Enhanced dexamethasone resistance in cystic fibrosis cells: potential use for heterozygote detection and prenatal diagnosis.

Cultured skin fibroblasts from patients with cystic fibrosis (CF) are more resistant to dexamethasone toxicity than are normal cells. We now report that, when fibroblasts cultured from obligate CF heterozygotes are exposed to dexamethasone, they have an intermediate survival compared to normal and homozygous CF cells. When dexamethasone survival was tested on cells from four patients undergoing amniocentesis, cells from a woman at risk of producing a child with CF showed significant dexamethasone resistance, similar to that of fibroblasts derived from lnown CF homozygotes; the other amniotic cell specimens showed dexamethasone sensitivity similar to that of normal skin fibroblasts. These data suggest that the dexamethasone resistance previously observed in skin fibroblasts may also be useful in the prenatal diagnosis of CF.

Resting metabolic rates of obese women after rapid weight loss.

Reduced energy expenditure associated with reduced energy intake has been used as an explanation for resistance to weight loss in obese patients. Decreases in serum T3 concentrations and body cell mass induced by restriction of energy intake may contribute to the reduced energy needs. In the present study, mean resting metabolic rate (RMR) was reduced by 9.4% after 5 weeks of a very low energy diet (472 Cal/day) in six obese women, and the mean serum T3 concentration decreased 46%. However, the lowest RMR values measured were similar in these subjects (mean, 1328 Cal/day; range, 1110-1578 Cal/day) to RMR values of lean women (n = 19; mean, 1241 Cal/day; range, 938-1450 Cal/day) and moderately overweight women ingesting ad libitum diets (n = 8; mean, 1335 Cal/day; range, 1064-1533). Decreases in total body potassium (10%) and 24-h urinary creatinine excretion (23%) suggested that there was a substantial loss of body cell mass during weight loss, whereas nitrogen balance suggested that changes in body cell mass were slight. These data and those of previous studies indicate that even after rapid weight loss, the resting energy requirements of obese or previously obese subjects are not abnormally low relative to those of nonobese subjects, even though the concentrations of T3, a major thermogenic hormone, are substantially reduced. The hypometabolic response to weight loss cannot explain the failure of obese subjects to lose weight on weight-reducing regimens.

Testosterone-estradiol-binding globulin in patients with Turner's syndrome: effects of estrogens and acute growth hormone administration.

The TeBG activity of plasma from patients with Turner's syndrome was measured quantitatively using polyacrylamide gel electrophoresis. Human growth hormone administration did not significantly change the plasma TeBG levels. However, oral replacement therapy with estrogens elevated plasma TeBG within 3 days; after 9 days these levels reached a maximum of three- to four-fold greater than that observed at a time prior to therapy.

Ventricular dilation on CAT scans of patients with anorexia nervosa.

Computerized tomographic brain scans of five patients with anorexia nervosa showed significantly more dilation of the third and lateral ventricles than in control subjects. Measurements of lean body mass suggest that these findings are secondary to the anorexic patients' protein malnutrition.

Do obese individuals gain weight more easily than nonobese individuals?

A review of studies done on human subjects who were overfed under controlled conditions for periods ranging from 2 to 12 wk shows that the energy cost of induced weight gain is a function of initial body weight and of lean body mass, body fat, and percent body fat. Therefore, bigger and fatter people need to eat more to gain a given amount of weight than do those who are thin. A likely explanation is that obese individuals tend to put on a large proportion of fat, a high-energy tissue, whereas thin people tend to gain more lean, which is a low-energy tissue.

Longitudinal changes in adult fat-free mass: influence of body weight.

BACKGROUND: Almost all of the data on changes in body composition during aging are cross-sectional in nature. These show that fat-free mass (FFM) declines with age. OBJECTIVE: The goal was to analyze results of assays done in the author's laboratory of the FFM of normal adults studied at intervals for >/=2 decades to ascertain longitudinal changes. DESIGN: (40)K counting was used to estimate FFM in adult university personnel (15 men, 5 women) over periods ranging from 21 to 38 y. No advice was given about diet or exercise. RESULTS: There was considerable variation in the change of FFM over time. Some subjects lost FFM as the years went by, whereas others actually gained FFM. Analysis of the data showed that change in body weight was a prime factor in determining the magnitude and direction of the FFM change (R(2) = 0.54). Adults who maintained their weight lost an average of 1.5 kg FFM per decade and so gained an equal amount of fat; those who lost weight lost even more FFM, whereas those who gained weight either gained FFM or lost it more slowly than the others. Data from the literature confirmed this trend. CONCLUSIONS: FFM loss is not inevitable during adulthood-at least up to age 81 y, the oldest age yet studied. The magnitude and direction of the FFM change, be it positive or negative, is strongly influenced by change in body weight.

