Limited exposure to ambient ultraviolet radiation and 25-hydroxyvitamin D levels: a systematic review.

Vitamin D can be synthesized following exposure to ultraviolet radiation (UVR), ingested in the diet or provided through oral supplementation. The medical literature frequently states that humans obtain most of their vitamin D from sunshine and that UVR exposure is essential to maintain vitamin D levels. A systematic review was conducted to determine the requirement for UVR in maintaining adequate (> 50 nmol L(-1) ) serum 25-hydroxyvitamin D [25(OH)D] levels. Studies reporting serum 25(OH)D during situations of negligible UVR exposure were sought. Forty-one studies (from a search yielding 42 698 articles) with a total of 4211 healthy adults met the inclusion criteria, providing 56 datasets from different population groups. Over 50% of subjects had > 50 nmol L(-1) 25(OH)D in 10 of 19 datasets reporting winter levels in areas with limited UVR. In addition, > 50% of subjects had adequate 25(OH)D levels in four of 12 datasets from polar regions during periods of negligible UVR, one of nine datasets documenting clothing-related minimal UVR and two of eight datasets detailing employment-related minimal UVR. The data demonstrate that many adults maintain adequate serum vitamin D levels despite negligible UVR exposure for several months. However, we acknowledge that preceding UVR exposure leading to vitamin D storage and delayed release may account for this maintenance of adequate serum vitamin D levels. There remains a need for further research on whether UVR exposure is required for longer-term maintenance of adequate vitamin D levels.

Clinical utility of 13C-liver-function breath tests for assessment of hepatic function.

13C-Liver-function breath tests have been used in clinical diagnostics and, to a limited extent, to investigate hepatic function. From a practical perspective, tests such as the 13C-aminopyrine and 13C-methacetin breath tests are simple to administer, safe, and relatively inexpensive to perform. Surprisingly, they have not entered the mainstream of clinical practice, because they are perceived to lack the specificity and adequate precision needed to give accurate results in real time. The dynamic nature of 13C-liver-function breath tests, their possible versatility in terms of assessing a range of different liver functions, and the ease with which they can be repeated to follow relative changes in liver function with time, all imply the potential for wider clinical application. Therefore, there is a need for these tests to be critically evaluated and their potential clinical application be tested systematically against defined objectives. We describe refinements in the methodology of the tests and propose several situations in which currently reliable methods for assessment of liver function do not exist and where 13C-liver-function breath tests might be of use. We propose that use has been constrained by practical methodological considerations which could be addressed to offer tests better suited to routine application in the out-patient or community setting.

L-serine uptake by human placental microvillous membrane vesicles.

The human fetus requires more glycine than any other amino acid but placental glycine transfer to the fetus is insufficient to meet fetal demand. L-Serine could represent a major metabolic source of glycine for the human fetus but little is known about the kinetics and physiology of L-serine uptake by the human placenta. We have characterised the amino acid transport systems involved in the uptake of L-serine by the microvillous membrane of the human placental syncytiotrophoblast and compared the uptake rates to those of glycine. L-Serine uptake into microvillous membrane (MVM) vesicles was primarily mediated by system A (MeAIB inhibitable) and system L (BCH inhibitable). Further characterisation using specific substrates of LAT1 and LAT2 found the pattern of L-serine uptake was consistent with that expected for uptake mediated by LAT2. Uptakes were performed with tracer levels of (14)C-L-serine, physiological levels of L-serine, or with physiological levels of amino acids. As amino acid concentrations rose, the proportion of uptake by System L decreased while uptake by uncharacterised Na(+)-independent systems increased. Uptake of Lserine into MVM vesicles had a V(max) of 2.1+/-0.4 nmol/mg protein/min, which was significantly higher than for glycine (V(max) 1.0+/-0.2 nmol/mg protein/min). This indicates that MVM vesicles have a higher uptake capacity for L-serine than glycine, despite a greater demand for glycine over serine for fetal protein synthesis. Further studies are now required to define the fate of L-serine taken up by the placenta and its importance for the fetus.

Relationship between birth weight and urea kinetics in children.

