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Biomedical subjects

A A Jackson

Publications and source records attributed to A A Jackson.

At least 37 records · Page 2Linked to original sources
PubMed2001

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.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Relationship of maternal protein turnover and lean body mass during pregnancy and birth length.

Epidemiological evidence shows that small size at birth is associated with an increased risk of developing cardiovascular and metabolic disease in adult life. We have examined the relationships between size at birth and maternal body composition and protein turnover in normal pregnant women. A group of 27 multiparous Caucasian women with singleton pregnancies were studied at around 18 and 28 weeks' gestation. Body composition was determined by anthropometry, and whole-body protein turnover was estimated by using a single oral dose of [(15)N]glycine and the end-product method. The baby's weight and length were measured within 48 h of birth. Mothers with a greater lean body mass had higher rates of protein turnover at 18 weeks' gestation. This association was largely accounted for by differences in the mother's visceral, rather than muscle, mass. Mothers who had higher protein turnover at 18 weeks' gestation had babies that were longer at birth. After adjustment for the duration of gestation and the baby's sex, 26% of the variation in length at birth was accounted for by maternal protein synthesis at 18 weeks' gestation. Maternal protein intake was not associated with the baby's birth length. Thus the mother's ability to nourish her fetus is influenced by her body composition and her rate of protein turnover. Dietary intake does not adequately characterize this ability.

Adult↗
PubMed2001

Gastrointestinal handling and metabolic disposal of 13C-labelled tripalmitin during rehabilitation from childhood malnutrition.

We investigated the gastrointestinal handling and post-absorptive metabolic handling of [1,1,1-13C]tripalmitin and [1-13C]glycocholate during recovery from severe childhood malnutrition. Eight children were studied on three occasions: at admission (phase 1), during rapid catch-up growth (phase 2) and when weight-for-height had reached 90 % of the reference (phase 3). Breath samples were obtained over a 24 h period and stools were collected over 3 d following the administration of each tracer. At admission, the lipid content of stool expressed as a percentage of ingested lipid was 6 (range 0.7-28.9) but less variation was shown between children at phase 2 (3.3 (range 0.9-4.1)) and phase 3 (1.4 (range 0.4-2.5)). The excretion of 13C in stool varied markedly between children at admission (11.1 (sd 5.4) % administered dose) and during rehabilitation (phase 2, 15.4 (sd 16.5) % administered dose; phase 3, 6.2 (sd 10.2) % administered dose). About 5 % of the absorbed label was recovered on breath at each stage (% absorbed dose; phase 1, 5.1 (sd 6.0); phase 2, 5.2 (sd 3.1); phase 3, 6.4 (sd 6.6)). None of the children exhibited significant bile salt malabsorption as a consequence of small intestinal overgrowth. Of the 13C measured in stool, more label was recovered in fatty acids than triacylglycerols during each of the three phases and this was interpreted to reflect a failure to absorb the products of digestion. The results show that not all the children had problems associated with the digestion and absorption of 13C-labelled tripalmitin in severe malnutrition and during recovery, which was not reflected in gross lipid balance across the gastrointestinal tract. Absorbed lipid was more likely to be deposited as adipose tissue than to satisfy the immediate needs for energy.

Adolescent↗
PubMed2001

Effect of pregnancy on plasma lipid concentration in Trinidadian women. Result of a pilot study.

In Trinidad and Tobago, cardiovascular disease and Type 2 diabetes mellitus are important causes of morbidity and mortality, and birth weight is significantly less than reference standards. Lower birth weight is associated with increased risk of these diseases. Variation in birth weight is due, in part, to deposition of adipose tissue in the foetus during the last trimester at the same time that maternal plasma triacylglycerol (TAG) increases. We conducted a pilot cross-sectional analysis of maternal plasma lipid status and birth weight in healthy, non-pregnant, primigravida Trinidadian women. Non-pregnant and pregnant women, in their second and third trimesters, and at term, were recruited at random from an antenatal clinic. Adult and umbilical cord plasma TAG, non-esterified fatty acids (NEFA) and phosphatidylcholine (PC) concentrations were determined from gas chromatographic analysis of fatty acids. Maternal height, weight, skinfold thickness and infant birth weight were measured. The infants born to Afro-Trinidadian and Indo-Trinidadian women were of low to normal birth weight (medians 3.07 and 3.22 kg, respectively). At term, plasma TAG concentration was approximately two fold (p < 0.05) greater than for non-pregnant women. The increment between 30-34 weeks was 1.5 to 1.9 fold lower than reported in other populations. There was a strong relationship (r = 0.8771, p = 0.019) between maternal and cord plasma TAG and NEFA, but not PC concentrations. There was no significant relationship between maternal TAG concentration at term and birth weight. The result suggests an impaired ability to increase plasma TAG concentrations during late gestation.

