Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity.

OBJECTIVE: To establish rates of skeletal mineralization in children and adolescents, and to identify factors that influence these rates. DESIGN: Three-year observational study. SETTING: University hospital. SUBJECTS: Ninety white children, aged 6 to 14 years. MEASUREMENTS: Bone mineral density of the radius, spine, and hip was measured at baseline and 3 years later. Physical activity was assessed by questionnaires at 6-month intervals and dietary calcium intake by diet diary 1 day per month for 36 months. Sexual maturation (Tanner stage) was determined by an endocrinologist at 6-month intervals, as necessary to classify children as prepubertal, peripubertal, or postpubertal. RESULTS: Skeletal mineralization accelerated markedly at puberty in the spine (0.077 vs 0.027 gm/cm2 per year, peripubertal vs prepubertal) and greater trochanter (0.050 vs 0.027 gm/cm2 per year), less markedly in the femoral neck (0.047 vs 0.030 gm/cm2 per year), and only slightly in the radius. Nearly one third (15 gm) of the total skeletal mineral in the lumbar spine of adult women (approximately 52 gm) was accumulated in the 3 years around the onset of puberty. Increases in height and weight were the strongest correlates of skeletal mineralization: weight changes were more strongly correlated with trabecular bone sites and changes in height with cortical bone sites. Increases in calf muscle area were strongly associated with mineralization, particularly in peripubertal children, and physical activity was associated with more rapid mineralization in prepubertal children. CONCLUSIONS: Puberty has varying effects on skeletal mineralization depending on skeletal site; trabecular bone is apparently more sensitive to changing hormone concentrations. Physical activity and normal growth are also positively associated with skeletal mineralization, also depending on skeletal site and sexual maturation.

Calcium supplementation and increases in bone mineral density in children.

BACKGROUND: Increased dietary intake of calcium during childhood, usually as calcium in milk, is associated with increased bone mass in adulthood; the increase in mass is important in modifying the later risk of fracture. Whether the increase is due to the calcium content of milk, however, is not certain. METHODS: We conducted a three-year, double-blind, placebo-controlled trial of the effect of calcium supplementation (1000 mg of calcium citrate malate per day) on bone mineral density in 70 pairs of identical twins (mean [+/- SD] age, 10 +/- 2 years; range, 6 to 14). In each pair, one twin served as a control for the other; 45 pairs completed the study. Bone mineral density was measured by photon absorptiometry at two sites in the radius (at base line, six months, and one, two, and three years) and at three sites in the hip and in the spine (at base line and three years). RESULTS: The mean daily calcium intake of the twins given placebo was 908 mg, and that of the twins given calcium supplements was 1612 mg (894 mg from the diet and 718 mg from the supplement). Among the 22 twin pairs who were prepubertal throughout the study, the twins given supplements had significantly greater increases in bone mineral density at both radial sites (mean difference in the increase in bone mineral density: midshaft radius, 5.1 percent [95 percent confidence interval, 1.5 to 8.7 percent]; distal radius, 3.8 percent [95 percent confidence interval, 1.4 to 6.2 percent]) and in the lumbar spine (increase, 2.8 percent [95 percent confidence interval, 1.1 to 4.5 percent]) after three years; the differences in the increases at two of three femoral sites approached significance (Ward's triangle in the femoral neck, 2.9 percent; greater trochanter, 3.5 percent). Among the 23 pairs who went through puberty or were postpubertal, the twins given supplements received no benefit. CONCLUSIONS: In prepubertal children whose average dietary intake of calcium approximated the recommended dietary allowance, calcium supplementation increased the rate of increase in bone mineral density. If the gain persists, peak bone density should be increased and the risk of fracture reduced.

Genetic influences on the urinary excretion of aldosterone in children.