OBJECTIVE: To explore the effect of birth weight on urea kinetics in young healthy children. DESIGN: Observational study. SETTING: Tertiary center for treatment of malnutrition. SUBJECTS: A total of 17 male children, 6-24 months old, who had recovered from malnutrition. INTERVENTIONS: Urea kinetics were measured using stable isotope methodology with [(15)N(15)N]-urea over 36 h. RESULTS: Birth weight was negatively related to urea hydrolysis after controlling for the intake of protein (adjusted R (2 ) = 0.91, P = 0.001) and separately for energy intake (adjusted R (2) = 0.95, P = 0.001), age (adjusted R (2) = 0.90, P = 0.001) and rate of weight gain (adjusted R (2) = 0.91, P = 0.001). There was a tendency for higher urea production in the children with lower birth weight after controlling for nitrogen intake (adjusted R (2) = 0.93, P = 0.099), and separately for age (adjusted R (2) = 0.94, P = 0.06) and rate of weight gain (adjusted (R (2) = 0.92, P = 0.096). Urea excretion was not significantly related to birth weight. CONCLUSIONS: The salvaging of urea nitrogen following urea hydrolysis contributed significantly more to the nitrogen economy in children with lower birth weight compared to those with higher birth weight. This may be as a result of reductive adaptation in the children with lower birth weight as a consequence of inappropriate prenatal nutrition and growth.

The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero.

Potential mechanisms underlying prenatal programming of hypertension in adult life were investigated using a rat model in which maternal protein intake was restricted to 9% vs. 18% casein (control) during pregnancy. Maternal low protein (MLP) offspring exhibit glucocorticoid-dependent raised systolic blood pressure throughout life (20-30 mm Hg above the control). To determine the molecular mechanisms underlying the role of alterations in glucocorticoid hormone action in the prenatal programming of hypertension in MLP offspring, tissues were analyzed for expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11betaHSD1, 11betaHSD2, and corticosteroid-responsive Na/K-adenosine triphosphatase alpha1 and beta1. GR protein (95 kDa) and messenger RNA (mRNA) expression in kidney, liver, lung, and brain was more than 2-fold greater in MLP vs. control offspring during fetal and neonatal life and was more than 3-fold higher during subsequent juvenile and adult life (P < 0.01). This was associated with increased levels of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA expression. Levels of MR gene expression remained unchanged. Exposure to the MLP diet also resulted in markedly reduced levels of 11betaHSD2 expression in the MLP placenta on days 14 and 20 of gestation (P < 0.001), underpinning similar effects on 11betaHSD2 enzyme activity that we reported previously. Levels were also markedly reduced in the kidney and adrenal of MLP offspring during fetal and postnatal life (P < 0.001). This programmed decline in 11betaHSD2 probably contributes to marked increases in glucocorticoid hormone action in these tissues and potentiates both GR- and MR-mediated induction of raised blood pressure. In contrast, levels of 11betaHSD1 mRNA expression in offspring central and peripheral tissues remained unchanged. In conclusion, we have demonstrated that mild protein restriction during pregnancy programs tissue-specific increases in glucocorticoid hormone action that are mediated by persistently elevated expression of GR and decreased expression of 11betaHSD2 during adult life. As glucocorticoids are potent regulators not only of fetal growth but also of blood pressure, our data suggest important potential molecular mechanisms contributing to the prenatal programming of hypertension by maternal undernutrition in the rat.

Maintenance of maternal diet-induced hypertension in the rat is dependent on glucocorticoids.

