Biomedical subjects

M A Hanson

Publications and source records attributed to M A Hanson.

At least 19 recordsLinked to original sources

PubMed2006

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.

Amino Acid Transport System A↗

PubMed2006

Changing times: the evolution of puberty.

An evolutionary and life history perspective is used to consider the evolution of puberty. The age of menarche would have evolved by the Neolithic to be matched to social maturity. It is suggested that in developed countries menarche is now returning to a similar age as in the Neolithic as infection and undernutrition, features of post-Neolithic society, have reduced impact. But recently the psychosocial expectations on adolescents in western societies have changed and social maturity now significantly follows menarche. The implications of the developing mismatch between the ages of biological puberty and social maturation are discussed. Evolutionary arguments are presented to explain the unique pubertal growth spurt of humans. Moreover, a life history perspective can reconcile the apparently conflicting observations that both poor fetal growth and better childhood nutrition are associated with earlier menarche.

Age Factors↗

PubMed2006

The consequences of being born small - an adaptive perspective.

Absolute definitions of fetal growth are being replaced by definitions that focus on an optimal life-course trajectory. The fetus makes responses to its environment that are determined by the maternal macro-environment, health and physiology. The processes of maternal constraint create significant variations within the normal range of maternal environments and function, and in the fetal environment, which are reflected in different patterns of growth. Deficient nutrient provision may induce immediate adaptation in the form of fetal growth impairment, but will also induce adaptive responses that have evolved for predictive advantage; that is, for a later phase of the life cycle. This latter class of response, probably mediated by epigenetic processes, explains many outcomes of a less-than-optimal pregnancy, including impaired growth, increased visceral obesity, impaired cognitive development, advanced maturation and a greater risk of metabolic and related disease in later life. While these adaptive processes evolved and were appropriate in the environments of prehistory, they are increasingly mismatched with modern environments. Such considerations suggest different approaches to intervention and prevention in population-specific contexts.

Adaptation, Physiological↗

PubMed2005

The effect of low protein diet in pregnancy on the development of brain metabolism in rat offspring.

The effect of maternal low protein diet in pregnancy on the function of offspring cerebral cytochrome c oxidase (CcO) was investigated in vitro immediately before and after birth, using fetal and neonatal rat pup forebrain tissue. Pregnant rat dams were fed either a control (C, 18% casein n = 22) or low protein (LP, 9% casein n = 14) diet. Cerebral tissues were harvested from pups the day before (E21) and after (P1) birth. A Clarke electrode chamber was used to determine O(2) consumption in brain tissue homogenate, under baseline conditions with and without the mitochondrial electron transport chain inhibitor myxothiazol and in the presence of incremental doses of the electron donor N',N',N',N'-tetramethyl-p-phenylenediamide (TMPD) with myxothiazol. Maximal stimulated CcO activity was less in LP versus C pups at both E21 (P < 0.001) and P1 (P < 0.05). At E21 only, sensitivity to electron flux (pEC(50)) was greater (P < 0.001) in LP compared to C offspring. In addition, was reduced and pEC(50) was greater after birth (i.e. P1 versus E21) in C (P < 0.001) but not in LP pups. This is the first report of the effects of maternal dietary imbalance in pregnancy on offspring cerebral metabolic function. The effects may form part of a developmental adaptive response to reduce energy consumption and promote perinatal survival, or to confer advantage in a postnatal environment predicted to be nutritionally poor.

Adaptation, Physiological↗

PubMed2004

Raised dietary n-6 polyunsaturated fatty acid intake increases 2-series prostaglandin production during labour in the ewe.