Several studies have shown an inverse relation between blood pressure and plasma aldosterone levels. Since blood pressure is in part genetically regulated, we looked for evidence that genetic factors might also affect aldosterone production. The nocturnal urinary excretion rate was used to estimate aldosterone production, and electrolyte excretion rates were used to estimate sodium and potassium intakes. Studies were carried out in monozygotic (MZ) (n = 37 pairs) and dizygotic (DZ) (n = 26 pairs) twins, aged 6-17 years. Both groups of twins were white. The intraclass correlation coefficient for aldosterone excretion was 0.686 (p = 0.0001) for MZ twins, and 0.290 (p = 0.079) for DZ twins, indicating high heritability for the aldosterone excretion rate. In a second study, we looked for a racial effect on the genetic regulation of aldosterone excretion. Siblings from both black and white families (72 black siblings and 157 white siblings) were selected from an ongoing longitudinal study. Mean values for nocturnal aldosterone excretion, rates measured every 6 months over 1.5-3.5 years, were used in the analysis. The intraclass correlation coefficient for aldosterone excretion, adjusted for sodium and potassium excretion, was 0.510 (p = 0.001) for black siblings and 0.087 (p = 0.228) for white siblings, indicating a strong familial aggregation for aldosterone excretion in black children. In conclusion, studies in twins showed that regulation of urinary aldosterone excretion in children is determined partially by genetic factors. A familial component affecting the aldosterone excretion rate appears to be much stronger in blacks than in whites.

Role of physical activity in the development of skeletal mass in children.

A group of 118 children, aged 5.3-14 years, were enrolled in a prospective study of calcium supplementation and bone mass. At entry to the study, questionnaires regarding the child's usual physical activity were administered to the children and their mothers. Repeated activity assessments at 6 month intervals indicated good within-person agreement for total activity and for most individual activities. Consistent positive associations were observed between bone mineral densities (BMD) in the radius, spine, and hip and most activities. A summary measure (total hours of weight-bearing activity) was significantly related to BMD in the radius and hip, independently of age or gender effects. Self-reported sports and play activities were associated with BMD, but neither time spent watching television nor hours of physical education classes were associated either positively or negatively with skeletal mass. These data suggest that important increments in skeletal mass may result from physical activity during childhood.

The relationship of bone mineral density and anthropometric variables in healthy male and female children.

The relationships among bone mineral measurements at hip, wrist, and spine sites and anthropometric measurements which provided estimates of frame size, skinfold thickness, and muscularity were examined in a population of 140 children. The average age of the children at the time of measurement was 9.5 +/- 2.5 years and all subjects were white. In this study population, the anthropometric measurements were generally highly intercorrelated. Univariate correlations among bone mass and density variables at the different sites were also high, especially in the female children. Model fitting procedures were employed to separate the effects of age, frame size, and fatness on the bone mass measures. Resulting models confirmed previous results which suggest that height is the best predictor of bone mass in children. As expected, models for bone mineral content and bone mineral density were similar. Models for hips and wrist sites were also similar in including an estimate of frame size, while in those for the spine hip circumference explained a greater percentage of the variance. It appears that there are several identifiable characteristics among the anthropometric variables which appear to exert differential effects on skeletal development in children.

Nutrient intake variability in a pediatric population: implications for study design.

Estimates of an individual's intake of specific nutrients is important in epidemiologic investigations of disease-diet relationships. The object of the present investigation was to determine the minimum number of daily food records required to estimate intake of specific nutrients in children. Both members of 70 pairs of twins (n = 140 children) completed a minimum of 3 and a maximum of 23 food records throughout a 2-y period. All subjects were white and range in age from 5 to 14 y. Assuming an attenuation of the correlation coefficient of 80%, the minimum number of daily food records required to estimate energy intake was seven for boys and eight for girls. As a group, the vitamin intakes were the most variable for both boys and girls, often requiring more than 20 records for either sex. Requirements for other nutrients generally fell between these two extremes. The results of the present investigation are particularly relevant to the interpretation and design of studies of associations with nutrient intake.

Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological responses.

To identify characteristics that may contribute to salt sensitivity, we conducted studies of normal subjects who are at risk for hypertension, namely blacks, subjects older than 40 years of age, and first-degree relatives of subjects with essential hypertension. We also formulated definitions for salt sensitivity and resistance with a short-term volume expansion and contraction protocol and additionally from data derived from studies of long-term reduced dietary salt intake. We examined the effects of augmented potassium and calcium intake and also those of sodium as the chloride or the bicarbonate salt. Finally, we sought genetic markers that are associated with salt sensitivity. We found that salt sensitivity is a function of age and is more common in blacks than whites. These groups also have relatively delayed acute salt excretion compared with controls. We were unable to identify effects of gender. Haptoglobin phenotypes (HP 1-1) may facilitate identification of salt-sensitive individuals. A high potassium intake may make individuals less salt sensitive. Sodium chloride and sodium bicarbonate differ in their effects on blood pressure. Sodium chloride augments urinary calcium excretion, but sodium bicarbonate does not. Differences between susceptible and nonsusceptible groups, together with improved knowledge of electrolyte interactions, may facilitate our understanding of salt-sensitive hypertension.

The effect of a household partner and home urine monitoring on adherence to a sodium restricted diet.

To evaluate the effects of social support and home urine monitoring on success with dietary sodium reduction, 114 essential hypertensive adults and a household partner were recruited. One of the pair was required to be the food preparer. Patients with their partners were randomly assigned to either an active or passive partner condition. During dietary counseling in the active condition, both patient and partner were involved in instructions to change their diet to reduce their daily sodium intake to 80 mmol or less. In the passive condition, the partners were present during the dietary counseling, but no effort was made to involve them directly in the instruction or to encourage them to make personal dietary changes. Patients and active partners collected two 24-hr urine collections between each of the first two counseling sessions and received feedback on the sodium results by a telephone call. In the passive partner condition, only patients collected urine for feedback. At the end of the 6 week instructional period, all patients and partners collected a 24-hr urine and had their blood pressure assessed. Half of each group was also randomly assigned to have access to a system for periodic home-monitoring of urine for sodium content during a 3-month period beginning at week 6 of the study (immediate). The delayed feedback group received the home-monitoring three months after completion of the dietary instruction. All patients, but only active partners, used the feedback system during their assignment periods and collected a 24-hr urine monthly between 6 and 30 weeks of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

The reproducibility and heritability of individual differences in osmoregulatory function in normal human subjects.

The rise in plasma vasopressin produced by infusion of hypertonic saline varies widely among healthy adults. To determine if these interindividual differences are reproducible, we used linear regression to analyze the relationship of plasma vasopressin to plasma osmolality during repeat hypertonic saline infusion in seven normal subjects. The results confirmed that the slope or sensitivity of the relationship differed widely between subjects (0.12 to 1.66 pg/ml/mOsm/kg) and revealed that these differences were highly reproducible. (r = 0.94 on repeat testing). The individual values for osmotic threshold were less variable (280 to 288 mOsm/kg) as well as less clearly reproducible (r = 0.61). To determine whether these differences are genetically influenced, we compared the vasopressin osmolality relationships within seven monozygotic and six dizygotic twin pairs. We found that the threshold and sensitivity values correlated significantly within monozygotes (r = 0.95 and 0.95) but not within dizygotes (r = 0.34 and 0.21). When the osmoregulation of thirst was similarly evaluated, the individual relationships were as variable as for plasma vasopressin, but only the threshold values in monozygotes correlated significantly (r = 0.92). In 80 healthy adults, the frequency distributions of the osmotic threshold and sensitivity of the vasopressin responses were essentially normal. We conclude that the sensitivity for vasopressin secretion as well as the osmotic thresholds for thirst and vasopressin demonstrate significant polygenetic variance among healthy adults.

Race and gender influence hemodynamic responses to psychological and physical stimuli.