Recent epidemiological evidence suggests that adult cardiovascular risk is determined by birth weight and factors that influence birth weight, such as maternal nutrition. Data from animal models suggest that an interaction between nutrition and glucocorticoid hormones "programs" increased risk of adult hypertension. Increased fetal exposure to maternal glucocorticoids that is proposed to occur from a reduction in the placental barrier to maternal glucocorticoid, 11beta-hydroxysteroid dehydrogenase, is suggested to program hypertension in the resultant offspring from both glucocorticoid-treated and maternally protein-restricted rats. The extent to which postnatal glucocorticoid stimulation may influence the progression of hypertension in the offspring from protein-restricted rat dams was assessed in 6-week-old male Wistar rats, prenatally exposed to either an 18% casein (control) or 9% casein (low protein) diet. Rats from each dietary group were sham operated, adrenalectomized or adrenalectomized, and treated with 20 mg corticosterone/kg body weight per day. Before surgery, systolic blood pressure was significantly higher in the low protein-exposed rats compared with controls (165+/-3.8 versus 142+/-3.3 mm Hg, P<.0001). Adrenalectomy of the low protein-exposed animals significantly reduced the blood pressure to control levels, while corticosterone replacement restored the hypertensive state. No effect of adrenalectomy on blood pressure was observed in 18% casein controls. In both dietary groups adrenalectomy decreased brain, but not hepatic, glucocorticoid-sensitive enzyme activities and corticosterone treatment elevated activities of all enzymes. The data suggest that maternal diet-induced hypertension is dependent on an intact adrenal gland postnatally and that glucocorticoids are key trophic agents in maintaining the high blood pressure.

Concomitant supplemental vitamin A enhances the response to weekly supplemental iron and folic acid in anemic teenagers in urban Bangladesh.

BACKGROUND: Iron deficiency is the most common micronutrient deficiency and affects >2 billion persons worldwide, leading to anemia in >40% of women of reproductive age in the developing world. OBJECTIVE: The objective was to determine whether weekly supplementation with iron and folate would reduce the frequency of anemia in teenage women in urban Bangladesh before they became pregnant. DESIGN: Participants with a hemoglobin concentration of 80-120 g/L were entered into a randomized, double-blind, placebo-controlled trial and received supplements of placebo, vitamin A, iron + folic acid, or iron + folic acid + vitamin A weekly for 12 wk. The supplements contained 2.42 mg vitamin A (retinol) as retinyl palmitate, 120 mg elemental Fe as ferrous sulfate, and 3.5 mg folic acid. RESULTS: Hemoglobin concentrations increased significantly more after supplementation with iron + folic acid or iron + folic acid + vitamin A than after either the placebo or vitamin A alone. There was a significantly greater increase in hemoglobin after iron + folic acid + vitamin A than after iron + folic acid, but the additional effect disappeared after adjustment for baseline hemoglobin, serum vitamin A, and ferritin and the number of supplements taken. Those with the lowest baseline hemoglobin had the greatest increase in hemoglobin. Compared with the placebo, iron + folic acid + vitamin A reduced anemia by 92%, iron deficiency by 90%, and vitamin A deficiency by 76%. CONCLUSION: There may be significant health benefits from a program that enhances the nutritional status of iron, folate, and vitamin A in poor urban young women before they become pregnant.

The energy cost of repleting tissue deficits during recovery from protein-energy malnutrition.

Five children with protein-energy malnutrition were were treated with a high calorie, high protein diet and the energy cost of growth in body weight and muscle mass were calculated. Energy expenditures correlated statistically with increases in muscle mass, estimated by [15N]creatine kinetics, but not with gains in body weight.

Urea production and salvage during pregnancy in normal Jamaican women.

The pattern of aggregate nitrogen demand during pregnancy and the fetal and maternal components are unclear. Excess demand enhances efficiency of nitrogen utilization. Urea salvage contributes to enhanced efficiency. Dietary protein intake, urea production, and salvage of urea nitrogen were measured in eight nonpregnant control subjects, and trimesterly in nine pregnant women. Production was measured after prime-intermittent intravenous doses of [15N 15N]-urea by dilution of label in urinary urea. Dietary protein intake was greater in trimester 1 than in nonpregnant women (167 +/- 36 vs 224 +/- 60 mg N.kg-1.d-1), and increased further in trimester 2 (266 +/- 59 mg N.kg-1.d-1). Urea production was not higher during pregnancy. Despite higher protein intake, urea salvage was higher in pregnancy (40 +/- 24 nonpregnant vs 77 +/- 23, 61 +/- 31, and 51 +/- 12 mg N.kg-1.d-1). Therefore, the demand-supply gap for nitrogen was greatest early in pregnancy when fetoplacental growth is slowest, and implies heightened maternal demand.

Variability of fecal energy content measured in healthy women.