Adult↗
PubMed2000

Nutrients, growth, and the development of programmed metabolic function.

For each individual, the genetic endowment at conception sets the limits on the capacity or metabolic function. The extent to which this capacity is achieved or constrained is determined by the environmental experience. The consequences of these experiences tend to be cumulative throughout life and express themselves phenotypically as achieved growth and body composition, hormonal status and the metabolic capacity for one or other function. At any time later in life the response to an environmental challenge, such as stress, infection or excess body weight is determined by an interaction amongst these factors. When the metabolic capacity to cope is exceeded, the limitation in function is exposed and expresses itself as overt disease. During early life and development the embryo, fetus and infant are relatively plastic in terms of metabolic function. The effect of any adverse environmental exposure is likely to be more marked than at later ages and the influence is more likely to exert a fundamental effect on the development of metabolic capacity. This has been characterised as "programming" and has come to be known as "the Barker hypothesis" or "the fetal origins hypothesis". Barker has shown that the size and shape of the infant at birth has considerable statistical power to predict the risk of chronic disease in later life. These relationships are graded and operate across a range of birth weight, which would generally be considered to be normal, and are not simply a feature of the extreme of growth retardation. The first evidence showed strong relations between birth weight and heart disease, the risk factors for heart disease, diabetes and hypertension, and the intermediary markers for heart disease, blood cholesterol and fibrinogen. Strong associations have also been found for bone disease, allergic disease and some aspects of brain function. In experimental studies in animals it is possible to reproduce all of the metabolic features predicted from this hypothesis by moderating the consumption of food, or its pattern during pregnancy, and determining metabolic behaviour in the offspring. It has been shown that aspects of maternal diet exert an influence on fetal growth, especially the dietary intake of carbohydrate, protein and some micronutrients. However, these relationships are less strong than might have been predicted, especially when compared with the associations which can be drawn with maternal shape, size and metabolic capacity. Maternal height, weight and body composition relate to the metabolic capacity of the mother and her ability to provide an environment in which the delivery of nutrients to the fetus is optimal. Current evidence suggests that the size of the mothers determines her ability to support protein synthesis, and that maternal protein synthesis, especially visceral protein synthesis, is very closely related to fetal growth and development. It is not clear the extent to which the effect of an adverse environment in utero can be reversed by improved conditions postnatally, but some care is needed in exploring this area, as the evidence suggests that "catch-up" growth imposes its own metabolic stress and may in itself exert a harmful effect.

Adaptation, Biological↗
PubMed2000

Whole body protein turnover can be measured non-invasively in women using the end product method with [15N]glycine to show changes with the menstrual cycle and pregnancy.

OBJECTIVES: To assess the effect of the menstrual cycle and pregnancy on whole body protein turnover. DESIGN AND SUBJECTS: Whole body protein turnover was determined using oral [15N]glycine in normal women from enrichment measured in urine at days 7 and 14 of the menstrual cycle and in pregnant women at 17-20 weeks and 30-32 weeks gestation. RESULTS: Nitrogen flux was 38.2 (5.8) mg N/kg/h using a single dose and 31.1+/-4.1 mg N/kg/h with prime-intermittent doses-the same as in men using the same methods. Nitrogen flux around the time of ovulation, 32.3 (8.2) mg N/kg/h, was greater than at day 7, 26.8 (3.0) mg N/kg/h (P<0.05). For women taking the contraceptive pill flux at day 7, 22.7 (0.2) mg N/kg/h, and day 14, 21.3 (2.1) mg N/kg/h, were similar, but were lower at day 14 than for women not taking the pill (P<0.05). Protein synthesis increased between mid and late pregnancy (1.7-2.0 g N/h; P=0.012), but not when expressed in relation to body weight CONCLUSIONS: Protein turnover can be measured reproducibly in women using a non-invasive method, provided care is taken to standardize the conditions, and especially the duration over which urine is collected. There is an increase around the time of ovulation when hormonal levels are at their highest and during pregnancy the results obtained are similar to those reported using [13C]leucine. SPONSORSHIP: University of Southampton and Medical Research Council.

