Maternal predictors of neonatal bone size and geometry: the Southampton Women's Survey.

Early growth is associated with later risk of osteoporosis and fractures. In this study, we aimed to evaluate the relationships between maternal lifestyle and body composition and neonatal bone size, geometry and density in the offspring. Participants were recruited from the Southampton Women's Survey, a unique prospective cohort of 12,500 initially non-pregnant women aged 20-34 years, resident in Southampton, UK. These women were studied in detail before and during pregnancy, and the offspring underwent anthropometric and bone mineral assessment (using dual energy-X-ray absorptiometry) at birth. A total of 841 mother-baby pairs were studied (443 boys and 398 girls). The independent predictors of greater neonatal whole body bone area (BA) and bone mineral content included greater maternal birthweight, height, parity, triceps skinfold thickness and lower walking speed in late pregnancy. Maternal smoking was independently associated with lower neonatal bone mass. Neonatal BA adjusted for birth length (a measure of bone width) was predicted positively by maternal parity and late pregnancy triceps skinfold thickness and negatively by late pregnancy walking speed. These findings were similar in both genders. We have confirmed, in a large cohort, previous findings that maternal lifestyle and body build predict neonatal bone mineral; additionally, maternal parity and fat stores and walking speed in late pregnancy were associated with neonatal bone geometry. These findings may suggest novel public health strategies to reduce the burden of osteoporotic fracture in future generations.

Paternal skeletal size predicts intrauterine bone mineral accrual.

BACKGROUND: We have previously demonstrated that maternal body build and lifestyle factors predict neonatal bone mineral accrual. However, the paternal determinants of neonatal bone mass are not known. In this study we explored the relationship between a father's bone mass and that of his offspring. METHODS: A total of 278 pregnancies (142 male and 136 female neonates) were recruited from the Southampton Women's Survey, a unique, well-established cohort of women, aged 20-34 yr, who had been assessed before and during pregnancy. The neonates and their fathers underwent whole body dual-x-ray absorptiometry (DXA) within 2 wk of birth using a Lunar DPX (General Electric Corp., Madison, WI) and Hologic Discovery instrument (Hologic Inc., Bedford, MA), respectively; correlation and regression methods were used to explore the parental determinants of neonatal bone mass. RESULTS: After adjusting the paternal DXA indices for father's age and the neonatal for baby's gestational age and age at DXA scan, there were highly significant positive associations between baby's whole body bone area, bone mineral content, and bone mineral density and the corresponding indices in the father (P = 0.003, 0.0002, 0.046, respectively) among female infants. These relationships were independent of maternal height and fat stores. The associations for male infants with paternal DXA indices did not achieve statistical significance. CONCLUSIONS: The father's skeletal size predicts skeletal size more strongly in female than male offspring, independently of the mother's body build. These data point toward the importance of considering paternal genotype in studies exploring the developmental origins of osteoporotic fracture and raise intriguing mechanistic questions about the gender specificity of influences on intrauterine bone mineral accrual.

Placental calcium transporter (PMCA3) gene expression predicts intrauterine bone mineral accrual.

Evidence is accruing that environmental exposures during critical periods of early development induce persisting changes in skeletal growth, and alter fracture risk in later life. We have previously demonstrated that placental calcium transport, partly determined by maternal 25-(OH) vitamin D status, may underlie this phenomenon. However, the precise relationship between expression of calcium transport proteins in the human placenta, and neonatal bone mineral accrual in the offspring, remains unknown. Tissue samples from 70 human placentae were fast frozen in liquid nitrogen and stored at -70 degrees C. A quantitative real time reverse transcriptase polymerase chain reaction was used to measure the mRNA expression of PMCA isoforms 1-4, using beta-actin as a control gene. Neonatal whole body bone area, mineral content and areal density (BA, BMC, BMD) were measured within 2 weeks of birth using DXA. PMCA3 mRNA expression predicted BA (r=0.28, p=0.02), BMC (r=0.25, p=0.04), placental weight (r=0.26, p=0.04) and birth weight (r=0.33, p=0.006) of the neonate. In a multivariate model, the relationship between placental PMCA3 expression and neonatal BMC was independent of maternal height, pre-pregnant fat stores, parity, physical activity, smoking, and calcium intake (p<0.05). Expression of the placental calcium transporter PMCA3 mRNA predicts neonatal whole body bone mineral content. This association may explain, in part, the mechanism whereby a mother's 25(OH)-vitamin D stores influence her offspring's bone mass.