Preterm labour is the major cause of perinatal morbidity and mortality in humans. The incidence is around 10% and the causes are often unknown. Consumption of dietary n-6 polyunsaturated fatty acids (PUFAs) in western societies is increasing. These are metabolized to arachidonic acid, the precursor for 2-series prostaglandins (PGs), major signalling molecules during labour. This study investigated the effect of dietary supplementation with linoleic acid (LA, 18: 2, n-6) on parturition. Ewes were fed a control or LA-supplemented diet from 100 days gestation. Labour was induced using a standardized glucocorticoid challenge (dexamethasone, Dex) to the fetus, starting on day 139. Electromyographic (EMG) activity and fetal and maternal circulating PG concentrations were monitored. One third of LA-fed ewes delivered early (pre-Dex) although basal uterine EMG activity preceding Dex was higher in control ewes (P < 0.05). A steep increase in EMG activity occurred 18-38 h after the start of Dex infusion. Twice basal EMG activity (defined as established labour) occurred on average 7 h earlier in the LA-supplemented ewes (P < 0.05). The basal concentrations of maternal and fetal PGFM and fetal PGE(2) were approximately doubled in LA-supplemented ewes before the start of Dex infusion (P < 0.01). The rise in fetal PGE(2) and maternal oestradiol concentrations post-Dex occurred earlier in the LA-supplemented ewes. All PG measurements remained significantly higher in the LA-supplemented ewes during labour onset. This study suggests that consumption of a high LA diet in late pregnancy can enhance placental PG production and may thus increase the risk of preterm labour.

Animals↗

PubMed2004

A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring.

Epidemiological and animal studies suggest that diet-induced epigenetic modifications in early life can contribute to development of the metabolic syndrome in adulthood. We previously reported features of the metabolic syndrome in adult offspring of rats fed a diet rich in animal fat during pregnancy and suckling. We now report a study to compare the relative effects of high-fat feeding during 1) pregnancy and 2) the suckling period in the development of these disorders. As observed previously, 6-mo-old female offspring of fat-fed dams suckled by the same fat-fed dams (OHF) demonstrated raised blood pressure, despite being fed a balanced diet from weaning. Female offspring of fat-fed dams "cross fostered" to dams consuming a control diet during suckling (OHF/C) demonstrated raised blood pressure compared with controls (OC) [systolic blood pressure (SBP; mmHg) means +/- SE: OHF/C, 132.5 +/- 3.0, n = 6 vs. OC, 119.0 +/- 3.8, n = 7, P < 0.05]. Female offspring of controls cross fostered to dams consuming the fat diet (OC/HF) were also hypertensive [SBP (mmHg) 131.0 +/- 2.5 mmHg, n = 6 vs. OC, P < 0.05]. Endothelium-dependent relaxation (EDR) of male and female OHF and OHF/C mesenteric small arteries was similar and blunted compared with OC (P < 0.001). OC/HF arteries showed profoundly impaired EDR (OC/HF vs. OHF, P < 0.001). OHF/C and OC/HF demonstrated hyperinsulinemia and increased adiposity. Features of the metabolic syndrome in adult offspring of fat-fed rats can be acquired both antenatally and during suckling. However, exposure during pregnancy confers adaptive protection against endothelial dysfunction induced by maternal fat feeding during suckling.

Animals↗

PubMed2004

Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy.

We recently reported vascular dysfunction in adult offspring of rats fed a fat-rich (animal lard) diet in pregnancy. This study reports further characterization of constrictor and dilator function in mesenteric and caudal femoral arteries from 180-day-old offspring of dams fed the high fat diet (OHF). Endothelium-dependent relaxation in response to acetylcholine (10(-9)-10(-5)m) was impaired in mesenteric small arteries from male and female OHF compared with offspring of dams fed normal chow (males (maximum percentage relaxation): OHF 67.92 +/- 2.89, n= 8 versus control 92.08 +/- 2.19, n= 8, P < 0.01). Substantial relaxation in response to acetycholine in control mesenteric arteries remained after inhibition of nitric oxide synthase, soluble guanylate cyclase and cyclo-oxygenase but was blocked by 25 mm potassium. This component of relaxation, attributed to EDHF, was significantly reduced in OHF mesenteric arteries compared with controls. However, EDHF played a minor role in acetylcholine-induced relaxation in both control and OHF femoral caudal arteries (male and female). In these arteries, in contrast to mesenteric vessels, acetylcholine-induced relaxation was significantly enhanced in OHF but only in males (ACh (maximum percentage relaxation): OHF 58.40 +/- 4.39, n= 8 versus male controls 32.18 +/- 6.36, P < 0.05). This was attributable to enhanced nitric oxide-mediated relaxation. In conclusion, reduced endothelium-dependent relaxation in OHF mesenteric arteries is due to impaired EDHF-mediated relaxation. This defect was not apparent in femoral arteries in which EDHF has a less prominent role.

Acetylcholine↗

PubMed2004

Altered regional blood flow in the fetus: the origins of cardiovascular disease?

