ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium.

BACKGROUND AND PURPOSE: Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib. MATERIALS AND METHODS: Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment. RESULTS: Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG. CONCLUSIONS: ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

Influence of maternal dietary Zn intake on expression of diabetes-induced teratogenicity in rats.

Diabetic rat pregnancies are characterized by altered maternal and fetal Zn metabolism and a higher frequency of fetal malformations. In this study, the effect of varying maternal dietary Zn on pregnancy and fetal outcome and on maternal and fetal trace element status were investigated. Starting on day 0 of gestation, streptozocin-induced diabetic and nondiabetic control rats were fed a low-Zn diet (4.5 micrograms/g diet), an adequate-Zn diet (24.5 micrograms/g diet), or a high-Zn diet (500 micrograms/g diet) throughout gestation. Fetuses were taken by cesarean section on gestation day 20. Fetuses from diabetic dams were smaller, weighed less, and had less calcified skeletons and more malformations than fetuses from control dams. In the controls, maternal dietary Zn had a minor effect on fetal malformation frequency. In contrast, in the diabetic animals, the low-Zn diet had a strong teratogenic effect. In diabetic dams, the adequate- and high-Zn diets improved fetal length and weight more than it did in fetuses from nondiabetic dams. However, supplemental dietary Zn during diabetic pregnancy did not further improve malformation frequencies. Liver and kidney Zn, Cu, and metallothionein concentrations were higher in diabetic dams than in control dams. In contrast, liver Zn, Cu, and metallothionein concentrations in fetuses of diabetic dams were lower than in fetuses from control dams, regardless of maternal dietary Zn intake. These results show that diabetes during pregnancy can amplify the teratogenic effects of a mild maternal Zn deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of maternal diabetes on trace element status and fetal development in the rat.

Despite improvements in prenatal care, there is a high incidence of congenital malformations in diabetic pregnancies. Not only is the diabetic patient characterized by a disorder of total fuel metabolism, but abnormal trace element metabolism occurs as well. In the present study, maternal and fetal zinc (Zn), copper (Cu), manganese (Mn), iron (Fe), magnesium (Mg), and calcium (Ca) status has been studied in Sprague-Dawley (SD) and Wistar rats. In addition, the effect of maternal diabetes on fetal development was also investigated. Rats were injected 27 days before mating with streptozocin (STZ, 45 mg/kg) in citrate buffer. On day 20 of gestation, litters were taken by cesarean section. Fetuses from diabetic dams weighed less, and had shorter crown-rump lengths and larger placentas than fetuses from controls. Evaluation of fetal skeletal development revealed fewer calcified sternal sites, anterior phalanges and caudal vertebrae, and an increased frequency of malformations in fetuses of diabetic dams. In dams, diabetics had larger adrenals, kidneys, and liver, and smaller thymus. Abnormal trace element metabolism was evident in diabetic dams and their fetuses. Mn was elevated in maternal liver, kidney and placenta of diabetic animals as well as in fetal liver of pups from diabetic dams. Maternal Cu and Zn levels were also higher in the liver and kidney of diabetic rats. In contrast, fetal liver Zn from fetuses of diabetic mothers was significantly decreased when compared with controls. These results suggest that diabetes may have induced fetal Zn deficiency. If this deficiency is present during embryogenesis/organogenesis, this could be one of the mechanisms of the teratogenicity of the diabetic state.

Complications of pregnancy and fetal development.

