/night variations of high-molecular-weight adiponectin and lipocalin-2 in healthy men studied under fed and fasted conditions.

AIMS/HYPOTHESIS: Adiponectin and lipocalin-2 are adipocyte-derived plasma proteins that have been proposed to have opposite effects on insulin sensitivity. Given the epidemiological, physiological and molecular links between sleep, the circadian timing system and glucose metabolism, the aim of this study was to assess effects of the sleep/wake cycle and the fasting/feeding cycle on high-molecular-weight adiponectin (HMW-adiponectin; the biologically active form) and lipocalin-2. We also aimed to compare the 24 h rhythms in the levels of these proteins with those of cortisol, leptin, leptin-binding protein and total adiponectin. METHODS: Lean men underwent a 3 day in-laboratory study, either in the fed state (n = 8, age: 20.9 ± 2.1 years, BMI: 22.8 ± 2.3 kg/m²) or fasting state (3 day fast, n = 4, age: 25.3 ± 3.9 years, BMI: 23.3 ± 2.2 kg/m²). The sleep episode was scheduled in darkness from 23:00 to 07:00 hours. Blood was sampled every 15 min for 24 h on the third day of each study. RESULTS: While fed, HMW-adiponectin and lipocalin-2 had large daily rhythms with troughs at night (HMW-adiponectin: ~04:00 hours, peak-to-trough amplitude 36%, p < 0.0001; lipocalin-2: ~04:00 hours, 40%, p < 0.0001). On the third day of fasting, the timing and relative amplitudes were unchanged (HMW-adiponectin: ~04:00 hours, 38%, p = 0.0014; lipocalin-2: ~05:00 hours, 38%, p = 0.0043). CONCLUSIONS/INTERPRETATION: These data show that HMW-adiponectin and lipocalin-2 both have significant day/night rhythms, both with troughs at night, that these are not driven by the feeding/fasting cycle, and that it is important to report and/or standardise the time of day for such assays. Further studies are required to determine whether the daily rhythm of HMW-adiponectin levels influences the daily rhythm of insulin sensitivity.

Palmitate and glycerol kinetics during brief starvation in normal weight young adult and elderly subjects.

Data obtained in vitro suggest that the ability to mobilize fat decreases with age. We determined lipolytic rates in vivo in normal weight young adult (22-33 yr) and elderly (65-77 yr) subjects using a simultaneous infusion of [1,2-13C2]palmitate and [2H5]glycerol. The subjects were studied after a 12-h fast and again after 60-82 h of fasting. When lipolysis was expressed per unit of adipose tissue the values for the young adults were more than double those for the elderly (P less than 0.05). However, the amount of body fat in the elderly was twice that of the young adults, so that lipolysis per unit of body weight was similar in both groups. These results demonstrate that lipolysis per unit of adipose tissue is lower in elderly subjects. This may be due to their increase in body fat, however, since the total amount of potential energy mobilized from adipose tissue was similar to that of the young adults.

Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1.

To improve our understanding of the metabolic role of cytokines in protein wasting, we estimated the rates of protein synthesis and degradation in muscle and liver tissues in intact rats treated with several doses of recombinant IL 1 and/or tumor necrosis factor (TNF)/cachectin. Protein breakdown in muscle and liver were derived in vivo from the relationship between [14C]leucine distribution and tissue dilution in reference to circulating leucine. Synthesis was derived from the relationship between [14C]leucine appearance in the protein-bound and free-tissue leucine pools. To specifically relate changes in leucine tracer metabolism to protein dynamics, we separately measured the effect of these cytokines on blood flow to different tissues. The increase in dilution of the tissue-free [14C]leucine by TNF and TNF/IL 1 mixture, but not by IL 1 alone, could not be explained by a hemodynamic effect of these cytokines. Rather, this finding indicated that muscle proteolysis is enhanced by TNF and synergistically augmented by the addition of IL 1. Compatible with these data was the finding that more prolonged infusions of recombinant TNF/cachectin and the combination with IL 1 increased urinary nitrogen excretion. Changes in [14C]leucine dilution in the liver were less pronounced than those in skeletal muscle and consistent with net anabolic effect of TNF on liver protein. We conclude that rats exposed systemically to sublethal doses of TNF respond with increasing muscle and decreasing liver proteolysis, similar to that observed in inflammation and in cancer.