UNLABELLED: A fetal response to hypoxia and other adverse influences is to redistribute blood flow in order to "spare" the brain. This, however, is associated with reduced growth of the liver and kidneys. CONCLUSION: The long-term consequences of fetal redistribution of blood flow are unknown, but preliminary evidence suggests that there is an increased risk of coronary heart disease and hypertension in later life.

Chronic Disease↗

PubMed2003

Glycine rectifies vascular dysfunction induced by dietary protein imbalance during pregnancy.

Protein restriction in rat pregnancy programmes the development of elevated systolic blood pressure and vascular dysfunction in the offspring. A recent study has shown that hypertension is reversed by maternal glycine supplementation. Whether this protective effect is exerted directly on the embryo and fetus, or indirectly via effects on the mother, is unknown although we have previously shown abnormalities in the maternal vasculature. We tested the hypothesis that dietary glycine repletion would reverse endothelial dysfunction in protein-restricted pregnant rat dams using wire myography. Impaired acetylcholine- (P < 0.01) and isoprenaline-induced (P < 0.05) vasodilatation in isolated mesenteric arteries (MA) from protein-restricted pregnant dams was accompanied by reduced vascular nitric oxide (NO) release (P < 0.05). Dietary glycine supplementation reversed vascular dysfunction in MA (P < 0.05) and improved NO release thus potentially protecting the maternal circulation. The impaired NO release in the MA of low protein diet dams was not accompanied by reduced eNOS mRNA expression, suggesting that eNOS activity was altered. Protein restriction did not alter the vascular function of a conduit artery, the thoracic aorta. These results provide evidence that adequate provision of glycine, a conditionally essential amino acid in pregnancy, may play a role in the vascular adaptations to pregnancy, protecting the fetus from abnormal programming of the cardiovascular system.

Animals↗

PubMed2003

Mechanisms underlying the programming of small artery dysfunction: review of the model using low protein diet in pregnancy in the rat.

Human and animal studies have shown that unbalanced maternal nutrition is associated with the development of cardiovascular and metabolic disease in adulthood. In the Southampton maternal low protein model (SMLP), protein deprivation (50%) throughout pregnancy in rats leads to elevated blood pressure in adult offspring. Impaired peripheral arterial function may contribute to the cardiovascular dysfunction observed in these offspring. This review discusses the impact of such a dietary insult on the vascular function of resistance arteries from pregnant rats (pF(o)), their offspring (F(1)), the pregnant offspring (pF(1)) and the second generation (F(2)). At each stage, disturbances in endothelium-dependent relaxation were observed, implicating changes in endothelial nitric oxide (NO)-guanylate cyclase (GC) signalling pathway in the vascular adaptations to pregnancy and the programmed effects on offspring.

Animals↗

PubMed2003

Uterine artery function in pregnant rats fed a diet supplemented with animal lard.

We hypothesised that maternal uterine artery vascular dysfunction could contribute to cardiovascular dysfunction in offspring of rats fed a diet rich in fat. Sprague-Dawley rats were fed for 10 days prior to pregnancy and throughout gestation either: (a) a control breeding diet, or (b) the same diet supplemented with 20 % w/w lard, vitamins, essential micronutrients and protein to control values. At 20 days gestation vascular function was assessed in uterine arteries and third-order mesenteric arteries. Vascular reactivity in response to application of potassium, noradrenaline, the thromboxane analogue U46619, acetylcholine and nitric oxide was assessed. Maternal plasma concentrations of factors likely to contribute to endothelial dysfunction were measured. Maximum acetylcholine-induced relaxation was impaired in the mesenteric arteries of the lard-fed dams (max % relaxation: lard-fed, 69.7 +/- 6.48; control, 85.37 +/- 2.69, P = 0.03). Uterine artery vascular function was similar in the two groups (max % acetylcholine-induced relaxation: lard-fed, 73.7 +/- 4.01; control, 77.5 +/- 4.72, P = 0.98). Concentrations of plasma lipids, 8-epi-PGF(2alpha) and leptin were normal, whereas insulin and corticosterone concentrations were raised in the lard-fed group (insulin (ng ml(-1)): lard-fed, 8.04 +/- 0.47; control, 1.35 +/- 0.37, P < 0.0001; corticosterone (ng ml(-1)): lard-fed, 1164.0 +/- 170.9; control, 541.9 +/- 96.3, P = 0.005). Fetal and placental weights were reduced in lard-fed dams (fetus (g): lard-fed, 4.27 +/- 0.38; control, 2.96 +/- 0.40, P = 0.025; placenta (g): lard-fed, 0.72 +/- 0.06; control, 0.57 +/- 0.04, P = 0.05). Cardiovascular dysfunction in offspring is not associated with reduced uterine artery endothelial function but is associated with activation of the hypothalamic-pituitary-adrenal axis, hyperinsulinaemia and fetoplacental growth retardation.