Although the outcome of pregnancy for women with diabetes mellitus has improved in recent years, the infant of the diabetic mother has an increased risk of major clinical problems, particularly in the early neonatal period. These include birth injury due to macrosomia, neonatal hypoglycemia, respiratory distress syndrome, and serious congenital anomalies. Because of the great difficulties encountered during attempts to investigate these problems in clinical research protocols, there is a continuing need to establish appropriate animal models of the diabetic pregnancy. Studies carried out over the past decade, primarily with chemically-induced diabetes have suggested techniques which might be useful. In general, the choice of the animal to be studied will depend on the hypotheses being addressed. For instance, small animals such as rabbits and rats made diabetic with streptozotocin have been successfully used for investigation of fetal lung development. Furthermore, the rat model has been helpful for evaluation of fetal anomalies associated with maldevelopment of the spine and central nervous system. Larger animals, such as the nonhuman primate, are more appropriate for studying placental function and amniotic fluid composition in diabetic pregnancies. The task group on pregnancy and fetal development recommends that animal models of diabetes mellitus be used for a more extensive hormonal and metabolic characterization of diabetic mothers during pregnancy, for investigation of placental physiology with respect to the transfer of substrates from mother to fetus, for systematic and comprehensive study of mechanisms controlling fetal lung development, and for delineation of the pathophysiology of neonatal hypoglycemia. It is further recommended that animal models of spontaneous diabetes such as the BB/W rat be used in future studies dealing with pregnancy and fetal development. Because females with spontaneous diabetes show reduced conception rates, there is a pressing need to enhance the fertility of these animals in order to intensify studies on fetal development.

A randomized trial of improved weight loss with a prepared meal plan in overweight and obese patients: impact on cardiovascular risk reduction.

OBJECTIVE: To assess the long-term effects of a prepackaged, nutritionally complete, prepared meal plan compared with a usual-care diet (UCD) on weight loss and cardiovascular risk factors in overweight and obese persons. DESIGN: In this randomized multicenter study, 302 persons with hypertension and dyslipidemia (n = 183) or with type 2 diabetes mellitus (n = 119) were randomized to the nutrient-fortified prepared meal plan (approximately 22% energy from fat, 58% from carbohydrate, and 20% from protein) or to a macronutrient-equivalent UCD. MAIN OUTCOME MEASURES: The primary outcome measure was weight change. Secondary measures were changes in blood pressure or plasma lipid, lipoprotein, glucose, or glycosylated hemoglobin levels; quality of life; nutrient intake; and dietary compliance. RESULTS: After 1 year, weight change in the hypertension/dyslipidemia group was -5.8+/-6.8 kg with the prepared meal plan vs -1.7+/-6.5 kg with the UCD plan (P<.001); for the type 2 diabetes mellitus group, the change was -3.0+/-5.4 kg with the prepared meal plan vs -1.0+/-3.8 kg with the UCD plan (P<.001) (data given as mean +/- SD). In both groups, both interventions improved blood pressure, total and low-density lipoprotein cholesterol levels, glycosylated hemoglobin level, and quality of life (P<.02); in the diabetic group, the glucose level was reduced (P<.001). Compared with those in the UCD group, participants with hypertension/dyslipidemia in the prepared meal plan group showed greater improvements in total (P<.01) and high-density lipoprotein (P<.03) cholesterol levels, systolic blood pressure (P<.03), and glucose level (P<.03); in participants with type 2 diabetes mellitus, there were greater improvements in glucose (P =.046) and glycosylated hemoglobin (P<.02) levels. The prepared meal plan group also showed greater improvements in quality of life (P<.05) and compliance (P<.001) than the UCD group. CONCLUSIONS: Long-term dietary interventions induced significant weight loss and improved cardiovascular risk in high-risk patients. The prepared meal plan simultaneously provided the simplicity and nutrient composition necessary to maintain long-term compliance and to reduce cardiovascular risk.

Nutritional management of cardiovascular risk factors. A randomized clinical trial.