To evaluate factors influencing hemodynamic responses to psychological and physical stress, 117 normotensive college students were studied. The standardized tests included arithmetic, Stroop word-color, mirror draw, isometric handgrip and cold pressor challenges. The responses of blood pressure and pulse during the tests were compared to the baseline measurements. All the challenges produced a significant (P less than 0.01) increase in systolic and diastolic pressure and pulse rate, with the greatest increase being seen with the isometric handgrip test. The increases in the systolic and diastolic pressure and the heart rate to the psychological stressors were highly correlated (P less than 0.001). The responses to the physical stressors were correlated for the diastolic pressure (P less than 0.01) and the heart rate (P less than 0.001), but not for the systolic pressure. The responses of the systolic and diastolic pressure, but not the heart rate, to the isometric handgrip correlated with the responses to the psychological stressors. The responses of the diastolic pressure and the heart rate, but not the systolic pressure, to the cold pressor stimulus correlated with the responses to the psychological stressors. The gender influenced the response to all the stressors with males having a greater (P less than 0.05) blood pressure response and a lesser (P less than 0.001) heart rate response than females. Black subjects had greater blood pressure responses to the cold pressor test and a greater diastolic pressure response to the handgrip, but there were no observed racial differences in the responses to the psychological stressors.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleotide sequences responsible for the inability of a herpes simplex virus type 2 strain to grow in human lymphocytes are identical to those responsible for its inability to grow in mouse tissues following ocular infection.

A study was undertaken to determine whether genes associated with herpes simplex virus (HSV) neuroinvasiveness in mice influence the growth of HSV in man, the virus's natural host. HSV-2(186), a nonneuroinvasive HSV strain, was found to replicate poorly (less than 3-fold) in cultures of phytohemagglutinin (PHA) stimulated human peripheral blood mononuclear cells (PBMC). In contrast, seven other HSV strains all multiplied 40- to 100-fold. The paucity of HSV-2(186) growth in PBMC was not due to a failure of this strain to grow in primary human cells because high titers (greater than 10(8) PFU/ml) were obtained following infection of human foreskin fibroblasts. The genetic basis for the deficient growth was analyzed by marker rescue experiments. Recombinant HSV-2 strains were generated in marker rescue experiments utilizing HSV-2(186) DNA and plasmids containing a cloned DNA polymerase gene isolated from a neuroinvasive HSV strain possessing the capacity to replicate in human PBMC. Progeny which rescued DNA from the cloned HSV DNA polymerase gene replicated 40- to 100-fold in PHA-stimulated PBMC. Moreover, unlike the HSV-2(186) parent, HSV-2(186) isolates possessing rescued DNA grew well in the eye, trigeminal ganglion, and brain of mice and induced fatal encephalitis. The results indicate that nucleotide sequences responsible for increasing the capacity of HSV-2(186) to grow in PBMC of man are identical to those responsible for increasing the capacity of this strain to grow in mouse tissues and to spread from the eye to the brain.

The effect of dietary interventions to reduce blood pressure in normal humans.

Changes in electrolyte intake have been advocated to lower the prevalence of hypertension in the normal population. To elucidate the potential impact of such strategies, we conducted a comprehensive analysis of data from three interventions, namely, salt (NaCl) restriction, calcium (Ca) supplementation, and potassium (K) supplementation in normal volunteers. Eighty-two adults lowered their Na intake from 157 +/- 6 S.E. to 68 +/- 3 mEq/day for 12 weeks. Population mean systolic and diastolic blood pressure decreased less than or equal to 2 mm Hg. Ca supplementation, 1.5 g daily for 12 weeks in 37 men, decreased blood pressure compared to 38 men receiving placebo. Ca supplementation, 1 g daily for 8 weeks in an older group of 44 normal subjects, decreased supine diastolic and standing systolic blood pressure. K supplementation with a nonchloride salt in 64 normal adults for 4 weeks had no effect on systolic or diastolic blood pressure even though urinary excretion was increased by 20 mmol/day. The responses to all interventions were Gaussian in distribution. A potentially adverse effect on blood pressure in some normal individuals cannot be excluded on the basis of the currently available data. Although all three interventions may benefit some hypertensive and some normal individuals, the data from these relatively short-term cross-sectional studies are insufficient to warrant generalized dietary recommendations for the normal population.