The variability of daily stool energy losses was examined in six healthy adult women over a complete menstrual cycle. On average, stool energy was 0.74 +/- 0.15 kJ/d (mean +/- SD) for the group. For a given individual, daily stool energy varied up to twofold. The variability for rolling averages of daily fecal energy losses over 3-, 5-, and 7-d periods showed no significant differences between collection periods of 3 and 5 d and 5 and 7 d. There was a close linear relationship between the energy content of the stool and either the wet or dry weight of stool (range 17-460 g wet wt). In metabolic studies of healthy women representative values for daily losses of energy in stool can be obtained from a 3-d collection. The energy content of wet stool was approximately 7 kJ/g. Under field conditions, weighing the stool provides a simple, useful method of assessing fecal energy losses.

Protein turnover and thermogenesis in response to high-protein and high-carbohydrate feeding in men.

The rates of energy expenditure and wholebody protein turnover were determined during a 9-h period in a group of seven men while they received hourly isocaloric meals of high-protein (HP) or high-carbohydrate (HC) content. Their responses to feeding were compared with those to a short period of fasting (15-24 h). The 9-h thermic response to the repeated feeding of HP meals was found to be greater than that to the HC meals (9.6 +/- 0.6% vs 5.7 +/- 0.4% of the energy intake, respectively, means +/- SEM, p less than 0.01). The rate of whole-body nitrogen turnover over 9 h increased from 17.6 +/- 2.2 g on the fasting day to 27.4 +/- 1.4 g during HC feeding (NS) and there was a further increase to 58.2 +/- 5.3 g resulting from HP feeding (p less than 0.001). By using theoretical estimates (based upon ATP requirements) of the metabolic cost of protein synthesis, 36 +/- 9% of the thermic response to HC feeding and 68 +/- 3% of the response to HP feeding could be accounted for by the increases in protein synthesis compared with the fasting state.

Interactions between growth and nutrient status in school-age children of urban Bangladesh.

The relationship between biochemical, anthropometric, and sociodemographic indexes was investigated in 242 children aged 5-12 y from five schools in Dhaka City, Bangladesh. As height-for-age increased so too did the mean serum concentrations of hemoglobin, protein, vitamin A, and zinc; serum copper concentrations were highest in the shortest group. Serum copper concentrations were highest in those with the lowest serum vitamin A concentrations. By multiple regression analysis, family income, age, weight-for-age, hemoglobin, and serum copper were strongly related to serum vitamin A. For every unit change in serum vitamin A there was a 4.92 unit change in hemoglobin, when all the other factors were taken into account. This study shows that there is a complex interaction between concentrations of biochemical indexes of nutritional status and other anthropometric, biochemical, and sociodemographic variables.

PIP: Between February and March 1990, health workers interviewed and took anthropometric measurements and blood samples from 242 children 5-12 years old, attending 3 primary schools in affluent areas and 2 primary schools in poorer areas around a university campus in Dhaka, Bangladesh. Researchers wanted to study the interaction between anthropometric and biochemical measures of nutritional status in seemingly healthy school children. As the height-for-age increased, so did the mean serum levels of protein, hemoglobin, and vitamin A (p = 0.001 for protein and 0.01 for hemoglobin and vitamin A). The rising trends were strongest for hemoglobin and vitamin A. Children in the group with the highest serum vitamin A level ( 1.05 mcmol/L) had significantly higher hemoglobin levels than did those with lower vitamin A levels (adjusted, 138.9 g/L vs. 133.8 g/L for 0.7-1.07 mcmol/L and 132.8 g/L for 0.7 mcmol/L; p = 0.002). For every unit change in vitamin A, a 4.92 unit change in hemoglobin existed. Children who had the lowest serum vitamin A levels had the highest serum copper levels (22.8 mcmol/L vs. 22.3 mcmol/L middle vitamin A group and 19.8 mcmol/L highest vitamin A group; p = 0.05). Multiple regression analysis showed that family income, age, weight-for-age, and hemoglobin and serum copper levels were significantly associated with serum vitamin A levels. These findings reveal that short children who were light for their age had lower serum vitamin A and hemoglobin levels and higher serum copper levels than their taller and heavier counterparts. They demonstrate a complex interaction between serum levels of biochemical indexes of nutritional status and other anthropometric, biochemical, and sociodemographic variables.