BACKGROUND: Adherence to dietary recommendations for disease management is often hindered by the complexity of incorporating them into the daily diet. Nutrition and cardiovascular scientists and food technologists collaborated to develop a prepared meal plan that meets national dietary guidelines for cardiovascular risk reduction. OBJECTIVE: To assess the clinical effects of this plan, which incorporates all National Academy of Sciences National Research Council recommended dietary allowances for vitamins, minerals, and macronutrients, compared with a patient-selected American Heart Association Step I and Step II diet plan. METHODS: This multicenter, randomized, parallel-intervention trial was conducted at 10 medical centers in the United States and Canada and involved 560 men and women with hypertension, dyslipidemia, or diabetes. Following calculation of prescriptions to meet individual nutritional requirements based on the Harris-Benedict equation, participants were randomized to the Campbell's Center for Nutrition and Wellness (CCNW) plan, which is composed of prepackaged breakfast, lunch, and dinner meals provided to participants, or a nutritionist-guided American Heart Association Step I and Step II diet, in which participants self-selected foods to meet their nutrition prescription for 10 weeks. MAIN OUTCOME MEASURES: Blood pressure (BP); lipid, glucose, glycosylated hemoglobin (HbA1c), and insulin levels; body weight; dietary intake; and quality of life. RESULTS: Patients' BP, lipid levels, carbohydrate metabolism, weight, and quality of life (P < or = .001 for all findings except low-density lipoprotein-high-density lipoprotein ratio, P = .25) all improved on both nutrition plans. Mean differences (+/-SD) between baseline and treatment clinical values for the CCNW and the self-selected diet groups (between-group P values), respectively, were as follows: systolic BP, -6.4 +/- 9.2 mm Hg and -4.6 +/- 9.0 mm Hg (P = .02); diastolic BP, -4.2 +/- 5.7 mm Hg and -3.0 +/- 5.1 mm Hg (P = .006); cholesterol, -0.32 +/- 0.58 mmol/L and -0.27 +/- 0.56 mmol/L (-12.4 +/- 22.5 mg/dL and -10.4 +/- 21.9 mg/dL) (P = .30); glucose, -0.65 +/- 1.88 mmol/L and -0.75 +/- 2.03 mmol/L (-11.7 +/- 34.0 mg/dL and -13.5 +/- 36.6 mg/dL) (P = .10); and HbA1c, -0.4% +/- 0.8% and -0.3% +/- 0.7% (P = .66). Weight loss with the CCNW and self-selected plans, respectively, was as follows: men, -4.5 +/- 3.6 kg and -3.5 +/- 3.3 kg; and women, -4.8 +/- 3.0 kg and -2.8 +/- 2.8 kg. Quality of life was significantly improved for daily and work activities (P < .05) and nutritional health perceptions (P < .05) with the CCNW plan relative to the self-selected group. Overall nutrient intake and compliance were both significantly (P < .001) better with the CCNW plan. CONCLUSIONS: Nutritionally balanced meals that meet the recommendations of national health organizations improved multiple risk factors for patients with cardiovascular disease. The CCNW plan resulted in greater clinical benefits, nutritional completeness, and compliance than the self-selected diet. The CCNW is a comprehensive nutrition plan, convenient for both prescription and practice, and appears viable for effecting favorable dietary changes in patients at high risk for cardiovascular disease.

Multicenter randomized trial of a comprehensive prepared meal program in type 2 diabetes.

OBJECTIVE: To evaluate the clinical effects of a comprehensive prepackaged meal plan, incorporating the overall dietary guidelines of the American Diabetes Association and other national health organizations, relative to those of a self-selected diet based on exchange lists in free-living individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 202 women and men (BMI < or = 42 kg/m2) whose diabetes was treated with diet alone or an oral hypoglycemic agent were enrolled at 10 medical centers. After a 4-week baseline period, participants were randomized to a nutrient-fortified prepared meal plan or a self-selected exchange-list diet for 10 weeks. On a caloric basis, both interventions were designed to provide 55-60% carbohydrate, 20-30% fat, and 15-20% protein. At intervals, 3-day food records were completed, and body weight, glycemic control, plasma lipids, and blood pressure were assessed. RESULTS: Food records showed that multiple nutritional improvements were achieved with both diet plans. There were significant overall reductions in body weight and BMI, fasting plasma glucose and serum insulin, fructosamine, HbA1c, total and LDL cholesterol, and blood pressure (P < 0.001 or better for all). In general, differences in major end points between the diet plans were not statistically significant. CONCLUSIONS: Glycemic control and cardiovascular risk factors improve in individuals with type 2 diabetes who consume diets in accordance with the American Diabetes Association guidelines. The prepared meal program was as clinically effective as the exchange-list diet. The prepared meal plan has the additional advantages of being easily prescribed and eliminating the complexities of meeting the multiple dietary recommendations for type 2 diabetes management.