Racial differences in aldosterone excretion and plasma aldosterone concentrations in children.

Blacks are more likely to have hypertension, have lower levels of plasma renin activity, and typically consume less potassium than whites. Whether blacks and whites secrete different amounts of aldosterone is less clear. We estimated aldosterone secretion indirectly in 715 children, 249 of whom were black, by measuring their nocturnal rates of urinary excretion of aldosterone. Dietary sodium and potassium intakes were estimated from their excretion rates. The mean (+/- SE) aldosterone-excretion rate was lower in the black children than in the white children (0.045 +/- 0.003 vs. 0.078 +/- 0.004 nmol per micromole of creatinine per kilogram of body weight; P less than 0.001). The potassium-excretion rate was also lower in the black children than in the white children (0.13 +/- 0.01 vs. 0.18 +/- 0.01 mmol per micromole of creatinine per kilogram; P less than 0.001). Aldosterone excretion was highly correlated with potassium excretion (P less than 0.001), but the lower aldosterone-excretion rate in blacks was explained only in part by their lower dietary intake of potassium. Systolic blood pressure was higher in black children (P less than 0.001), as was diastolic pressure (P = 0.037). In a second study of 99 children, the plasma aldosterone level was found to be significantly lower in black children than in white children (230 +/- 30 vs. 400 +/- 30 pmol per liter; P less than 0.001). Plasma renin activity and plasma cortisol levels were the same in both groups. In summary, we found that black children secrete about 40 percent less aldosterone than white children. The role of the lower aldosterone-secretion rate in the genesis of the higher blood pressures observed in black children is not known.

Calcium absorption in children estimated from single and double stable calcium isotope techniques.

In order to determine whether the specific activity in a single serum sample estimates calcium absorption, six healthy children participated in a study using stable isotopic calcium tracers, one given orally and the second intravenously. High-resolution, fast atom bombardment mass spectrometry was used to quantify the 44Ca and 42Ca tracers in serum and urine. Subjects ingested 250 mg of calcium (215 mg calcium enriched with 35 mg 44Ca) in the form of a chewable calcium citrate malate tablet with a standard meal, followed 30 min later with an i.v. injection of 42Ca tracer. Blood for tracer determinations was obtained at 90, 120, 150, 180, and 300 min after oral ingestion, and a urine sample was obtained 24 h after oral calcium tracer administration. The average calcium absorption estimated from the ratio of urinary tracers was 41.4 +/- 8.2%. This study indicates that the level of oral tracer in serum taken 150 min post-ingestion is significantly correlated (r = 0.85, p less than 0.05) with calcium absorption, as determined by the tracer levels in the urine. These results show that an oral stable isotopic tracer coupled with a single blood sample can be used to estimate calcium absorption in children.

Indianapolis cholesterol screening 1987: does mass screening accomplish its goal?

To evaluate the impact of large scale population screening for elevated total cholesterol, a city-wide event was scheduled in Indianapolis during nine days in February 1987. Altogether, 29,954 individuals were screened, and more than 32% were found to be at moderate or high risk using the classification recommended by the National Institutes of Health at the time of the screening for heart disease on the basis of their total plasma cholesterol concentrations. Although larger numbers of females and whites volunteered to be screened, the screened population represented a broad range of age and education levels. Results of a followup questionnaire returned by 18% of those at moderate of high risk revealed that after receipt of an elevated cholesterol result, 67% of the respondents scheduled a physician visit. The majority of those not doing so (53%) contacted their physician for other reasons or by telephone. Results of the followup indicate that screened subjects responded appropriately to the results received. The results of this project indicate that mass screening is only one tool to successfully identify individuals at risk. Given the biases present in the screened population, other strategies should be used to identify at-risk members of population groups unlikely to participate in similar screening events.

