Anne Jaquiery

Fetal growth restriction (FGR) is associated with compromised metabolic function throughout adulthood. Here, we explored the long-term effects of fetal IGF-I therapy on the adult pancreas and skeletal muscle. This is the first study demonstrating that IGF-I therapy of FGR has sex-specific long-term effects at both the tissue and molecular level on metabolically active tissues in adult sheep.

ABSTRACT Triplet lambs have reduced survival and most deaths occur due to starvation and exposure, but there are a few simple and safe interventions. We hypothesised that buccal dextrose gel would increase blood glucose concentration, vigour, survival and early feeding in less vigorous triplet lambs. Triplet lambs meeting criteria for decreased vigour were randomised to 40% dextrose or placebo gel 1 mL/kg via the buccal mucosa at 1 hour of age. Primary outcome was survival at 3 hours. An additional study exploring the effect of gel on interstitial glucose concentrations was assessed by continuous glucose monitoring in twin lambs. Lambs randomised to dextrose gel did not have higher blood glucose concentrations or better survival than those randomised to placebo. Low temperature at 1 hour after birth, rather than birthweight or blood glucose concentrations, was associated with decreased survival. Interventions to address hypothermia rather than hypoglycaemia may be most effective in improving survival in less vigorous triplet lambs.

Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15–20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7–10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P ...

Fetal growth restriction (FGR) is associated with compromised growth and metabolic function throughout life. Intrauterine therapy of FGR with intra-amniotic insulin-like growth factor-1 (IGF1) enhances fetal growth and alters perinatal metabolism and growth in a sex-specific manner, but the adult effects are unknown. We investigated the effects of intra-amniotic IGF1 treatment of FGR on adult growth and body composition, adrenergic sensitivity, and glucose-insulin axis regulation. Placental embolization-induced FGR was treated with four weekly doses of 360 µg intra-amniotic IGF1 (FGRI) or saline (FGRS). Offspring were raised to adulthood (18 mo: FGRI, n = 12 females, 12 males; FGRS, n = 13 females, 10 males) alongside offspring from unembolized and untreated sheep (CON; n = 12 females, 21 males). FGRI females had increased relative lean mass compared with CON but not FGRS ( P < 0.05; 70.6 ± 8.2% vs. 61.4 ± 8.2% vs. 67.6 ± 8.2%), decreased abdominal adipose compared with CON and F...

Antenatal exogenous glucocorticoids (ANG) are standard management for women at risk of preterm birth but are reputed to impair glucose tolerance in preterm offspring. We compared lambs born preterm (137 days gestation) following labour induced with exogenous glucocorticoids (G-Prem, glucocorticoid-induced preterm group), or with a progesterone synthesis inhibitor (NG-Prem, non-glucocorticoid-induced preterm group), with term-born lambs (Term; 149 days). We assessed glucose tolerance, insulin secretion and sensitivity at 4 and 10 months n = 11–14/group) and pancreatic and hepatic gene and protein expression at 4 weeks post-term (4 weeks; n = 6/group) and 12 months (12 months; n = 12–13/group). NG-Prem had higher plasma glucose concentrations than G-Prem, but not Term, at 4 months (Mean[SEM] mM: NG-Prem = 4.1[0.1]; G-Prem = 3.4[0.1]; Term = 3.7[0.1]; p = 0.003) and 10 months (NG-Prem = 3.9[0.1]; G-Prem = 3.5[0.1]; Term = 3.7[0.1]; p = 0.01). Insulin sensitivity decreased from 4 to 10 ...

To evaluate the costs of using dextrose gel as a primary treatment for neonatal hypoglycemia in the first 48 hours after birth compared with standard care. We used a decision tree to model overall costs, including those specific to hypoglycemia monitoring and treatment and those related to the infant's length of stay in the postnatal ward or neonatal intensive care unit, comparing the use of dextrose gel for treatment of neonatal hypoglycemia with placebo, using data from the Sugar Babies randomized trial. Sensitivity analyses assessed the impact of dextrose gel cost, neonatal intensive care cost, cesarean delivery rate, and costs of glucose monitoring. In the primary analysis, treating neonatal hypoglycemia using dextrose gel had an overall cost of NZ$6863.81 and standard care (placebo) cost NZ$8178.25; a saving of NZ$1314.44 per infant treated. Sensitivity analyses showed that dextrose gel remained cost saving with wide variations in dextrose gel costs, neonatal intensive care...

Twins are often born small and early and have increased risk of obesity and diabetes later in life. Twin conception in sheep, regardless of whether the pregnancy continues as twins or is reduced to singleton in early gestation, alters offspring growth trajectory and body composition in young adulthood. We hypothesized that twin conception would result in insulin resistance in adulthood, with insulin-resistant adipose tissue and skeletal muscle phenotypes. At 3 years of age, body weight was not different among singletons, twins, and reductions; females weighed less than males. Singletons were leaner than reductions, with twins intermediate. Twins and reductions had decreased insulin sensitivity compared with singletons (singletons: mean [standard error of the mean]: 4.75 [0.4], twins: 3.34 [0.3], reductions: 3.67 [0.2] mg·I μU(-1)·kg(-1)·min(-1), P < .01). There were no group differences in adipocyte size, adipose tissue, or circulating tumor necrosis factor α, monocyte chemoattra...