Administration, Oral↗
PubMed1999

Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat.

Epidemiological evidence suggests that hypertension and coronary heart disease are programmed by exposure to a poor diet during intrauterine life. It has been proposed that the prenatal environment may exert an adverse effect on the development of the kidney and hence later control of blood pressure. These assertions are supported by animal experiments. In the rat, fetal exposure to a maternal low protein diet is associated with disproportionate patterns of fetal growth and later elevation of blood pressure. Pregnant female rats were fed control (18% casein) or low protein diets throughout pregnancy, or during specific periods. Nephron number was determined at day 20 gestation, full term and 4 weeks of age. Exposure to low protein throughout gestation, or in mid-late gestation increased total nephron number at day 20. By term nephron number was reduced, relative to controls, in rats that were undernourished between days 8-14 or 15-22 gestation. At 4 weeks postnatally rats exposed to low protein throughout fetal life had a reduced (13%) nephron complement and blood pressures 13 mmHg above control animals. Lower renal size and elevated blood pressure persisted to 19 weeks of age, at which time glomerular filtration rate was normal. The data are consistent with the hypothesis that maternal undernutrition may programme the renal nephron number and hence impact upon adult blood pressure and the development of renal disease.

Animals↗
PubMed1999

Limits of adaptation to high dietary protein intakes.

Ingested protein is made available to the body following digestion and absorption as amino acids and contributes to the body's demand for amino acids for protein synthesis and other metabolic pathways. As the pattern of amino acids required for metabolism is substantially different from that ingested, extensive metabolic interchange serves to improve the match. As a matter of course oxidation of amino acids contributes to satisfying the energy needs of the body. Amino acids in excess of immediate requirements follow degradative pathways and if the capacity of these pathways is exceeded adverse consequences ensue. In pathological states, such as inborn errors of metabolism, there is an obvious constraint on metabolic flow with serious sequelae. Pathways may be constrained to a lesser extent due to genetic polymorphisms, metabolic programming, limitation of cofactors or lack of associated substrates. Any of these can result in metabolic derangements, which do not manifest as overt disease, but limit normal function. There is the need to determine the dose response to increases in dietary protein and amino acid availability, using critical metabolic intermediates as outcome indices in order to clarify the upper limit of intake with which the body can cope under a range of physiological and pathological states.

Adaptation, Physiological↗
PubMed1999

Intrauterine programming of hypertension: the role of the renin-angiotensin system.

From experiments with prenatal undernutrition in the rat, it is clear that fetal exposure to glucocorticoids of maternal origin is a key first step in the programming of hypertension and perhaps coronary heart disease. The chain of events leading from glucocorticoid action in the fetal tissues to hypertension in adulthood involves the development of hypersensitivity to glucocorticoids in adult life (Scheme 1). This has the effect of activating the RAS through induction of key genes such as ACE, which, in turn, may increase sensitivity of the blood vessels to the actions of ANGII. Another consequence of prenatal undernutrition, which may or may not involve glucocorticoids, is the abnormal development of the kidney [35]. Impaired nephrogenesis must surely have an impact upon lifelong renal function and cardiovascular control. Progress has been made in demonstrating that hypertension can be prenatally programmed through maternal dietary manipulation and some of the putative mechanisms involved have been identified. The priorities in this field of research must now be to clarify the role of maternal diet as a programming stimulus in order to generate an effective series of public health guidelines for pregnant women. Although the identification of metabolic mechanisms might suggest possible pharmacological interventions in early life as a means of reducing cardiovascular risk in adult life [49], it will always be more desirable to optimize maternal diet.

Adult↗
PubMed1999

Dietary protein, growth and urea kinetics in severely malnourished children and during recovery.

The case mortality for severe malnutrition in childhood remains high, but established best approaches to treatment are not used in practice. The energy and protein content of the diet at different stages of treatment appears important, but remains controversial. The effect on growth, urea kinetics and the urinary excretion of 5-L-oxoproline was compared between a standard infant formula (HP group) provided in different quantities at each stage of treatment and a recommended dietary regimen, which differentiates the requirements of protein and energy during the acute phase of resuscitation (maintenance intake of energy and protein, relatively low protein to energy ratio, LP group) from those during the restoration of a weight deficit (energy and nutrient dense). The energy required to maintain weight was less in the HP than the LP group, but the HP group was not able to achieve as high an energy intake during repletion of wasting because of the high volume which would have had to be consumed. Compared to the LP group, in the HP group during catch-up growth there was significantly greater deposition of lean tissue and higher rates of urea production, hydrolysis and salvage of urea-nitrogen. These, together with higher rates of 5-L-oxoprolinuria, suggest a greater constraint of the formation of adequate amounts of nonessential amino acids, especially glycine, in the face of enhanced demands. Although more effective rehabilitation might be achieved using a standard formula, there is the need to determine the extent to which it might impose metabolic stress compared with the modified formulation.