Metabolic effects of very low calorie weight reduction diets.

A randomized comparison trial of two very low calorie weight reduction diets was carried out for 5 or 8 wk in 17 healthy obese women. One diet provided 1.5 g protein/kg ideal body weight; the other provided 0.8 g protein/kg ideal body weight plus 0.7 g carbohydrate/kg ideal body weight. The diets were isocaloric (500 kcal). Amino acid metabolism was studied by means of tracer infusions of L-[1-13C]leucine and L-[15N]alanine. After 3 wk of adaptation to the diets, nitrogen balance was zero for the 1.5 g protein diet but -2 g N/d for the 0.8 g protein diet. Postabsorptive plasma leucine and alanine flux decreased from base line by an equal extent with both diets by approximately 20 and 40%, respectively. It was concluded that protein intakes at the level of the recommended dietary allowance (0.8 g/kg) are not compatible with nitrogen equilibrium when the energy intake is severely restricted, and that nitrogen balance is improved by increasing the protein intake above that level. Basal rates of whole body nitrogen turnover are relatively well maintained, compared with total fasting, at both protein intakes. However, turnover in the peripheral compartment, as evidenced by alanine flux, may be markedly diminished with either diet.

Alterations in whole body, muscle, liver, and tumor tissue protein synthesis and degradation in Novikoff hepatoma and Yoshida sarcoma tumor growth studied in vivo.

The rate of protein synthesis in vivo was assessed in tumor tissue, skeletal muscle, liver, and the whole body of rats bearing either the Yoshida sarcoma or Novikoff hepatoma after 18 days of tumor growth and compared to tumor-free controls. Changes in size of the whole animal and tumor (i.e., growth) were measured, and fractional rates of growth, synthesis, and degradation were estimated. Muscle protein synthesis and whole-body growth were significantly reduced in both groups of tumor-bearing rats after 18 days of tumor growth. In addition to reductions in muscle protein synthesis, whole-body protein synthesis was significantly reduced in the Yoshida tumor-bearing group (587 +/- 36 versus 401 +/- 40 mg/h; mean +/- SEM; control versus Yoshida group, respectively, P less than 0.01). Tumor protein synthesis was not statistically different between the Yoshida tumor (76 +/- 21 mg/h) and the Novikoff tumor (50 +/- 8) after 18 days of growth despite the fact that the Yoshida tumors were significantly larger (33.9 +/- 4.2 g versus 11.9 +/- 1.2 g; P less than 0.01). The fractional synthesis rate (Ks) was, in fact, significantly slower in the Yoshida versus the Novikoff tumor (36.8 +/- 7.6 versus 55.1 +/- 4.8%/day). Tumor growth (Kg) followed first order growth rates for both tumor types (r = 0.945, 0.869; Kg = 17.2 +/- 1.6, 15.5 +/- 1.9%/day; Yoshida and Novikoff, respectively). The fractional degradation rate of tumor protein (Kd) was determined as the difference between the two first order rate constants Ks and Kg. The tumor protein degradation rate was significantly reduced in the Yoshida tumors compared to the Novikoff tumors (19.6 +/- 8.2% versus 39.6 +/- 4.2%/day, respectively). The greater size in the Yoshida sarcoma can be attributed to reduction in fractional protein degradation rather than change in synthesis rates, which supports the theory that some tumors can regulate their growth by alteration in tumor protein degradation rates (J. A. Tayek et al., Cancer Res., 46:5649-5654, 1986).

Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis.