Obese Zucker (fa/fa) rats exhibit normal target sensitivity to corticosterone and increased drive to adrenocorticotropin during the diurnal trough.

Genetically obese Zucker (fa/fa) rats exhibit numerous metabolic and endocrine disorders associated with modest hypercorticosteronemia and reported changes in peripheral target tissue sensitivity to glucocorticoids. In this study we investigated phenotypic differences in basal and stress-induced ACTH and corticosterone (B) secretion in intact and adrenalectomized lean and obese male Zucker rats. In addition, we determined whether differences in the sensitivity to B of plasma ACTH and insulin secretion as well as other peripheral B targets could be observed between the two phenotypes. There were no significant differences in basal ACTH or B in either the morning (AM) or evening (PM) in intact obese and lean rats; however, mean B was increased in the obese rats in the AM, and signs of chronically increased adrenocortical activity were observed, including increased adrenal weight and intraadrenal phenylethanolamine-N-methyl transferase activity and decreased thymus weight. In a second experiment, B was significantly elevated 3 min after either administration in obese compared to lean rats; however, there was no significant difference in B between the groups at 10 min, nor were ACTH levels at these times different. Five days after adrenalectomy with sc B replacement, ACTH was decreased as a function of B in both phenotypes under AM basal and stress conditions. The IC50 values for inhibition of basal ACTH by B were 3.16 and 4.17 micrograms/dl in lean and obese rats, respectively. Under stress conditions, the IC50 values were not different (4.39 micrograms/dl for lean and 4.24 micrograms/dl for obese rats). B dose-dependent increases in body and epididymal fat depot weights were greater in obese than in lean rats, an expected result because of elevated insulin levels in this group. Insulin exhibited only small B-dependent increases, and thymus weight decreased in a B-dependent fashion; there were no differences in the sensitivity to B of these measures between lean and obese rats. We conclude that 1) there is no evidence for altered sensitivity to B in obese rats for any of the B-sensitive end points measured; and 2) basal adrenocortical activity is slightly elevated, and the sensitivity of ACTH to B feedback is decreased in obese rats under AM conditions in the absence of external stress.(ABSTRACT TRUNCATED AT 400 WORDS)

Autonomic nervous system mediation of the pancreatic polypeptide response to insulin-induced hypoglycemia in conscious rats.

To investigate the neural regulation of pancreatic polypeptide (PP) secretion during hypoglycemia in the rat, insulin was administered to chronically cannulated rats, and plasma PP responses were compared between saline-treated animals and animals pretreated with a ganglionic blocking agent (hexamethonium), a muscarinic antagonist (atropine), combined alpha- and beta-adrenergic receptor blockade (propranolol + tolazoline), or combined adrenergic blockade + atropine. PP was measured using a new RIA which selectively detects PP in rat plasma. In control rats (n = 10), plasma PP increased from a baseline level of 30 +/- 3 pg/ml to 271 +/- 41 pg/ml during hypoglycemia (plasma glucose = 29 +/- 2 mg/dl) (delta PP = +241 +/- 42 pg/ml, P less than 0.0005), demonstrating that in rats, as in other species, insulin-induced hypoglycemia is a potent stimulus for PP release. PP only increased by 31 +/- 10 pg/ml during similar hypoglycemia in 7 hexamethonium-treated rats (P less than 0.01 vs. control animals). Thus, at least 90% of the PP response to hypoglycemia is neurally mediated. The plasma PP response to hypoglycemia was +85 +/- 24 pg/ml in atropine-treated rats (P 0.01 vs. control rats), suggesting that approximately 65% of the PP response is mediated via muscarinic acetylcholine receptors on the islet F cell. The PP response to hypoglycemia in rats with combined adrenergic blockade (delta = +168 +/- 32 pg/ml) was slightly, but not significantly smaller than that in control rats. The combination of combined blockade + atropine resulted in a PP response (delta = +26 +/- 7 pg/ml) to hypoglycemia that was similar to that in hexamethonium-treated rats (P less than 0.01 vs. control rats). These results suggest: 1) The PP response to hypoglycemia is predominantly the result of muscarinic, cholinergic activation. 2) There is a minor adrenergic contribution to the response. 3) The plasma PP response may be useful as an index of autonomic neural input to the islet during hypoglycemia.

Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes.

Circulating leptin secreted from adipocytes is correlated with fat mass and plasma insulin concentrations in humans and rodents. Plasma leptin, insulin, and glucose decrease during fasting and increase after refeeding; however, the underlying mechanisms regulating the changes of leptin secretion are not known. To investigate the role of insulin-stimulated glucose metabolism in the regulation of leptin secretion, we examined the effects of insulin and inhibitors of glucose transport and metabolism on leptin secretion from rat adipocytes in primary culture. Insulin (0.16-16 nM) increased leptin secretion over 96 h; however, the increase in leptin was more closely related to the amount of glucose taken up by the adipocytes (r = 0.64; P < 0.0001) than to the insulin concentration per se (r = 0.20; P < 0.28), suggesting a role for glucose transport and/or metabolism in regulating leptin secretion. 2-Deoxy-D-glucose (2-DG), a competitive inhibitor of glucose transport and phosphorylation, caused a concentration-dependent (2-50 mg/dl) inhibition of leptin release in the presence of 1.6 nM insulin. The inhibitory effect of 2-DG was reversed by high concentrations of glucose. Two other inhibitors of glucose transport, phloretin (0.05-0.25 mM) and cytochalasin-B (0.5-50 microM), also inhibited leptin secretion. Inhibition of leptin secretion by these agents was proportional to the inhibition of glucose uptake (r = 0.60 to 0.86; all P < 0.01). Two inhibitors of glycolysis, iodoacetate (0.005-1.0 mM) and sodium fluoride (0.1-5 mM), produced concentration-dependent inhibition of leptin secretion in the presence of 1.6 nM insulin. In addition, both 2-DG and sodium fluoride markedly decreased the leptin (ob) messenger RNA content of cultured adipocytes, but did not affect 18S ribosomal RNA content. We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. Thus, in vivo, decreased adipose glucose metabolism may be one mechanism by which fasting decreases circulating leptin, whereas increased adipose glucose metabolism would increase leptin after refeeding.

Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss.