Diet↗
PubMed1999

Long-term modification of the excretion of prostaglandin E(2) by fetal exposure to a maternal low protein diet in the rat.

Prenatal exposure to maternal undernutrition in both humans and animals is associated with long-term changes in the structure, physiological functions and metabolism of key tissues and organs. This phenomenon, termed programming, is implicated in the aetiology of cardiovascular disease. Using an established rat model of hypertension programmed by prenatal protein restriction, assessment was made of the long-term influence of maternal diet upon prostaglandin metabolism. Pregnant rats were fed isoenergetic diets containing 18% casein (control) or 9% casein (low protein) from conception until littering. The offspring of these pregnancies were studied at day 20 of gestation, full-term gestation and at 4, 7 or 12 weeks postnatal age. Prostaglandin E(2) concentrations in plasma were similar in control and low-protein diet-exposed rats at 4 weeks of age. Urinary prostaglandin E(2) excretion was, however, significantly increased by prenatal undernutrition in rats at both 4 and 12 weeks postnatal age. The principal enzyme of prostaglandin E(2) degradation, 15-hydroxyprostaglandin dehydrogenase (PGDH) exhibited significantly lower activity in the kidneys of 4-week-old rats exposed to a maternal low-protein diet. This effect was transient and absent by 12 weeks postnatal age. There was also some evidence of an altered developmental profile of PGDH activity in the lungs of low-protein diet-exposed rats. These data are consistent with the long-term programming effects of the maternal diet upon renal prostaglandin metabolism. In the rat, increased local prostaglandin E(2) concentrations associated with impaired degradation may contribute to increased renovascular resistance and hypertension.

Animals↗
PubMed1999

Metabolism of lactose-[13C]ureide and lactose-[15N,15N]ureide in normal adults consuming a diet marginally adequate in protein.

Oral lactose-ureide is resistant to human digestive enzymes, but is fermented by the colonic microflora. Nine normal adults consuming a diet which provided 36 g of protein/day were given oral doses of lactose-[(13)C]ureide and lactose-[(15)N,(15)N]ureide. The appearance on breath of (13)CO(2) derived from lactose-[(13)C]ureide was followed for 48 h. The fate of (15)N derived from lactose-[(15)N, (15)N]ureide was determined by measuring the recovery of (15)N in stools and urine in various forms. About 80% of the label given as lactose-[(13)C]ureide was recovered on the breath, and about 80% of label given as lactose-[(15)N,(15)N]ureide was not recovered in stool, indicating that 80% of the dose was completely fermented. At least 5% of the labelled urea was absorbed and excreted as the intact molecule. Of the (15)N derived from lactose-[(15)N, (15)N]ureide and available for further metabolic interaction, 67% was retained and 33% was excreted in urine. The time taken for [(15)N,(15)N]urea to appear in urine was similar for all subjects, but the appearance of either (13)CO(2) on the breath or [(15)N, (14)N]urea in urine varied. It is concluded that the hydrolysis of the sugar-urea bond may reflect oro-caecal transit time, but that other factors related to colonic bacterial metabolism determine the duration and extent of hydrolysis of urea by urease enzymes. Lactose-ureide can be used to probe the metabolic activity of the colonic microflora in normal individuals.

Adult↗
PubMed1999

Maternal pre-pregnancy weight and placental weight determine birth weight in normal Jamaican infants.