Soy isoflavones exhibit a number of biological effects, suggesting that they may have a role in cancer prevention. Our objectives are to determine whether components of soy products or purified soy isoflavones can inhibit the progression of bladder cancer. We compared the in vitro effects of pure soy isoflavones and soy phytochemical concentrate on growth curves, cell cycle progression, and apoptosis in murine and human bladder cancer cell lines. Pure soy isoflavones (genistein, genistin, daidzein, and biochanin A) and soy phytochemical concentrate exhibit dose-dependent growth inhibition of murine (MB49 and MBT-2) and human (HT-1376, UM-UC-3, RT-4, J82, and TCCSUP) bladder cancer cell lines, although the degree of inhibition varies among lines. Soy isoflavones induce a G2-M cell cycle arrest in all human and murine lines evaluated by flow cytometry. In addition, some bladder cancer lines show DNA fragmentation consistent with apoptosis. We next evaluated the ability of genistein, soy phytochemical concentrate, and soy protein isolate, respectively, to inhibit the growth of transplantable murine bladder cancer in vivo. C57BL/6 mice were randomly assigned to treatment groups (n = 12/group): (a) AIN-76A diet; (b) AIN-76A diet plus genistein, i.p., 50 mg/kg body weight/day; (c) AIN-76 diet with soy phytochemical concentrate at 0.2% of the diet; (d) AIN-76 diet with soy phytochemical concentrate at 1.0% of the diet; and (e) AIN-76A diet with soy protein isolate, 20% by weight. Mice were inoculated s.c. with 5 x 10(4) syngeneic MB49 bladder carcinoma cells, and tumor growth was quantitated. Neither genistein nor soy products reduced body weight gain. Tumor volumes from mice treated with genistein, dietary soy phytochemical concentrate at 1%, or dietary soy protein isolate were reduced by 40% (P < 0.007), 48% (P < 0.001), or 37% (P < 0.01), respectively, compared with controls. We characterized the effects of treatment on several biomarkers in tumor tissue: proliferation index by proliferating cell nuclear antigen staining, apoptotic index by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining, and angiogenesis by microvessel quantitation. Soy products reduced angiogenesis, increased apoptosis, and slightly reduced proliferation while showing no histopathological effects on the normal bladder mucosa. Our data suggest that soy isoflavones can inhibit bladder tumor growth through a combination of direct effects on tumor cells and indirect effects on the tumor neovasculature. Soy products warrant further investigation in bladder cancer prevention and treatment programs or as antiangiogenic agents.

Effects of branched chain amino acid-enriched total parenteral nutrition on amino acid utilization in rats bearing Yoshida sarcoma.

We have studied the ability of branched chain amino-acid enriched total parenteral nutrition solutions to improve nutritional status without stimulating tumor growth. Protein kinetics, nitrogen balance, tumor kinetics, fractional synthetic rates of individual tissues, and albumin synthesis were compared in male Sprague-Dawley rats (125-145 g) that had either s.c. Yoshida sarcoma (n = 15) or sham implantations (n = 18). Ten days postinjection, rats were randomly assigned to 2 diet groups and given parenteral infusions of 4 days at 170 kcal/kg.body wt.day as dextrose and 2 g N/kg.body wt.day as either 19 or 50% branched chain amino acid-enriched diet. During the last 4 h of feeding, protein kinetic values were studied using a constant infusion of [14C]tyrosine. Plasma tyrosine appearance, synthesis, and breakdown were unchanged by branched chain amino acid infusion. Percentage of tyrosine flux oxidized and tyrosine oxidation decreased (P less than 0.05) and net tyrosine balance improved (P less than 0.05) in rats receiving the branched chain amino acid-enriched diet. Greater nitrogen balance and lower tumor growth rates were also found in branched chain amino acid-infused rats although not statistically significant. Tumor intracellular specific activity was significantly higher in tumor animals receiving crystalline infusions, suggesting greater tumor protein breakdown with branched chain amino acid-enriched infusion. Fractional synthetic rates of liver, muscle, and tumor were unchanged. Hence, branched chain amino acid-enriched total parenteral nutrition increases amino acid utilization for net protein synthesis principally by reducing oxidation without stimulating tumor growth.

Influence of the Walker 256 carcinosarcoma on muscle, tumor, and whole-body protein synthesis and growth rate in the cancer-bearing rat.

