Household decision-making about delivery in health facilities: evidence from Tanzania.

This study investigated how partners' perceptions of the healthcare system influence decisions about delivery-location in low-resource settings. A multistage population-representative sample was used in Kasulu district, Tanzania, to identify women who had given birth in the last five years and their partners. Of 826 couples in analysis, 506 (61.3%) of the women delivered in the home. In multivariate analysis, factors associated with delivery in a health facility were agreement of partners on the importance of delivering in a health facility and agreement that skills of doctors are better than those of traditional birth attendants. When partners disagreed, the opinion of the woman was more influential in determining delivery-location. Agreement of partners regarding perceptions about the healthcare system appeared to be an important driver of decisions about delivery-location. These findings suggest that both partners should be included in the decision-making process regarding delivery to raise rates of delivery at facility.

Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update.

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.

Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans.

Stimulation of beta3-adrenoceptors by selective agonists improves insulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta3-adrenoceptor stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta3-adrenoceptor agonist on insulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment with either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Insulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal (NOGD), oxidative glucose disposal (OGD) (indirect calorimetry), and splanchnic glucose output (SGO; beta3-[H3]glucose) were determined during a 100-min hyperinsulinemic-euglycemic glucose clamp (40 mU x m(-2) x min(-1)) before and after 4 and 8 weeks of treatment. The 24-h energy expenditure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rates of fat and carbohydrate were determined in a respiratory chamber before and after 8 weeks. After 4 weeks, treatment with CL 316,243 increased IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner (r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 316,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and leptin were unaffected by treatment, while free fatty acid concentrations increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 316,243 had no effect on heart rate or blood pressure and caused no cases of tremors. We conclude that treatment of lean male subjects with CL 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrate unequivocal metabolic effects of a highly selective beta3-adrenoceptor agonist in humans.

Endurance training with constant energy intake in identical twins: changes over time in energy expenditure and related hormones.

The effects of exercise training and of its interaction with the genotype on components of energy expenditure and related hormones were examined in young male monozygotic twins. Energy intake was maintained at the pretraining level for a 93-day training period. The estimated net energy deficit induced by training was 244 MJ and was associated with a 5-kg body weight loss that was almost entirely explained by body fat loss. Resting metabolic rate (RMR) was significantly decreased by 8% after training despite the preservation of fat-free mass (FFM). Accordingly, plasma norepinephrine (NE) concentrations, NE appearance rate, and plasma levels of triiodothyronine (T3), free T3, and total thyroxine (T4) were lower after training. The energy cost of standardized exercise was also reduced after the training program. A modest to significant within-twin-pair resemblance was observed for absolute changes in the RMR, thermic effect of food, energy cost of exercise, NE clearance, and plasma concentrations of thyroid hormones. These results suggest that when exercise training is associated with a substantial negative energy balance, energy expenditure and levels of related hormones are decreased, and this effect is partly accounted for by heredity.

Exercise increases fat oxidation at rest unrelated to changes in energy balance or lipolysis.

The hypothesis that exercise increases fat oxidation at rest independently of changes in energy balance, body composition, and/or lipolysis was tested in 21 volunteers. After a period of energy balance, volunteers were randomly allocated to one of four groups: control, overfed (OF), overfed and exercised (OF-EX), and exercised (EX). OF and OF-EX were overfed 50% excess of energy balance calories; OF-EX and EX spent 50% excess of energy balance calories during daily exercise sessions. Exercise increased fat oxidation at rest independently of dietary intake (OF-EX = + 22 +/- 2.4, EX = + 23 +/- 1.5 mg/min) and reduced carbohydrate oxidation (OF-EX = - 49 +/- 6.2, EX = - 46 +/- 5.4 mg/min). Volunteers in the OF group had an increase in carbohydrate oxidation (85 +/- 5.9 mg/min) and a decline in fat oxidation (- 33 +/- 1.4 mg/min). Protein oxidation did not change in any group. These changes occurred without a direct relation with changes in lipolysis and persisted even when expressed as a percentage or as an absolute equivalent of resting metabolic rate in calories. Thus exercise, independent of changes in energy intake and body composition and not related to changes in lipolysis, increases fat oxidation at rest, which may explain the beneficial effects of exercise in weight loss programs.

Comparison of body fat estimates derived from underwater weight and total body water.