Unmeasured losses of potassium in balance studies.

A comparison of changes in body K content calculated from metabolic balance and from 40K counting shows that the former technique overestimates K retention and underestimates K losses. The disparity in results by the two methods increases with increasing K intakes.

Loss of body nitrogen on fasting.

An analysis of the change in total body nitrogen during fasting shows that it declines exponentially, a small fraction being lost rapidly (t 1/2 of a few days), and the remainder being lost slowly (t 1/2 of many months). The obese faster loses N, and weight, at a slower relative rate than the nonobese; and the ratio of N loss to weight loss during an extended fast is inversely related to body fat content, being about 20 g/kg in the nonobese and about 10 g/kg in those with body fat burdens of 50 kg or more. The loss of body N on a low protein-calorie adequate diet can also be described in exponential terms, and this function allows an estimate to be made of the N requirement.

Urinary creatinine excretion and lean body mass.

In a group of 34 adult and child subjects a high correlation (r = 0.988) was found between lean body mass, as determined by potassium-40 counting, and urinary creatinine excretion. The effect of technical errors was reduced by averaging the results of two or three 40K assays on each subject, and by making consecutive 3-day collections of urine. It appears that one can make a reasonable estimate of lean body mass from urinary creatinine excretion.

Arm muscle plus bone area: anthropometry and CAT scan compared.

Arm muscle plus bone (M + B) cross-sectional area of the arm estimated from area circumference and skinfold thickness was compared with that estimated from CAT scans. The anthropometric technique overestimated M + B area, and the degree of overestimation varied directly with arm adiposity.

Errors in potassium balance.

Six overweight adult subjects given a low calorie diet containing adequate amounts of nitrogen but subnormal amounts of potassium (K) were observed on the Clinical Research Center for periods of 29 to 40 days. Metabolic balance of potassium was measured together with frequent assays of total body K by 40K counting. Metabolic K balance underestimated body K loses by 11 to 87% (average 43%); the intersubject variability is such as to preclude the use of a single correction value for unmeasured losses in K balance studies.

Bromide space determination using anion-exchange chromatography for measurement of bromide.

A high-pressure liquid chromatographic method for bromide measurement is used to determine extracellular water volume in humans. The method uses 5 microL serum ultrafiltrate and has a sensitivity of 7.5 pmol. Because of the extreme sensitivity of this method, relatively small quantities of Br can be administered and small amounts of blood are needed for the analysis. By this method, the mean corrected Br space in 82 healthy adults representing a wide range of body weights was 0.218 +/- .034 L/kg (mean +/- 1 SD) with a range of 0.153-0.295 L/kg, which is consistent with reported values. There was a significant, inverse relationship between corrected Br space per kilogram and obesity as measured by body mass index. The corrected Br space in six children aged 3-36 mo was 0.335-0.394 L/kg, which is also consistent with reported values in children of this age. This method for Br measurement can easily and readily be applied for the determination of extracellular water volume.

Body composition changes during recovery from anorexia nervosa: comparison of two dietary regimes.

Twelve patients with anorexia nervosa were studied on the Clinical Research Center for periods of 15 to 58 days. Five patients were fed a diet providing 20% of energy from protein and seven patients were fed a diet with only 10% of energy from protein. These patients had a reduced lean body mass in addition to a loss of body fat, and during recovery about two-thirds of the weight gain was lean tissue. The average energy cost of the weight gain was 5.3 kcal/g. There was no significant difference between the two diets for elemental metabolic balance, changes in anthropometric measures, in weight gain, or in potassium-40 counts; nor was there any difference in the energy cost of weight gain, in the rise in basal metabolic rate, or the change in hematocrit, serum albumin, or cholesterol. However, blood urea nitrogen was higher in those patients who received the high protein diet. Satisfactory nutritional rehabilitation of patients with anorexia nervosa does not require a high protein diet.

Energy expenditure under free-living conditions in normal-weight and overweight women.