The in vivo rates of protein synthesis were assessed in tumor tissue, skeletal muscle, and whole body of rats bearing the Walker 256 carcinosarcoma. Estimates of protein synthesis in the nontumorous tissues were compared to tumor-free controls. Changes in size of the whole animal and tumor (i.e., growth) were measured, and fractional rates of growth, synthesis, and breakdown were estimated. Muscle protein synthesis and whole-body growth were significantly reduced in rats bearing larger tumors, and both were negatively correlated with tumor size (r = -0.723 and -0.825, respectively; P less than 0.01). Furthermore, whole-body and muscle protein synthesis were positively correlated with body growth (r = 0.380 and 0.563, respectively; P less than 0.05). Tumor growth followed first-order kinetics between days 7 and 13 following implantation, with a mean rate constant of 34.3%/day for the larger tumors and 27.7%/day for the small tumors. The difference in tumor growth became statistically significant over the final 3 days of tumor volume measurements. Fractional protein synthesis was significantly lower in the larger compared to the smaller tumors (48.6 versus 84.8%/day; P less than 0.05) as measured on day 14. This finding indicates a lower protein breakdown rate for the larger tumors (14.3 versus 59.0%/day; P less than 0.01) and suggests that the process of protein breakdown could play a significant role in determining tumor size, leading support to the theory of tumors acting as nitrogen traps.

Altered amino acid kinetics in rats with progressive tumor growth.

The present study was designed to determine whether alterations in host metabolism associated with progressive tumor growth were a result of the anorexia frequently observed with cancer or could be attributed to other direct tumor effects. Rates of tyrosine flux, oxidation, and incorporation into protein, as well as fractional protein-synthetic rates in nonsecretory liver, muscle, and tumor, were determined in overnight-fasted rats, 5 to 6 (Stage I), 10 to 11 (Stage II), and 15 to 16 (Stage III) days following s.c. implantation of RNC-254 fibrosarcoma. Tumor-bearing rats were allowed to consume a purified diet containing 20% protein ad libitum, and results were compared to non-tumor-bearing rats pair fed quantities of food equivalent to tumor-bearing animals or allowed to consume the diet ad libitum. Results demonstrate that during later stages of tumor growth (Stage III) calorie intake and nontumor body weight gain were reduced in tumor-bearing rats (p less than 0.05). Fifteen and 16 days following implantation, there were significant changes in amino acid kinetics that were not observed after earlier periods of tumor growth and that could not be explained by any reduction in dietary intake. Rates of tyrosine appearance in the plasma and subsequent incorporation into whole-body protein were increased 33 and 34%, respectively (p less than 0.05), when compared to non-tumor-bearing rats fed equivalent quantities of food. Whole-body tyrosine oxidation rates were unchanged. Skeletal protein synthesis, as reflected by gastrocnemius or rectus abdominus muscle, was reduced from 10.5 and 10.1%/day to 7.4 and 6.0%/day, respectively (p less than 0.05), in tumor-bearing compared to pair-fed animals. The findings suggest that significant alterations in protein metabolism occur in advanced stages of experimental neoplastic disease which cannot be explained by reductions in dietary intake and are aimed at providing adequate quantities of endogenous amino acids for net tumor growth.

Adherence to a dietary fat intake reduction program in postmenopausal women receiving therapy for early breast cancer. The Women's Intervention Nutrition Study.