ARP1 interacts with the 5' flanking region of the coagulation factor VII gene.

Factor (F)VII plays a critical role in initiation of coagulation. Several segments within the 5' flanking region of the FVII gene were previously demonstrated to recognize hepatic nuclear proteins, but few have been identified. To identify a regulatory protein binding the nuclear hormone response region (-237 to -200) of the FVII 5' flanking region and demonstrate that the interaction is functional. Electrophoretic mobility shift assays and mutation analysis showed that ARP1, an orphan nuclear hormone receptor, interacted with two regions of the FVII 5' flanking region, the hepatic nuclear factor 4 binding region (-77 to -47) and the nuclear hormone response region (-237 to -200). Transfection experiments demonstrated that reporter gene expression was decreased from vectors including the nuclear hormone response segment compared with that containing only the minimal promoter between positions -109 and +1, and that ARP1 also repressed expression through an interaction with the minimal promoter. These data indicate a role for ARP1 in transcriptional modulation of the FVII gene.

A functional haplotype in the 5' flanking region of the factor VII gene is associated with an increased risk of coronary heart disease.

AIMS: The aim of this study was to investigate associations between coronary heart disease risk and polymorphisms in the coagulation factor (F)VII gene in participants of a large prospective study. METHODS: One thousand nine hundred and fifty-seven men were genotyped for four FVII polymorphisms, -670A-->C, -402G-->A, a 10 base pair insertion at -323 (0 > 10) in the promoter, and R353Q in the structural gene. Associations among genotypes and estimated haplotypes, plasma FVII levels, and coronary heart disease risk were evaluated, and the function of the promoter polymorphisms was assessed in reporter gene assays. RESULTS: The -670A-->C and -402G-->A polymorphisms were in complete allelic association. The haplotype containing -670C and -402A (frequency =0.23) was associated with significantly increased plasma FVII coagulant activity and increased risk of an initial coronary event, particularly acute myocardial infarction, which remained after correction for conventional risk factors. In contrast, the -323 insertion and Q353 alleles (frequency =0.11 and 0.10, respectively) were associated with decreased plasma FVII levels, but hazard ratios for coronary events in carriers of these alleles were not significantly different from unity. In transiently transfected hepatoma cells, increased basal expression of the reporter gene was directed by a promoter fragment with rare haplotype -670C/-630G/-402A rather than by a promoter fragment with common haplotype -670A/-630A/-402G; -402A was not responsible for this effect. CONCLUSIONS: The promoter haplotype, -670C/-630G/402A, was associated with significantly increased plasma FVII coagulant activity, risk of an initial coronary event, particularly acute myocardial infarction, and reporter gene expression.

A model for the measurement of whole-body protein turnover incorporating a protein pool with lifetime kinetics.

The hypothesis is proposed that the body contains a pool of protein turning over by lifetime rather than traditional first-order kinetics. The basis of the hypothesis is the observation of a step in the labelling curve or urinary ammonia during constant infusion of [15N]glycine. A four pool model has been constructed with different values for the rate of uptake of tracer into the lifetime pool; the calculated curves of tracer concentration show a step quite similar to that observed experimentally. It is concluded that it is possible, from an experimental curve, to derive an approximate estimate of the relative flux to the lifetime protein pool. Some suggestions are proposed for the physiological nature of this pool.

Glycine is not formed through the amino transferase reaction in human or rat placenta.

The fetus has a substantial demand for glycine, which is satisfied in part by placental formation. The ability to form glycine through the activity of alanine:glyoxylate aminotransferase enzyme was measured in placentae from normal term human pregnancies and placentae from rats at day 20 of gestation. There was no detectable enzyme activity in either human or rat placentae, although activity was measured in rat liver. It is concluded that in the placenta glycine is only formed from serine through the activity of serine hydroxymethyl transferase enzyme, which uses folate as a cofactor, because there are no other known metabolic pathways for endogenous glycine production.

Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat.