Birth weight is related to neonatal health and long-term risk of chronic disease. Since animal studies have shown that birth outcome is related to placental function, the present project was designed to explore the relationship between birth weight and placental growth and composition with maternal factors during pregnancy among normal term pregnancies in 51 primiparous and 40 multiparous women delivering at the University Hospital of the West Indies. Both groups were followed from 15 weeks of gestation to term. The primiparous group was generally younger than the multiparous (mean age 22 +/- 4 versus 31 +/- 5 yr). They were significantly lighter (55 +/- 8 versus 61 +/- 9 kg) with a lower body mass index (21 +/- 3 versus 23 +/- 4 kg/m2) during early pregnancy, but gained more weight during pregnancy, 11 kg compared with 8 kg, respectively. The duration of pregnancy was similar for both groups. Although the size of the placenta was not significantly different between the two groups, the mean weight of the multiparous placentae was more than that of the primiparous placentae. Also, for all mothers both placental weight and initial maternal weight related directly to birth weight. Placental non collagen protein (NCP), sodium and potassium contents were significantly higher for multiparous women and were related to birth weight. The primiparous group had babies who were significantly lighter, 3.03 kg compared with 3.36 kg, for the multiparous and this could be attributed to differences in placental function and maternal weight. When account was taken of the difference in maternal weight at the start of pregnancy and the difference in placental weight, parity no longer explained any of the differences in birth weight. It is concluded that maternal body weight at the time of becoming pregnant and the early development of the placenta determine the efficiency with which nutrients might be delivered to the foetus and hence foetal growth. The difference in birth weight between primiparous and multiparous women can be explained by the differences in maternal weight at the time of becoming pregnant.

Adult↗
PubMed1998

Accurate separation of biliary lipid aggregates requires the correct intermixed micellar/intervesicular bile salt concentration.

The intermixed micellar/intervesicular bile salt (BS) concentration (IMC), composed of BS monomers and simple micelles, is in dynamic equilibrium with mixed micelles and vesicles. Accurate separation of biliary lipid aggregates is believed to depend on accurately measuring the IMC. Using centrifugal ultrafiltration, we measured the IMC of cholesterol-supersaturated model biles that were physiologically composed. Gel chromatography was performed using eluants containing the following: 1) the IMC; 2) the same BS composition as the IMC but higher or lower BS concentrations; 3) the same BS concentration as the IMC, but with more hydrophilic or hydrophobic BS; and 4) 10 mmol/L cholate. Compared with an eluant containing the same BS composition as the IMC, an eluant containing the same relative BS composition but 75% of the IMC increased the proportion of cholesterol in vesicles and decreased the vesicular cholesterol/egg yolk phosphatidylcholine (EYPC) ratio. In contrast, an eluant containing 150% of the IMC entirely transformed vesicles to micelles. Eluants containing slightly more hydrophobic or more hydrophilic BS eliminated or increased vesicular cholesterol content, respectively. An eluant of 10 mmol/L cholate overestimated vesicular cholesterol and in concentrated biles reproducibly produced an incompletely separated intermediate peak, possibly because of re-equilibration between mixed micelles and vesicles. Further, in concentrated biles, fractions eluting at volumes corresponding to mixed micelles were visibly turbid, irrespective of the eluant used. The correct IMC allows accurate separation of biliary lipid aggregates, but differences in BS concentration or composition substantially alter the vesicular percentage of cholesterol as well as the cholesterol/EYPC ratio. Elution with 10 mmol/L cholate may introduce artifactual gel-filtration peaks and inadequate separation of particles with widely differing molecular weights, both of which have confused previous analyses of biliary lipid aggregates.

Bile↗
PubMed1998

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.

Animals↗
PubMed1998

Infants in Trinidad excrete more 5-L-oxoproline (L-pyroglutamic acid) in urine than infants in England: an environmental not ethnic difference.

The demand for glycine to satisfy normal growth during early life is considerable and most has to be made endogenously. The extent to which adequate glycine is available can be assessed by measuring the urinary excretion of 5-L-oxoproline. The excretion of 5-L-oxoproline at 6 weeks of age for infants in Trinidad of African, Indian or mixed parentage (398 mumol/mmol creatinine) was significantly greater than for infants born in England of Caucasian parentage (194 mumol/mmol creatinine). There was no relationship between 5-L-oxoproline excretion and either sex or pattern of feeding. There were significant inverse relationships between 5-L-oxoproline/creatinine and birth weight, and head circumference either at birth or 6 weeks of age, suggesting that limited availability of glycine is associated with poorer growth before and after birth. For a group of infants born in England of Indian parentage, excretion of 5-L-oxoproline (155 mumol/mmol creatinine) was not different to infants of Caucasian parentage, but significantly less than infants born in Trinidad. The demonstration that 5-L-oxoproline/creatinine was similar in infants born in England, regardless of parentage, shows that the differences between England and Trinidad are related to environment and are unlikely to be accounted for by genetic differences or ethnicity.

Africa↗