PURPOSE: To evaluate the feasibility of integrating a program based on dietary fat intake reduction into adjuvant treatment strategies for postmenopausal women receiving therapy for early breast cancer. PATIENTS AND METHODS: Two hundred ninety postmenopausal women with localized (stage I to IIIa) breast cancer receiving conventional systemic therapy provided informed consent and were randomized in a multicenter trial to either a dietary intervention group receiving a program of individualized instruction for reducing total fat intake or a dietary control group with minimal dietary counseling. RESULTS: Significantly reduced (P < .001) fat intake (in terms of percent calories derived from fat) was observed in the intervention group versus the control group at 3 months (20.3% +/- 2.4% v 31.5% +/- 2.6%, mean +/- SD, respectively) and maintained throughout 24 months of observation. The 50% reduction in daily fat-gram intake (from 66 +/- 23 to 33 +/- 14 g, P < .001) seen at 6 months was associated with reduced saturated fat, monounsaturated fat, polyunsaturated fat, and linoleic acid (P < .001). Significantly lower body weight was also seen in intervention compared with control patients at all observation periods, resulting in a 3.3-kg weight difference 18 months after randomization (P < .001). CONCLUSION: Substantial and sustained dietary fat reduction with associated weight change can be achieved at relatively low cost within the context of conventional multimodality clinical management of postmenopausal women with localized breast cancer. This result supports the feasibility of conducting a full-scale evaluation of the influence of dietary fat intake reduction on the clinical outcome of breast cancer patients.

Nitrogen metabolism and insulin requirements in obese diabetic adults on a protein-sparing modified fast.

A protein-sparing modified fast (PSMF), which is a total fast modified by the intake of 1.2-1.4 gm. protein per kilogram ideal body weight (IBW), fluids ad libitum, and vitamin and mineral supplementation, allows effective control of carbohydrate metabolism and hunger. It reduces serum glucose and insulin concentrations in obese diabetic patients and increases free fatty acid and ketone body concentrations; ketonuria appears within 24-72 hours. When this fast was applied to seven obese adult-onset diabetics who were receiving 30-100 units of insulin per day, insulin could be discontinued after 0-19 days (mean, 6.5). In the three patients who had extensive nitrogen-balance studies, balance could be maintained chronically by 1.3 gm. protein per kilogram IBW, despite the gross caloric inadequacy of the diet. The PSMF was tolerated well in an outpatient setting after the initial insulin-withdrawal phase had occurred in the hospital. Significant improvements in blood pressure, lipid abnormalities, parameters of carbohydrate metabolism, and cardiorespiratory, symptoms were associated with weight loss and/or the PSMF. For diabetics with some endogenous insulin reserve, the PSMF offers significant advantages for weight reduction, including preservation of lean body mass (as reflected in nitrogen balance) and withdrawal of exogenous insulin.

Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months.

OBJECTIVES: This investigation sought to determine the effect of phentermine-fenfluramine (phen-fen) on the prevalence of valvular heart disease in 226 obese subjects enrolled in a prospective, strict weight loss, research protocol. BACKGROUND: Early reports have suggested that the use of phen-fen for weight loss may be associated with increased valvular heart disease. Such reports were based on small numbers of patients, limited data on dose and duration of phen-fen therapy, and no correlation with matched controls. METHODS: All subjects underwent transthoracic echocardiography for significant valvular lesions within a mean of 97 days from the manufacturer's announcement of the voluntary withdrawal of fenfluramine and dexfenfluramine. All echocardiograms were interpreted by two independent readers. RESULTS: The study population included 183 women and 43 men with a mean age of 46.9 +/- 8.9 years and mean starting body mass index of 39.8 +/- 7.7 kg/m2. Using the Food and Drug Administration criteria, significant aortic regurgitation was detected in 15 subjects (6.6%) and mitral regurgitation in 3 subjects (1.3%). Only one patient had significant regurgitation of both aortic and mitral valves. No valves had severe regurgitation. Significant valvular disease did not correlate with the dose or duration of phen-fen therapy. Furthermore, the prevalence of valvular regurgitation is comparable to the normal offspring in the Framingham Heart Study, who are similar in age, gender, and geographical location. CONCLUSIONS: Phen-fen therapy is associated with a low prevalence of significant valvular regurgitation. Valvular regurgitation in our subjects may reflect age-related degenerative changes.

Cellular immunity in adult marasmus.