Parental determinants of neonatal body composition.

BACKGROUND: The prevalence of both childhood and adult obesity is rising in the developed world, and there is increasing interest in its underlying causes. A number of studies suggest a positive relationship between birth weight and childhood body mass index, but less is known about specific prenatal environmental influences on more direct measures of obesity. We used data from the Southampton Women's Survey to investigate parental influences on neonatal body composition ascertained by dual x-ray absorptiometry. METHODS: Participating mothers were characterized in detail (anthropometry, lifestyle, diet) before and during pregnancy; information was also obtained on their partners. The offspring underwent assessment of fat and lean body mass by dual x-ray absorptiometry within 2 wk of birth. Linear regression methods were used to explore the parental determinants of neonatal body composition. RESULTS: Complete data were available for 448 mother-offspring pairs. Taller women and those with higher parity had offspring with increased birth weight, fat, and lean mass (P < 0.05). Mothers who were taller, of greater parity, had greater fat stores, or walked more slowly also had offspring with greater proportionate body fat at birth (all P < 0.05). There was a weaker trend toward lower percentage fat and greater percentage lean in the offspring of mothers who smoked during pregnancy. CONCLUSION: Maternal size, parity, smoking history, walking speed, and fat stores are independent determinants of neonatal body composition. If these influences are shown to have persisting effects on body composition through to adulthood, they point to novel public health interventions early in life to prevent later obesity.

Inflammatory responses to the occupational inhalation of metal fume.

Occupational exposure to metal fume promotes a reversible increase in the risk of pneumonia, but by mechanisms which are unclear. To investigate, the current authors measured various markers of host defence function in welders and nonwelders. Induced sputum and venous blood samples were collected from 27 welders with regular long-term exposure to ferrous metal fume and 31 unexposed matched controls. In sputum, the present authors measured cell counts, the soluble and cellular iron concentration, and levels of interleukin-8, tumour necrosis factor-alpha, myeloperoxidase, matrix metalloproteinase-9, immunoglobulin (Ig)A, alpha(2)-macroglobulin and unsaturated iron-binding capacity. Blood samples were assayed for evidence of neutrophil activation and pneumococcal IgG antibodies. Welders had significantly higher iron levels and a substantially lower unsaturated iron-binding capacity in their sputum, but, despite a high iron challenge, there was a noteworthy absence of an inflammatory response. Only blood counts of eosinophils and basophils were significantly related to the extent of welding. Weak nonsignificant trends were observed for several other measures, consistent with low-grade priming of neutrophils. In conclusion, these data suggest that chronic exposure to metal fume blunts responsiveness to inhaled particulate matter. However, the mechanism behind the lack of detectable local inflammatory response requires further investigation.

Size at birth, adult intestinal calcium absorption and 1,25(OH)(2) vitamin D.

BACKGROUND: Adult bone mineral status is modified by early environmental influences, but the mechanism of this phenomenon is unknown. Intestinal calcium absorption and vitamin D metabolism are integrally involved in bone metabolism and may be programmed during early life. AIM: To examine the early-life influences on calcium absorption and its control in 322 post-menopausal female twins. METHODS: Intestinal calcium absorption was assessed by the stable strontium (Sr) method. Serum PTH, 25(OH) and 1,25(OH)(2) vitamin D were measured and recalled birth weight recorded. RESULTS: Fractional intestinal Sr absorption (alpha Sr) was correlated with serum 1,25(OH)(2) vitamin D (p<0.001), but not with 25(OH) vitamin D. Birth weight was inversely associated with serum 1,25(OH)(2) vitamin D (p=0.04), the association being independent of serum calcium, phosphate, creatinine and PTH. Birth weight was inversely correlated with alpha Sr (p=0.03), this association being independent of age, season, customary calcium intake and serum 25(OH) vitamin D; however, when serum 1,25(OH)(2) vitamin D was added into the model, the association became non-significant, suggesting that the association was partially mediated via serum 1,25(OH)(2) vitamin D. DISCUSSION: We found a significant inverse association between birth weight and intestinal calcium absorption that is partially explained by an association between serum 1,25(OH)(2) vitamin D and birth weight. This suggests a mechanism whereby the intra-uterine environment might affect adult skeletal status.

Modification of therapy from insulin to chlorpropamide decreases HDL cholesterol in patients with non-insulin-dependent diabetes mellitus.