Total energy expenditure under free-living conditions of 12 normal-weight and 26 overweight women was determined with the 2H2(18)O method. Overweight women tended to expend more energy (mean +/- SD, 11.20 +/- 1.79 MJ/d) than normal-weight women (9.46 +/- 0.87 MJ/d, P less than 0.005). Approximately half of this effect was explained by an increase in basal metabolic rate (BMR) in the overweight group compared with the normal-weight group (6.47 +/- 0.74 vs 5.68 +/- 0.39 MJ/d, respectively, P less than 0.005) and the other half by an increase in above-basal energy expenditure (4.73 +/- 1.49 vs 3.78 +/- 0.94 MJ/d, P less than 0.05). Total energy expenditure was approximately 1.7 times the BMR in both groups. After adjusting energy expenditure for weight or lean body mass by analysis of covariance, there was no significant difference between normal-weight and overweight groups. We conclude that most overweight subjects must consume more energy than lean subjects to maintain their excess weight, although some could maintain their obesity without eating more than lean subjects.

A high protein, low calorie liquid diet in the treatment of very obese adolescents: long-term effect on lean body mass.

The use of Optifast-70, a high protein liquid diet, when used in the range of 500 to 700 cal over 5 months in very obese adolescents, was associated with weight loss of 20 to 25% of initial weight of which 70 to 75% of the loss was due to fat. No significant side effects were noted. Twenty-four hour electrocardiographic monitoring showed no significant changes, and linear growth continued. Lean body mass loss was 36% of the weight lost during the first 5 wks, but was only 10% of the weight lost during the next few months. Two adolescent males had negative phosphorus and nitrogen balances over the first 4 wk, implying that males may have slightly higher phosphorus, nitrogen, and calorie requirements.

Hormonal response to overfeeding.

We assessed the hormonal status of adult female volunteers before and during a 3-wk period of weight gain induced by mixed diet overfeeding. Forty-six percent of the 4.3-kg average weight gain experienced by these subjects consisted of lean body mass (LBM) and it is of interest that there were also increases in plasma Somatomedin-C/Insulin-like Growth Factor (SM-C/IGF-1) and testosterone concentrations as well as insulin. We suggest that it was the combined anabolic effect of these three hormones that facilitated the increase in LBM. Of the other assays done, increases were recorded for urinary 17-ketosteroids, 17-hydroxysteroids, epinephrine, and creatinine, whereas there were no changes in serum cortisol or triiodothyronine (T3), or urine norepinephrine; serum thyroxine (T4) fell slightly. Thus it appears that energy surfeit as well as energy deficit (reported by others) has an effect on blood hormone concentrations.

3-methylhistidine excretion in myotonic dystrophy.

3-Methylhistidine (3-MH) excretion reflects the rate of muscle protein catabolism, since 3-MH occurs almost exclusively in muscle actin and myosin and is not reutilized or catabolized. We studied 3-MH excretion in 9 patients with myotonic dystrophy, 8 normals, and 10 disease controls with Duchenne dystrophy and other disorders. 3-MH excretion was expressed relative to muscle mass as determined by both urinary creatinine and total body potassium (40K method). Absolute 3-MH excretion was decreased in myotonic dystrophy patients but was normal when related to muscle mass. The finding of normal 3-MH excretion in myotonic dystrophy suggests that the muscle wasting in this disorder results from impaired anabolic processes rather than accelerated muscle destruction.

Exercise and lean weight: the influence of body weight.

Exercise can produce a modest gain of lean body mass (LBM) and loss of fat in weight-stable individuals, but it is important to realize that if much weight is lost during exercise there is a risk of some erosion of the LBM. Data from both human and animal experiments show that exercise cannot conserve lean weight in the face of significant energy deficit, although moderate obesity affords a modicum of protection in this respect.

Diet and exercise in obese subjects: self-report versus controlled measurements.

Past decades have witnessed a continuing discussion on the relative role of food intake in the pathogenesis of obesity. Some observers argue that overeating is paramount; others claim that the obese are metabolically more efficient in energy utilization, and thus may not need as much food. There is a considerable amount of evidence that big people do need more food than those who are smaller and thinner. However, a recent study using advanced techniques has revealed a clear discrepancy between self-reported and actual energy intake and self-reported and actual physical activity in obese subjects, especially those who had great difficulty in losing weight by dietary means.

Science, Volume 133, 1961: Estimation of total body fat from potassium-40 content.

On the assumption that the potassium content of the lean body mass is constant, it should be possible to estimate fat content in living man from a measurement of potassium-40 activity in the whole-body scintillation counter. A series of such measurements on children and young adults shows good correlations with skin-fold thickness and weight/height ratio as indices of fatness.