Hypertension is strongly predicted by a low birthweight:placental weight ratio. Two independent models have been described to explain this association; less than optimal maternal protein nutrition leading to fetal undernutrition, or glucocorticoid excess. Pregnant rats were fed diets containing 18 per cent casein (control) or 9 per cent casein, balanced for energy. On day 20 of gestation the pregnancies were terminated and placentae collected for determination of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) activity. Placental 11 beta HSD normally protects the fetus from the effects of maternal glucocorticoids. Activity was specifically attenuated by mild protein restriction (33 per cent in activity), whilst activities of glucocorticoid-insensitive control enzymes were unchanged and glucocorticoid-inducible glutamine synthetase activity was increased (27 per cent), relative to activity in placentae from control animals. The nutritional manipulation during pregnancy significantly increased systolic blood pressure (17 mmHg) in the resulting offspring in early adulthood. A possible common pathway whereby maternal environmental factors may influence fetal and placental growth and programme disease is inferred.

Persistence of lower birth weight in second generation South Asian babies born in the United Kingdom.

OBJECTIVE: To assess differences in birth weight between all first and second generation South Asian babies born in Southampton, and trends since 1957. DESIGN: Retrospective, cohort study. SETTING: Birth records for babies born in Southampton from 1957 to 1996 were searched to identify all babies born of South Asian origin (including from the Indian subcontinent, East Africa, and elsewhere). MAIN OUTCOME MEASURES: All information recorded in the birth record about the mother and baby was extracted. RESULTS: 2395 full term (>37 weeks; mean birth weight 3110; 95%CI 3092 to 3129) singleton births were identified. Detailed analysis was restricted to mothers either born in the Indian subcontinent (India, Pakistan, or Bangladesh (1435)) or United Kingdom (283). Mean birth weight and % low birth weight (<2500 g) were 3133 g (95%CI 3108 to 3157) and 7.5%, for first generation babies and 3046 g (2992 to 3099) and 11.7% for second generation babies. There was no trend over time to increased average birth weight in either first or second generation babies. Adjusting for other factors that were statistically significantly related to birth weight (gender, gestational age, mother's age, maternal weight at 15 weeks, parity, and mother's ethnic group) did not alter the trends. CONCLUSIONS: For that group in the UK who derive from the Indian subcontinent, average birth weight is significantly less than the national average. There has not been any increase in the average birth weight over the past 40 years, and the birth weight of babies of women who were born in the UK are no greater. The persistence of lower than desirable birth weight may result long term in higher than average rates of diabetes and heart disease in these groups.

Blood glutathione in severe malnutrition in childhood.

The blood glutathione (GSH) concentration was measured in 25 severely malnourished children and compared with a group of normal adults. In children with marasmus GSH (3.3 +/- 0.7 mg/gHb) was not different from normal (2.9 +/- 0.4 mg/gHb). However there was a highly significant decrease in all forms of oedematous malnutrition, kwashiorkor (1.5 +/- 0.4 mg/gHb) and marasmic kwashiorkor (1.7 +/- 0.7 mg/gHb). There was no relationship between wasting or stunting and blood GSH.

Urea kinetics: effect of severely restricted dietary intakes on urea hydrolysis.

Urea kinetics (urea-N production-P, excretion-E, hydrolysis-H, recycling-R and retention-S) were measured in 7 healthy adults consuming a standard diet compared with 4 fasted for 24 and/or 96 h, using primed/intermittent doses of [(15)N (15)N]-urea and mass spectrometry. Standard values were P = 196, E = 132, H = 65, R = 13 and S = 51, mgN/kg/day. After 24 h fasting all urea kinetics were reduced, and P and H were significantly reduced compared with the standard diet (p < 0.01 and < 0.05 respectively). After 96 h fasting, urea kinetics returned to standard values (P = 187, E = 136, H = 51, R =13 and S = 38, mgN/kg/day), although nitrogen intake was significantly lower (p < 0.001). Relative urea excretion (E/P) was 67%, standard diet, and 75% after fasting. Consequently H/P was slightly reduced from 33 to 25%. S/P was 26%, standard diet, 15% after 24 h and 20% after 96 h fasting, suggesting increased urea-N retention with prolonged fasting. These results imply a slight temporary shift towards increased nitrogen excretion at 24 h and subsequent return to the kinetics of the fed state after 96 h. Urea-N retention increases with prolonged fasting.