Leptin, the product of the human homologue of the ob gene, which is defective in the obese (ob/ob) mouse, may be a humoral regulator of human adiposity. Plasma leptin concentrations were measured by RIA in 19 normal weight [body mass index (BMI) = 24.5 +/- 0.6 kg/m2] and 19 overweight to obese (BMI = 34.7 +/- 1.2 kg/m2) nondiabetic postmenopausal women on sequential controlled weight-maintaining diets containing 31%, 23%, and 14% of energy as fat, each for 4-6 weeks. Thereafter, the subjects ate a very low fat diet (< 15%) ad libitum; plasma leptin and insulin concentrations, BMI, percent body fat (%BF), and resting energy expenditure were determined after 6 and 8 months. Absolute and adiposity-corrected plasma leptin levels were higher in overweight/obese women (37.7 +/- 3.5 ng/mL; 1.01 +/- 0.07 ng.mL-1.%BF-1) than in normal weight women (16.9 +/- 2.2 ng/mL; 0.57 +/- 0.06 ng.mL-1.%BF-1, both P < 0.005 vs. obese), but were not different between the 31%, 23%, and 14% fat diets when body weight was stable. Plasma leptin was highly correlated with BMI (r = 0.81, P < 0.0001), %BF (r = 0.80, P < 0.0001), and fasting plasma insulin (r = 0.61, P < 0.0001). After 8 months on the ad libitum low fat diet, the women had lost an average of 6.9 +/- 1.0% of body mass (-2.0 +/- 0.3 kg/m2, P < 0.0001). In 15 subjects who lost more than 7% of body mass (-12.3 +/- 1.0%), plasma leptin concentrations decreased (-9.6 +/- 1.9 ng/mL, P < 0.0005), and the decrease of plasma leptin per change of adiposity (delta leptin/delta %BF) was greater in overweight/obese women (3.6 +/- 0.5) than in normal weight women (0.9 +/- 0.4, P < 0.01 vs. obese). In 18 other subjects who lost less than 7% of body mass (-2.7 +/- 0.6%), plasma leptin was unchanged (+1.4 +/- 1.4 ng/mL). Overall, the change of plasma leptin was significantly correlated with change of BMI (r = 0.43, P < 0.02), the change of %BF (r = 0.49, P < 0.005), the change of resting energy expenditure (r = 0.40, P < 0.02), and with the change of plasma insulin independently of changes of body adiposity (r = 0.45, P < 0.01). We conclude that plasma leptin concentrations are: 1) not affected by dietary fat content per se; 2) highly correlated with BMI, %BF, and plasma insulin in both overweight/obese and normal weight women; 3) decreased in parallel with plasma insulin after sustained weight loss; and 4) decreased more in overweight/obese than in normal weight women.

The gene encoding rat liver glycogen phosphorylase contains multiple polyadenylation signal sequences.

RNA blot analysis of rat liver and adipose tissues detected two glycogen phosphorylase (GP)-encoding transcripts. The polymerase chain reaction was used to characterize the 3'-noncoding region of the gene (L-GP) encoding liver-GP (L-GP) from the lean Zucker rat (Fa/Fa). Three distinct classes of colinear cDNA clones were identified by nucleotide (nt) sequence analysis, demonstrating that the L-GP gene contains at least three functional polyadenylation sites. The predominant L-GP transcript was generated by polyadenylation 130 nt 3' from the end of the coding region. A previously uncharacterized L-GP transcript is generated by polyadenylation at 346 nt 3' of the first polyadenylation site. Polyadenylation site selection does not appear to be regulated in a tissue-specific fashion. The relative steady-state L-GP mRNA levels in the different types of adipose tissues were comparable to, or exceeded transcript levels in liver.

Maintenance and relapse after weight loss in women: behavioral aspects.

Obese women who regained weight after successful weight reduction (relapsers, n = 44); formerly obese, average-weight women who maintained weight loss (maintainers, n = 30); and women who had always remained at the same average, nonobese weight (control subjects, n = 34) were interviewed. Most maintainers (90%) and control subjects (82%) exercised regularly, were conscious of their behaviors, used available social support (70% and 80%, respectively), confronted problems directly (95% and 60%, respectively), and used personally developed strategies to help themselves. Few relapsers exercised (34%), most ate unconsciously in response to emotions (70%), few used available social support (38%), and few confronted problems directly (10%). These findings suggest the advisability of development and prospective evaluation of individualized treatment programs designed to enhance exercise, coping skills, and social support.

Energy expenditure in rats with diet-induced obesity.

Effects of a diet high in fat on body weight, adiposity, and energy expenditure were investigated. Male rats were fed 8% (control) or 50% fat (by weight) for 6 mo. The high-fat group increased body weight (+26%), adipocyte size (+61%), and adipocyte number (+48%). However, food intake and resting oxygen consumption, although higher in absolute amount, were normal in that both were commensurate with the greater body mass the rats maintained. When body weight and adipocyte size were reduced by caloric restriction, the high-fat group displayed the same adaptive adjustments in resting oxygen consumption as controls. We conclude that rats fed high-fat diets for prolonged periods 1) have energy intakes and expenditures appropriate for the greater tissue mass and adipocyte number they maintain, and 2) show adaptive reductions in energy expenditure when food is restricted, which provide further evidence that the regulated level of body weight can be altered by such diets.

Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women.

BACKGROUND: On the basis of observations in rodents, leptin is thought to play a key role in the regulation of energy expenditure and food intake, but less is known of its influence on ingestive behavior and energy balance in humans. OBJECTIVE: We examined the effect in women of a chronic energy deficit on plasma leptin concentrations and self-reported appetite and explored possible relations between leptin and appetite sensations. DESIGN: Twelve healthy women (body mass index, in kg/m2: 23-37) participated in a metabolic ward study in which 3 wk of neutral energy balance was followed by 12 wk of energy deficit (energy intake reduced by 2 MJ/d and energy expenditure increased by 0.8 MJ/d). Body weight and composition were monitored, fasting leptin concentrations were measured 4 times, and feelings of hunger, fullness, desire to eat, and prospective consumption were monitored hourly throughout the day on 7 selected days. RESULTS: Adiposity-adjusted leptin decreased by 54% after 1 wk of a moderate energy deficit and remained low after 6 and 12 wk. Leptin was associated with self-reported hunger, desire to eat, and prospective consumption (range of r: -0.6 to -0.7, P < 0.01). The greatest hunger increase coincided with the largest percentage drop in circulating leptin and the lowest final leptin concentration. The relation between leptin and hunger was not influenced by amount of weight or body fat loss. CONCLUSIONS: These findings support the idea that leptin is a physiologic regulator of hunger during energy deficits in humans; the role of leptin in the long-term regulation of food intake warrants further study.

Inflammation and Native American medicine: the role of botanicals.

There is a growing interest in medicinal botanicals as part of complementary medicine in the United States. In particular, both physicians and consumers are becoming aware of the use of herbals by Native American societies; many botanicals sold today as dietary supplements in the United States were used by Native Americans for similar purposes. Yet, these supplements represent only a small number of the >2500 different plant species from vascular taxa, and >2800 species from all taxa, known to have been prized for their medicinal properties by the indigenous inhabitants of the North American continent. We review some of the studies of the immunomodulatory activities of botanicals used by native peoples of North America, the bioactive constituents responsible for those activities, and the mechanisms by which these constituents might modulate the immune system. We focus particularly on 3 species of purple coneflower (ECHINACEA:) because of the widespread use of purple coneflower in the United States to boost immunity and prevent upper respiratory infections. Seven of the 10 most common botanicals sold in the United States were used extensively by Native Americans. However, there are very few data to support such use and even less information about drug toxicity or interactions.

Variability in commercial ginseng products: an analysis of 25 preparations.

BACKGROUND: Because dietary supplements are not subject to the same regulations that pharmaceuticals are, there is concern among medical professionals that these products may lack purity or potency. OBJECTIVE: To determine the variability in a range of ginseng herbal products available in the United States, we identified and measured the concentration of marker compounds by using HPLC and liquid chromatography-tandem mass spectrometry. DESIGN: Twenty-five commercial ginseng preparations from the genera Panax or Eleutherococcus were obtained from a local health food store and analyzed for 7 ginsenosides (marker compounds for Panax species, which include Asian and American ginseng) and 2 eleutherosides (marker compounds for Eleutherococcus senticosus, also known as Siberian ginseng). RESULTS: All plant products were correctly identified by botanical plant species (ie, Panax species or E. senticosus); however, concentrations of marker compounds differed significantly from labeled amounts. There was also significant product-to-product variability: concentrations of ginsenosides varied by 15- and 36-fold in capsules and liquids, respectively, and concentrations of eleutherosides varied by 43- and 200-fold in capsules and liquids, respectively. Although a systematic search for adulterants was not conducted, review of the HPLC and liquid chromatography-tandem mass spectrometry data suggest that no substances other than ginsenosides or eleutherosides were extracted from the plant material. CONCLUSION: Our data suggest that US ginseng products are correctly labeled as to plant genus; however, variability in concentrations of marker compounds suggests that standardization may be necessary for quality assurance and that characterization of herbal products should be considered in the design and evaluation of studies on herbal products.

