Dietary composition and physiologic adaptations to energy restriction

BACKGROUND: The concept of a body weight set point, determined predominantly by genetic mechanisms, has been proposed to explain the poor long-term results of conventional energy-restricted diets in the treatment of obesity. OBJECTIVE: The objective of this study was to examine whether dietary composition affects hormonal and metabolic adaptations to energy restriction. DESIGN: A randomized, crossover design was used to compare the effects of a high-glycemic-index (high-GI) and a low-glycemic-index (low-GI) energy-restricted diet. The macronutrient composition of the high-GI diet was (as percent of energy) 67% carbohydrate, 15% protein, and 18% fat and that of the low-GI diet was 43% carbohydrate, 27% protein, and 30% fat; the diets had similar total energy, energy density, and fiber contents. The subjects, 10 moderately overweight young men, were studied for 9 d on 2 separate occasions. On days -1 to 0, they consumed self-selected foods ad libitum. On days 1-6, they received an energy-restricted high- or low-GI diet. On days 7-8, the high- or low-GI diets were consumed ad libitum. RESULTS: Serum leptin decreased to a lesser extent from day 0 to day 6 with the high-GI diet than with the low-GI diet. Resting energy expenditure declined by 10.5% during the high-GI diet but by only 4.6% during the low-GI diet (7.38 +/- 0.39 and 7.78 +/- 0.36 MJ/d, respectively, on days 5-6; P = 0.04). Nitrogen balance tended to be more negative, and energy intake from snacks on days 7-8 was greater, with the high-GI than the low-GI diet. CONCLUSION: Diets with identical energy contents can have different effects on leptin concentrations, energy expenditure, voluntary food intake, and nitrogen balance, suggesting that the physiologic adaptations to energy restriction can be modified by dietary composition.     

Survival and developmental disability in infants with birth weights of 501 to 800 grams, born between 1979 and 1994

OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age.     

Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2 integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O- tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta2 integrin protein compared with the lower levels of beta2 integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 microg anti-beta2 integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P < 0.01 anti- beta2 integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta2 integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8- OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2 integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as anti-promoting and anti-progression agents.      

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.      

Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805.

PURPOSE: Flavopiridol has in vitro activity in chronic lymphocytic leukemia (CLL) and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol has activity in previously treated CLL using two schedules of administration. PATIENTS AND METHODS: Patients with previously treated CLL were enrolled in two sequentially done phase II studies. Patients in the first trial received flavopiridol (50 mg/m(2)/d) as a continuous infusion (CI) for 72 hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m(2) as a 1-hour bolus (IVB) daily for 3 days repeated every 3 weeks. Patients received up to 12 (CI cohort) or 8 (IVB cohort) cycles of therapy. RESULTS: Fifteen patients were enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate-risk (Rai stage I or II) and 9 (60%) had high-risk (Rai stage III and IV) stages. No responses were noted in this group; 27% had stable disease and 73% had progressive disease. Thirty-six patients were enrolled in the second IVB trial, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) had stable disease, and 13 (36%) had progressive disease. The progression-free survival for responders in the IVB trial was 3, 3, 9, and 19 months. The median progression-free survival was 2 months [95% confidence interval (95% CI), 1.8-3.8] for patients in the CI trial and 3 months (95% CI, 2.5-7.4) for the IVB trial. The median overall survival was 27 months (95% CI, 20-42) for the CI trial and 24 months (95% CI, 18-31) for the IVB trial. Toxicity was manageable and included mainly myelosuppression, infections, diarrhea, and fatigue. CONCLUSIONS: Flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.     

Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.

PURPOSE: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. EXPERIMENTAL DESIGN: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro. RESULTS: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. CONCLUSIONS: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.