The purpose of this study was to compare the techniques of underwater weighing and analysis of total body water for estimating body fat with that derived from a 3-compartment model combining total body density and total body water. Body fat was estimated from: (1) body density using the Siri equation; (2) total body water assuming a hydration factor of 0.73 for fat free mass; and (3) the 3-compartment model combining body density and body water. The criterion method in this study was body fat mass determined from Siri's 3-compartment model. The subjects in this study included 10 obese men (41 +/- 10 years; 115.5 +/- 16.6 kg), 7 elderly men (68 +/- 6 years, 77.1 +/- 7.4 kg), and 18 young men (24 +/- 5 years; 71.0 +/- 9.2 kg). Body density was obtained by underwater weight with simultaneous determination of lung volume by helium dilution. Body water was obtained from zero-time extrapolation of isotope washout over 10-14 days following an oral dose of 2H2O and H2(18)O. Estimates of body fat derived from total body water were significantly higher than that derived from underwater weight in the elderly (1.4 +/- 1.5 kg; P < 0.05) and younger (3.0 +/- 2.8 kg; P < 0.001) men. In the obese subjects, there was no significant difference in body fat estimates between the two techniques (mean difference = 1.3 +/- 5.1 kg). The overestimation of body fat from total body water relative to underwater weight was negatively associated with body fat mass estimated from the 3-compartment model combining measurement of density and water (r = -0.35; P = 0.04). It is concluded that total body water overestimates body fat relative to underwater weight, and that this effect is more pronounced in leaner subjects.

Effects of increased energy intake and/or physical activity on energy expenditure in young healthy men.

This study was designed to examine effects of alterations in energy balance on adaptive changes in components of total energy expenditure (TEE). Nineteen young healthy males were studied during a 10-day sedentary energy balance baseline period and then randomly assigned to one of four 10-day treatment groups: 1) no change in energy intake (EI) or physical activity (PA; energy balance at low energy flux), 2) EI increased by 50% with no change in PA (positive energy balance), 3) TEE increased by 50% by increasing PA, matched by a 50% increase in EI (energy balance at high energy flux), and 4) TEE increased by 50% by increasing PA with no change in EI (negative energy balance). TEE was measured with doubly labeled water, resting metabolic rate (RMR) by indirect calorimetry, and thermic response to feeding (TEF) by indirect calorimetry; energy expenditure of physical activity (EEPA) was estimated by subtracting RMR, TEF, and prescribed PA from TEE. TEE was significantly increased by PA (by design) but not EI. There was a significant main effect of intake and a significant intake-by-activity interaction for changes in RMR. In post hoc analysis, RMR was significantly increased during positive energy balance and energy balance at high energy flux relative to change in RMR when energy balance was maintained at low energy flux. A significant increase in RMR was also noted during negative energy balance after adjustment for change in fat-free mass. There was no significant difference in change in RMR among the three treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats.

The objective was to assess the effect of a new, highly selective beta 3-adrenergic agonist, CL-316,243 (CL) (J. D. Bloom, M. D. Dutia, B. D. Johnson, A. Wissner, M. G. Burns, E. E. Largis, J. A. Dolan, and T. H. Claus., J. Med. Chem. 35: 3081, 1992), on energy balance and brown and white adipose tissues (BAT and WAT, respectively) in young rats eating a high-fat diet to induce obesity. Chronic treatment with CL increased body temperature and 24-h energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular BAT was markedly hypertrophied, with three- to fourfold increases in the content of uncoupling protein (UCP) and cytochrome oxidase. Quantitative immunoelectron microscopy of interscapular BAT of CL-treated rats showed smaller mitochondria with an unchanged total amount of UCP per mitochondrion. The relative frequency of the four major cell types in BAT (mature brown adipocytes, preadipocytes, interstitial cells, endothelial cells) was not altered. The CL-induced hypertrophy differed from that induced by chronic stimulation by endogenous norepinephrine (as in cold-adaptation) in absence of hyperplasia (there was a slightly reduced DNA content), absence of an increase in the thyroxine (T4) 5'-deiodinase activity, and absence of a selective increase in UCP concentration. WAT depots weighed less and had fewer cells (lower DNA content) in the CL-treated rats. Some multilocular adipocytes appeared in these normally almost exclusively unilocular WAT depots (mesenteric, inguinal, epididymal, retroperitoneal). We conclude that CL not only promotes BAT mitochondrial proliferation and thermogenesis and overall energy expenditure and leanness, but also retards the development of WAT hyperplasia during the early stage of diet-induced obesity.