In 27 patients with non-insulin-dependent diabetes mellitus, we determined fasting serum glucose, hemoglobin A1, body weight, serum triglycerides, cholesterol, low-density lipoprotein cholesterol (LDL-chol), high-density lipoprotein cholesterol (HDL-chol), and very-low-density lipoprotein cholesterol during treatment with insulin and several months after changing treatment to chlorpropamide. In five patients, diabetic control deteriorated to the point where insulin was reinitiated. In the remaining 22 patients, despite a significant decrease in weight (122 +/- 5 vs. 114 +/- 5% ideal body wt; P less than .025) on chlorpropamide, HDL-chol fell from 49 +/- 4 to 40 +/- 4 mg/dl (P less than .01) when therapy was modified from insulin to the sulfonylurea. There was a concomitant increase in LDL-chol:HDL-chol from 3.6 +/- 0.3 to 4.4 +/- 0.5 (P less than .05). In the 5 patients in whom insulin was reinstituted, HDL-chol increased to its previous level on insulin (P less than .05). Changing antidiabetic medication from insulin to sulfonylureas may alter the lipoproteins in a manner that increases cardiovascular risk.

Hemoglobin A1 correlates with the ratio of low-to high-density-lipoprotein cholesterol in normal weight type II diabetics.

Because cardiovascular risk correlates with serum low density lipoprotein (LDL) cholesterol and is inverse with high density lipoprotein (HDL) cholesterol, the LDL-HDL cholesterol ratio has been advocated as a sensitive index of relative cardiovascular risk. In 50 normal weight insulin-treated Type II diabetic subjects, mean LDL-HDL ratios were significantly higher than for controls. In diabetic women, the LDL-HDL cholesterol ratio correlated with hemoglobin A1 better than any of the lipids or lipoprotein cholesterol fractions. When 8 poorly controlled diabetics were treated with insulin, the LDL-HDL ratio changed more significantly than did its component fractions, and the fall in LDL-HDL ratio paralleled the fall in hemoglobin A1.

Sequential liver-spleen scanning for documentation of wandering spleen.

An additional case of wandering spleen is reported. A brief review of the etiology of this entity, as well as various findings obtained with nuclear imaging of the spleen, is presented. The authors discuss the relevance of repeated spleen scans to the clinical decision making process. Particular significance is paid to preservation of the spleen to maintain immunologic competence.

Labile methyl balances for normal humans on various dietary regimens.

Normal young adult male and female subjects were maintained on fixed dietary regimens which were either essentially normal or were semisynthetic and curtailed in methionine and choline intakes and virtually free of cystine. The subjects maintained stable weights and remained in positive nitrogen balance or within the zone of sulfur equilibrium. Choline intakes were calculated, and urinary excretions of creatinine, creatine, and sacrosine were measured. Creatinine excretions of male subjects on essentially normal diets outweighed the total intakes of labile methyl groups. Taking into account the excretions of additional methylated compounds, as judged from published values, it appears that methyl neogenesis must normally play a role in both males and females. When labile methyl intake is curtailed, de novo formation of methyl groups is quantitatively more significant than ingestion of preformed methyl moieties. On the normal diets used in these experiments, the average homocysteinyl moiety in males cycled between methionine and homocysteine at least 1.9 times before being converted to cystathionine. For females, the average number of cycles was at least 1.5. When labile methyl intake was curtailed, the average number of cycles rose to 3.9 for males and 3.0 for females under the conditions employed.

Homocystinuria due to cystathionine synthase deficiency. Studies of nitrogen balance and sulfur excretion.

Apparent nitrogen balances and urinary sulfur excretions were determined for normal subjects, seven cystathionine synthase-deficient patients, and a single cystathioninuric patient on semisynthetic diets containing low-adequate amounts of methionine and very low amounts of methionine and very low amounts (12 mg daily, or less) of cystine. The amounts of supplemental cystine required to prevent abnormally high nitrogen or sulfur losses were determined. The five cystathionine synthase-deficient patients who had low residual activities of this enzyme detected in fibroblast and/or liver extracts did not lose more nitrogen or sulfur on diets virtually devoid of cystine than did the normal subjects. These results suggest that the widely expressed opinion that cystine is an essential amino acid for cystathionine syntase-deficient patients requires modification. Residual enzyme activity of only a few percent of normal may obviate such a cystine requirement. These results are compatible with, and lend support to, the working hypothesis which states that the pyridoxine response in cystathionine synthase-deficient patients is mediated by an increase in the residual activity of the affected enzyme.