Animal Feed↗

PubMed2001

Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring.

We have investigated the effects of moderate global undernutrition during gestation in the rat on the blood pressure of male and female offspring, and on the development of systemic vascular function. Pregnant Wistar rats were nutritionally restricted (R) by feeding with 70% of the normal gestation-matched dietary intake from 0 to 18 days gestation.R offspring were growth retarded at birth but of similar weight to controls (C) at 20 days. Systolic and/or diastolic and mean arterial blood pressures, measured directly by femoral artery catheter, were elevated from 60 days onward in male R offspring (mean arterial pressure: day 60, P < 0.01; day 100, P < 0.05; day 200, P < 0.005, R vs. C), and from 100 days onward in female R offspring (mean arterial pressure day 100 and day 200, P < 0.05; R vs. C). Maximal constriction to phenylephrine (PE) (P < 0.05) and to noradrenaline (NA) (P < 0.05) was reduced in isolated femoral arteries of day 20 R pups. These differences did not persist into adulthood. In male adult R offspring (200 days), maximal vasoconstriction to the thromboxane A2 mimetic, U46619 (P < 0.05) and sensitivity to potassium (P < 0.01) were enhanced. Moderate maternal undernutrition in rat gestation adversely affects cardiovascular function in the offspring. These abnormalities increase with age and are more pronounced in males.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Undernutrition during the first half of gestation increases the predominance of fetal tissue in late-gestation ovine placentomes.

OBJECTIVE: To investigate, in sheep, the effects of maternal undernutrition during the first half of pregnancy on placental growth and development and fetal growth. STUDY DESIGN: Six ewes (R) were subjected to a 15% reduction in nutrient intake for the first 70 days of gestation and thereafter received the recommended daily intake. Another group of six ewes (C) received the recommended daily intake throughout pregnancy. At 130 days gestation the ewes were killed and morphological and morphometrical measurements were carried out on the placenta and fetus. RESULTS: Undernutrition resulted in a significant alteration in placental morphology, which was seen as increased growth of the fetal side of the placenta in R animals. However, fetal size in late gestation was not affected by the undernutrition, suggesting that placental adaptation was successful in maintaining fetal growth. CONCLUSION: Placental adaptations, including changes in gross morphology, may preserve fetal growth if maternal undernutrition is not severe. The mechanisms remain to be elucidated.

Animals↗

PubMed2001

Online motion-gated dynamic three-dimensional echocardiography in the fetus--preliminary results.

The aim of this study was to visualise the fetal heart in dynamic three dimensions (4-D) during an ultrasound (US) scan (online), rather than after (offline). With special pairing and sequential setting to minimise interference between two scanners, umbilical arterial Doppler waveforms (UADWs) from one scanner were used as an online motion gating source to trigger simultaneous 3-D cardiac structural data acquisition by another. Of 25 data sets from 10 fetuses, 18 were acquired in 15 to 30 s per set with > or = 50% Doppler waveforms efficiently converted to triggering signals. Of 15 valid 4-D data sets, 10 were reconstructed in 2 to 20 min, compared to over 2 h previously reported (mainly for offline gating). Fine structures (including chordae tendinae and trabecular muscles) were depicted in six sets. The main problems in degrading 4-D images were extensive shadowing (6) from bony structures during rigid mechanical scanning, and random motion artefacts (6) from prolonged setting-up time with a complex combination of several systems. Integration of these systems is, therefore, recommended.

Artifacts↗

PubMed2001

Conversion of umbilical arterial Doppler waveforms to cardiac cycle triggering signals: a preparatory study for online motion-gated three-dimensional fetal echocardiography.