Experimental reliability of the doubly labeled water technique.

The experimental reliability of measuring CO2 production rates (rCO2) with the doubly labeled water (DLW) technique was assessed in five young healthy men (23 (DLW) technique was assessed in five young healthy men (23 +/- 4 yr; 66.1 +/- 4.6 kg). To minimize the confounding effects of fluctuations in physical activity and eating patterns on variation in energy expenditure, the subjects lived under sedentary living conditions by confinement to their own room at a Clinical Research Center and were maintained on a fixed and known level of energy intake. rCO2 was determined in duplicate over two identical 9-day study periods after separate loading doses of deuterium and oxygen-18. Turnover rates were determined from multipoint sampling to reduce error from analytical uncertainty. Dilution spaces were determined by both the intercept and plateau methods. The average experimental variation for rCO2 estimates was approximately +/- 8.5% and was not significantly different among three published calculation models that differ in their assumptions regarding the relationship between the dilution spaces of deuterium and oxygen-18. The experimental reliability of +/- 8.5% exceeds theoretical values generated from calculations based on propagation of error from analytical uncertainty. Between subjects, the experimental variation ranged from 1 to 21%, and the half-width of the 95% confidence interval for the precision of rCO2 estimates was high (+/- 12 mol/day) relative to the mean reported value of approximately 16 mol/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine turnover and energy expenditure in Pima Indian and white men.

There is growing evidence of the involvement of sympathetic nervous system (SNS) activity in determining metabolic rate. Whole-body plasma norepinephrine turnover and its relationship to resting metabolic rate (RMR) and 24-hour energy expenditure (24EE) were compared in 14 Pima Indian men (25 +/- 4 years, 96 +/- 33 kg, 25% +/- 9% fat) and nine white men (25 +/- 3 years, 88 +/- 43 kg, 17% +/- 13% fat). Plasma norepinephrine turnover rate correlated strongly with body surface area (r = .76 and .54 for clearance and appearance, respectively) and fat-free mass (r = .74 and .52, respectively). However, independent of body size, there was no difference in either norepinephrine clearance or appearance rates between Pima Indian and white men. Norepinephrine appearance rate correlated positively with absolute values of 24EE and RMR, but not when adjusted for differences in body surface area or fat-free mass. However, norepinephrine appearance rate adjusted for differences in body size correlated with spontaneous physical activity. The results indicate that Pima Indian and white men have similar plasma norepinephrine appearance rates, but Pima Indians tend to be more resistant to beta-adrenergic stimulation. Although energy expenditure and SNS activity were not directly related, a higher SNS tone may either promote or reflect elevated levels of spontaneous physical activity and therefore influence both energy balance and body composition.

Effect of gender, body composition, and equilibration time on the 2H-to-18O dilution space ratio.

Physiological sources of variation in the 2H-to-18O dilution space ratio (DSR) were examined in 34 males and 20 females (4-78 yr; 14.7-143.2 kg; 1.8-61.0% body fat). Dilution spaces were obtained by time 0 extrapolation of isotope washout over 10-14 days, and body composition was obtained by underwater weight (adults) or bioelectrical impedance (children). The mean DSR was 1.050 +/- 0.015 (range 1.029-1.111), significantly higher (P < 0.001) than the traditionally assumed value of 1.029 based on exchange over 4 h. Use of the value 1.029 causes a systematic 8% overestimate of energy expenditure from doubly labeled water, relative to use of the value 1.05. The DSR was not related to body composition or age but was significantly higher (P < 0.05) in males (1.052 +/- 0.016) than in females (1.044 +/- 0.012). This gender effect was not explained by differences in the number of exchangeable hydrogens in the body. We conclude 1) variation in the 2H-to-18O DSR is not explained by body composition but is influenced by the chemical availability of exchangeable hydrogens to undergo exchange; 2) because the DSR is not easily predicted, use of the observed dilution spaces are recommended; 3) if a fixed DSR is used, values of 1.044 and 1.052 are recommended in females and males, respectively.