Twelve patients with recent weight loss to less than 85% of standard weight-height ratio and a serum albumin level of at least 3 gm/100 ml were considered to have the adult equivalent to marasmus. Cellular immune function was assessed by delayed hypersensitivity skin testing to Monilia and streptokinase-streptodornase, peripheral lymphocyte count, proportion of T and B cells, whole blood and isolated lymphocyte transformation to phytohemagglutinin, pokeweed mitogen, concanavalin A, Monilia, and streptokinase-streptodornase. Significant impairment of skin test reactivity while in vitro responsiveness remained intact was noted in the marasmic patients. No impairment was found in 12 individuals with recent weight loss who remained at a weight greater than the 85% weight-height ratio. In four marasmic individuals in whom weight loss was arrested by nutritional repletion, skin reactivity returned without substantial change in weight. In this type of marasmus, both depleted nutritional status and weight loss must be present for impairement of skin test responsiveness. These findings confirm relative sparing of more vital functions dependent on protein metabolism in adult marasmus compared to the kwashiorkor-like syndromes of hypoalbuminemic malnutrition seen in adults.

Normal cardiac rhythm during hypocaloric diets of varying carbohydrate content.

Cardiac arrhythmias have been implicated in the deaths of 17 morbidly obese individuals subsisting on a collagen hydrolysate preparation ("liquid protein") during a modified fasting regimen for weight loss. Serious cardiac arrhythmias have been noted in three of six subjects studied prospectively within 28 days of starting a similar regimen, which used an inadequate protein source and was nearly devoid of all essential minerals. A comparative study of three 28-day weight loss diets of varying carbohydrate, protein, and energy content (450 to 820 kcal/day) but employing protein of good quality and adequate in micronutrients did not disclose substantial diet-related arrhythmias in five subjects on each of the three diets. The incidence of arrhythmia seen with liquid protein diets is not likely to be related to the absolute energy or carbohydrate content of the modified fasting regimen itself.

Insulin resistance versus insulin secretion in the hypertension of obesity.

We measured the degree of association between obesity, blood pressure, insulin resistance, and insulin secretion in 72 male and female obese hypertensive, obese nonhypertensive, and normal weight control subjects. Baseline weight, body mass index, percent body fat, waist/hip ratio, and systolic and diastolic blood pressures were obtained. Insulin sensitivity was assessed according to Bergman's minimal model. Twelve-hour urinary c-peptide was measured after a standard liquid meal. Insulin action was inversely associated with blood pressure status, obesity status, and age. Meal-stimulated c-peptide excretion significantly correlated with systolic blood pressure and percent fat but not with body mass index or age. Multivariate regression analysis indicated that, of the measures of body composition, percent fat and waist/hip ratio had the strongest correlation with insulin action either alone or in combination with c-peptide excretion. Obese hypertensive patients had an index of insulin action (10(-4).min-1/[microunits/ml]) of 1.34 +/- 0.19, which was significantly (p less than 0.003) lower than in the obese nonhypertensive patients (index, 2.26 +/- 0.10) or the nonobese subjects (index, 5.41 +/- 0.26, p less than 0.001). Meal-stimulated c-peptide excretion (nmol/kg lean body mass) was increased only in the obese hypertensive group (0.32 +/- 0.01) and was significantly higher (p less than 0.001) than in the obese nonhypertensive (0.16 +/- 0.01) or the nonobese subjects (0.14 +/- 0.01). These results support the hypothesis that abnormalities in blood pressure regulation, insulin-stimulated glucose uptake, and insulin secretion coexist.

Developing strategies for intervention/prevention trials of individuals at risk of hereditary colon cancer.

Environmental causes are thought to be the etiology of most colorectal cancers (sporadic colorectal cancer). However, about 10% of the cases result from one of two well-defined forms of hereditary colorectal cancer: hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis. The development of intervention/prevention strategies for patients with newly diagnosed colon cancer and their families at high risk for hereditary colon cancer was framed in the questions: "Who is the target?" and "How to identify those at high risk"? There is agreement that genetic analysis for hereditary colorectal cancer holds tremendous promise but that it requires the development of highly structured protocols to ensure that genetic testing is a positive experience for patients at high risk. Appropriate strategies to identify high-risk patients would include recruiting minority (ethnic, racial, and socioeconomic) populations into these studies. Implementation of the protocol would begin with primary-care physicians working with cancer prevention centers in a network to achieve informed consent, to obtain bank-blood samples for genotyping, and to provide the social support and genetic counseling necessary to achieve the goal of a positive experience in cancer prevention. Initial studies would be directed at the known hereditary colorectal cancer groups, including familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

Nutritional assessment and support during infection.