Genetic and environmental approaches to the prevention of hypertension.

While the familial and genetic nature of hypertension has long been recognized, the mechanisms involved are not clear. Recent studies suggest that an environmental factor, increased dietary sodium intake, may be required for the expression of this genetically determined form of hypertension. The evidence for this conclusion is based on physiological studies of humoral factors, renal function and the blood pressure response to sodium and volume expansion and reduction in several carefully characterized human populations.

Nutrient intake and blood pressure: families of adult identical twins.

To investigate the relationship of dietary intake to blood pressure, 198 adults and 53 children who were members of 92 nuclear families completed a 3-day diet diary prior to an outpatient clinic examination for cardiovascular disease risk factors. Nutrient intake was significantly related to age and anthropometric variables in adults. Sodium and potassium intake were related to blood pressure in adults, but this relationship was no longer significant after adjustment for caloric intake. The diet and blood pressure relationships in children were less clear. Multiple linear regression techniques using age, anthropometric variables, and nutrient intake demonstrated that in adults age and skinfold were the principal determinants of blood pressure, but in children age and saturated fat intake were most likely to enter the equations. In comparisons of normotensive and hypertensive adults, there were no differences in the dietary intakes of these electrolytes. The results of this investigation underscore the complex interaction of nutrient intake with body size and age. Investigators who focus only on a few nutrients and fail to account for other sources of variation can be misled.

Calcium absorption from calcium carbonate and a new form of calcium (CCM) in healthy male and female adolescents.

Calcium absorption from two Ca salts was investigated in a crossover design using stable isotopic tracers in 12 healthy adolescents (6 males, 6 females). A Ca supplement in the form of Ca carbonate or Ca citric and malic acids (CCM) was ingested with a standardized breakfast and the order of administration was randomized. The oral supplement contained 250 mg elemental Ca, 21.8 mg of which was highly enriched 44Ca tracer. Thirty minutes later subjects received 3.6 mg 42Ca tracer intravenously. The molar concentrations of 42Ca and 44Ca tracers in a urine sample obtained 24 h after tracer administration were quantified by fast-atom-bombardment mass spectrometry and used to determine fractional absorption of the Ca from the supplement. Ca in the form of CCM had an increased fractional absorption (p less than 0.03) relative to Ca carbonate in healthy adolescents (36.2 vs 26.4%). This increase was not related to body size, sex, or indices of Ca metabolism.

Heritable aspects of salt sensitivity.

Dietary salt reduction is an important nonpharmacologic remedy for mild hypertension as well as a useful adjunct to drug treatment. However, a reduced salt intake diet is not effective in reducing the blood pressure of all hypertensive patients. Several lines of evidence indicate that some patients are salt-sensitive whereas others are salt-resistant. A series of investigations have been conducted showing that the blood pressure responses to either acute salt and volume loading or to a reduced dietary salt intake are normally distributed. Blood pressure, humoral regulators of blood pressure and renal sodium handling are each found to be influenced by genetic variance. The change in blood pressure from dietary salt reduction is influenced by genetic variance as well. Definitions of salt sensitivity and resistance were formulated, and salt sensitivity of blood pressure was found to occur significantly more often in black than in white Americans. Furthermore, preliminary data suggest that measurement of phenotypes of haptoglobin in blood may assist in identifying salt-sensitive and salt-resistant subjects. Trials of a reduced salt intake diet in pharmacologically treated hypertensive patients are currently being conducted. The data suggest that at least half of the patients are salt-sensitive and that their medications may be reduced in response to the intervention. Results of this study may be of relevance to many of the 60 million Americans with hypertension, particularly to those who are black and elderly.