To remove motion artefacts, a device was built to convert "noisy" umbilical arterial Doppler waveforms (UADWs) from an ultrasound (US) system into sharp ECG R-wave-like cardiac cycle triggering signals (CCTSs). These CCTSs were then used to gate a simultaneous (online) 3-D acquisition of sectional fetal echocardiograms from another US system. To test the conversion performance, a study was carried out in sheep fetal twins. Pulmonary arterial flow waveforms (PAFWs) from implanted probes were traced, in the meantime, to determine the reference cardiac cycle. Interference caused by running the two nonsynchronised US systems was controlled to three degrees (not-noticeable, moderate, and severe), together with high (> or = 40 cm/s) and low (< 40) flow velocities on UADWs. The conversion efficiency, assessed by the percentage of UADWs converted into CCTSs, was in the range of 83% to 100% for not-noticeable and moderate interference, and 0% to 71% for severe interference. The triggering accuracy, assessed by [(time lag mean between the onsets of PAFWs and corresponding CCTSs) -- (its 99% confidence level)] / the mean, was 90% to 96% for the not-noticeable interference high- and low-flow groups and for the moderate interference high-flow group; 19% to 93% for the moderate interference low-flow group; and from not obtainable up to 90% for the severe interference groups. The results show that UADWs can be used as a satisfactory online motion-gating source even in the presence of moderate interference. The major problems are from severe interference or moderate interference with low-flow velocity, which can be minimised/eliminated by the integration of the individual systems involved.

Animals↗

PubMed2001

An examination of the comparative reliability, validity, and accuracy of performance ratings made using computerized adaptive rating scales.

This laboratory research compared the reliability, validity, and accuracy of a computerized adaptive rating scale (CARS) format and 2 relatively common and representative rating formats. The CARS is a paired-comparison rating task that uses adaptive testing principles to present pairs of scaled behavioral statements to the rater to iteratively estimate a ratee's effectiveness on 3 dimensions of contextual performance. Videotaped vignettes of 6 office workers were prepared, depicting prescripted levels of contextual performance, and 112 subjects rated these vignettes using the CARS format and one or the other competing format. Results showed 23%-37% lower standard errors of measurement for the CARS format. In addition, validity was significantly higher for the CARS format (d = .18), and Cronbach's accuracy coefficients showed significantly higher accuracy, with a median effect size of .08. The discussion focuses on possible reasons for the results.

Adult↗

PubMed2001

Maternal undernutrition in early gestation alters molecular regulation of the hypothalamic-pituitary-adrenal axis in the ovine fetus.

We have demonstrated previously that plasma adrenocorticotropin hormone and cortisol responses to exogenous and endogenous stimuli are reduced in fetuses of mildly undernourished ewes. In the present study, we examined the molecular regulation of fetal hypothalamic-pituitary-adrenal (HPA) axis function at 127-130 days gestation (dGA) following 15% reduction in maternal nutrition between 0 and 70 dGA. Using in situ hybridization, we found that corticotropin releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN) was lower in fetuses from nutrient restricted ewes than in controls. Restricted fetuses also had greater levels of mRNA encoding preproenkephalin (PENK) and magnocellular arginine vasopressin (AVP) in the PVN. Expression of oxytocin mRNA and parvocellular AVP mRNA in the PVN and pro-opiomelanocortin mRNA in the pituitary were unchanged. Glucocorticoid receptor mRNA expression was unaltered at the PVN, but was reduced (> 40%) in the anterior pituitary of restricted fetuses. Northern blot analysis demonstrated that levels of adrenal P450scc mRNA and P450(C17) mRNA were not different between the groups. We conclude that the reduction in HPA function reported previously is mediated, at least in part, by a decrease in expression of CRH mRNA and increase in PENK mRNA in the PVN.

Animals↗

PubMed2001

Animal models and programming of the metabolic syndrome.

The purpose of this review is to consider how current animal models of fetal programming contribute to knowledge of the metabolic syndrome in adult humans. Low birth weight infants have an increased risk of developing cardiovascular and coronary heart disease, hypertension, diabetes and stroke in adulthood. A number of animal studies confirm the association between events during fetal life and subsequent adult disease. This review considers how these have contributed to our understanding of this relationship, and how they may help to uncover the underlying mechanisms. The importance of dietary, pharmacological, genetic and surgical models is assessed, and their usefulness in the prevention of human disease evaluated. Although progress has been made, further investigations using animals are needed to clarify the mechanisms involved in the programming of adult disease. Once these processes are understood, it may be possible to identify and protect at-risk individuals.

Animals↗