Longevity in obese and lean male and female rats of the Zucker strain: prevention of hyperphagia.

Zucker obese (fa/fa) and lean (Fa/Fa) rats were fed a soy protein diet ad libitum under barrier conditions from 4 wk of age until death. Obese rats were also pair fed with lean controls to prevent hyperphagia. Time of death was determined and tissues collected at necropsy for histologic examination. Lean rats had longer 10th percentile survivorship (males 966 compared with 667 d, females 983 compared with 620 d) and maximum life spans (males 1067 compared with 803 d, females 1163 compared with 744 d) than did obese rats. Preventing hyperphagia increased maximum life span in both males (1010 d) and females (975 d). Pathologies in lean rats were similar to those reported for other rodent strains. For obese rats fed ad libitum, end-stage renal disease (ESRD) was the major cause of mortality (males: 91.1%, females: 93.3%). Prevention of hyperphagia decreased deaths attributable to ESRD (males: 64.4%, females: 51.1%). A smaller restriction in energy intake (8-18%) required to prevent hyperphagia compared with the 35-40% in most other studies produced similar increases in longevity, suggesting that obese Zucker rats are particularly sensitive to energy restriction. Amelioration of early onset of renal disease is a likely explanation. Percentage body fat in food-restricted obese rats did not differ from that of animals fed ad libitum; thus, reduced longevity is not the result of obesity per se, but rather is influenced by other metabolic pathologies occurring in this strain of rats homozygous for the fa gene. Because microalbuminuria with progression to ESRD is a complication in human obesity, the Zucker strain offers the opportunity to investigate initiating mechanisms of this pathology.

Effects of dietary energy density and feeding frequency on total daily energy intakes of recovering malnourished children.

To develop recommendations for the design of special foods for young children, we measured total daily energy consumption from semisolid food mixtures with energy densities of 1.67, 2.93, 4.18, or 6.28 kJ/g (0.4, 0.7, 1.0, or 1.5 kcal/g) and that were fed ad libitum three, four, or five times per day to 18 fully weaned children from 6 to 18 mo of age who were recovering in the hospital from malnutrition. The diets were generally indistinguishable by sensory qualities, and were fed in a randomized sequence. The mean amounts consumed (g.kg body wt-1.d-1) were significantly less with successively greater energy density of the diet (P < 0.001). The total daily consumption was approximately 16% more when the number of meals was increased from three to four per day, with energy density controlled for (P < 0.001), and 7% more when the feeding frequency rose from four to five meals per day (P = 0.005). The total daily energy intakes (kJ.kg body wt-1.d-1) increased significantly with the more concentrated diets (P < 0.001) and varied positively in relation to feeding frequency (P < 0.001). Approximately 15-20 min were required per meal for the children to reach satiety. The total amount of time required to feed the children each day was related to the number of meals served (P < 0.001) and not to energy density. Implications for child feeding are discussed.

Complementary medicine: a review of immunomodulatory effects of Chinese herbal medicines.

Popular demand for and scientific interest in complementary or alternative medicine, particularly medicinal botanicals, has increased considerably in recent years. The medicinal botanicals with the longest tradition, and for which extensive data are available, are Chinese herbal medicines and their Japanese counterparts--Kampo medicines. This review focuses on some representative examples of studies examining the effects of some traditional Chinese medicines on various aspects of the immune response. In vitro as well as in vivo studies are cited, the latter including not only animal experiments but also clinical trials. Although by no means exhaustive, this review attempts to show that much research has focused on the specific beneficial effects of Chinese herbal medicines. Studies examining the mechanisms by which they exert their immunomodulatory actions, however, are found much less frequently. Nonetheless, even the limited number of mechanistic experiments presented here reveal that numerous mechanisms are likely involved in the various actions of even a single medicine. It will be the elucidation of such mechanisms that will provide the scientific basis for establishing the efficacy and safety of not only Chinese herbal medicines but all forms of medicinal botanicals.