Protein malnutrition is one of the principal factors relating to morbidity and mortality during infection. Nutritional assessment is required to determine the severity of depletion and degree of hypermetabolism affecting this patient population. Simple anthropometric and 24-hr urine collections together with routine biochemical analyses can readily allow clinical assessment to occur. Optimal utilization of dietary intake is dependent on the degree of protein catabolism and energy expenditure in excess of the basal energy requirement. Urinary nitrogen excretion in 24-hr on a protein-free diet is especially valuable in aiding this assessment. This analysis together with urinary creatinine which provide important estimates of lean body mass and serial measures will allow estimates of the progression of malnutrition. In infected adults optimal protein intake to produce positive nitrogen balance is 1.5 to 2.0 g of protein/kg per day. This would appear to reflect the fact that 16% of the caloric expenditure comes from protein sources during injury. Since this value is approximately twice that seen during nonstress, the reutilization of body protein would appear to be decreased. Careful appreciation of the metabolic response during infection is necessary prior to consideration of the nutritional support plan. Knowledge regarding the phase of infection, severity of nutritional depletion, and degree of hypermetabolism will influence the attainable goals of nutritional support.

Bridging animal and human studies: what are the missing segments in dietary fat and prostate cancer?

Epidemiologic investigations have suggested an association of dietary fat intake with prostate cancer risk, especially risk of advanced prostate cancer. However, supporting evidence from animal studies is limited. Segments that would bridge animal and human studies on dietary fat and prostate cancer--which would determine the future directions of research--are missing. Such segments include 1) well-designed animal studies to evaluate whether dietary fat or fatty acid modulation, particularly by reducing dietary fat and supplementing n-3 fatty acids, reduces the progression of prostate cancer; 2) in vivo identification of intermediate biomarkers that are responsive to dietary fat and fatty acid treatment and may serve as surrogate endpoints in future clinical studies; 3) elucidation of mechanisms by which dietary fat or fatty acid modulation could prevent prostate cancer progression; 4) further epidemiologic studies to estimate dietary exposure more precisely to establish the correlation between dietary fat and risk of prostate cancer; 5) randomized clinical intervention trials evaluating whether dietary fat reduction combined with dietary n-3 fatty acid supplementation delays the recurrence of prostate cancer and improves survival in patients with clinical disease after therapeutic treatment, and whether it prevents or reduces the progression to clinically significant disease in men with latent disease; and 6) studies validating intermediate biomarkers as surrogate endpoints.

Criteria for choosing amino acid therapy in acute renal failure.

Metabolic studies were performed on 19 patients with acute renal failure. Therapy included intravenous hyperalimentation using 15 to 20 g of essential amino acids or 20 to 40 g of essential plus nonessential amino acids and hypertonic glucose (37 to 50%). The effect of this parenteral feeding appears to be primarily pharmacological. Hypertonic glucose promotes the hyperinsulinemia important to be membrane function, the operation of the sodium pump, and cell metabolism. Administration of high biological value crystalline amino acdis potentiates the effect of insulin by inhibiting protein breakdown and promoting protein synthesis, particularly in muscle. This reduces tissue catabolism and urea formation, and promotes potassium, magnesium, and phosphate homeostasis. The branched-chain ketogenic amino acids valine, leucine, and isoleucine may be of particular importance. When indicated, administration of renal failure hyperalimentation and peritoneal or hemodialysis can be expected to complement each other and accelerate recovery. This intravenous fluid therapy, in turn, must be coordinated with proper hemodynamics, usually requiring a colloidal solution to maintain intravascular volume, and cardiotrophic agents such as digitalis and dopamine. Early use of renal failure can be expected to demonstrate the most striking response in terms of survival, early recovery from acute renal failure, and the preservation of physiological homeostasis.