The perinatal environment has a major influence on long-term health and disease risk. Preterm birth alters early-life environment and is associated with altered metabolic function in adulthood. Whether preterm birth per se or the early nutritional interventions used to support growth in preterm infants underpins this association is unknown. Lambs born preterm, following dexamethasone induction of labour, or spontaneously at term were randomised to receive nutrient supplementation, analogous to the milk fortifier used clinically or water as a control for the first 2 weeks after birth. Thereafter, nutrition was not different between groups. Growth was monitored, and the glucose-insulin axis function was assessed in juvenile (4 months) and adult life (14 months). Early nutrition influenced adult metabolic function and body composition to a greater extent than preterm birth. In supplemented females, arginine-stimulated insulin secretion was increased in preterm but reduced in term-born ...

The nutritional plane and composition during fetal life can impact upon growth and epigenetic regulation of genes affecting pancreatic β-cell development and function. However, it is not clear whether β-cell development can be altered by nutritional factors or growth rate after birth. We therefore investigated the effect of neonatal nutritional supplements on growth, glucose tolerance and pancreatic development in lambs. Newborn lambs were randomised to daily nutritional supplements, calculated to increase macronutrient intake to a similar degree as human breast milk fortifier, or an equivalent volume of water, for two weeks while continuing to suckle ewe milk. Intravenous glucose tolerance test (IVGTT) was performed at 4 months of age, and pancreata collected for molecular analysis. Supplemented lambs had slower weight gain than Controls. In supplemented lambs, insulin response to IVGTT was increased in males but decreased in females, compared to same sex controls, and was unrelate...

Periconceptional undernutrition (UN) in sheep accelerates fetal hypothalamic-pituitary-adrenal (HPA) axis activation, resulting in preterm birth. In contrast, twin conception suppresses fetal HPA function and delays prepartum HPA activation. We hypothesized that these dissimilar effects on fetal HPA activity result from different influences of maternal glucocorticoid (GC) on maturation of the fetal HPA axis, mediated via different activities of placental 11beta-hydroxysteroid dehydrogenase (11betaHSD) isozymes. We examined the effects of twinning and maternal periconceptional UN from 60 days before until 30 days after mating on the ontogeny of placental 11betaHSD-1 and -2 enzyme activities. At day 85 of gestation, placental 11betaHSD-2 activity was lower in UN than in normally nourished (N) fetuses (P < .05) and was higher in twins than in singletons (P < .05). Furthermore, placental 11betaHSD-1 activity was not different between nutritional groups but was higher in twins than in singletons (P = .01). At day 85, fetal plasma cortisol (P < .001) and cortisone (P < .001) concentrations were lower in UN than in N fetuses, but the cortisol to cortisone ratio was higher in UN than in N fetuses (P = .01). There was no effect of fetus number on plasma cortisol or cortisone concentrations or on the ratio of cortisol to cortisone at day 85. Therefore, periconceptional UN and twinning may result in the alterations of placental 11betaHSD isozyme activities at particular times during gestation. Changes in these activities during critical periods of fetal development could affect transplacental transfer or placental generation of GCs that reach the fetus, potentially influencing the timing of activation of the fetal HPA axis, fetal maturation, and hence the development and health later in life.

To undertake population pharmacokinetic modeling and to determine the safety and efficacy of once daily (OD) gentamicin dosing in children with severe urinary tract infections (UTI). An open, randomized, controlled trial comparing OD with three times daily (TD) gentamicin dosing in hospitalized children ages 1 month to 12 years with UTI. Daily doses (milligrams per kg per day) of gentamicin in both groups were 7.5 (<5 years old), 6.0 (5 to 10 years old) and 4.5 (>10 years old). There were 179 children enrolled (90 OD, 89 TD). Baseline clinical characteristics and pathogens were similar, except that circulatory compromise and renal cortical scintigraphic defects were more common in the OD group. Median gentamicin treatment durations were 3.0 (OD) and 2.7 (TD) days. Mean peak gentamicin concentrations were 17.3 (OD) vs. 6.4 (TD) mg/l; 99% of peak concentrations were >7 mg/l in the OD group whereas 16% of peak concentrations were <5 mg/l in the TD group. Mean trough concentrations were 0.35 (OD) vs. 0.55 (TD) mg/l. In the OD group 4% of trough concentrations were > or = 2 mg/l, whereas in the TD group only 0.7% were > or = 2 mg/l. Age or prior elevated peak concentrations did not predict high trough concentrations. Population pharmacokinetic modeling of the data fitted a one-compartment model with first order elimination. There were no clinical or bacteriologic failures. The two disease-related complications were confined to the OD group. No nephro- or ototoxicity was identified. With age-appropriate dosing and measurement of serum trough concentrations before the second dose, OD gentamicin is safe and effective for the treatment of UTI requiring parenteral treatment in children aged 1 month to 12 years.

To assess the effects of periconceptional undernutrition on maternal adaptation of insulin-dependent metabolism during pregnancy. Romney ewes were randomly assigned to receive normal nutrition (n=12) or undernutrition before (from 60 days before until mating, n=7), after (2 days before to 30 days after mating, n=6) or before and after mating (from 60 days before to 30 days after mating, n=10). Insulin sensitivity was measured by hyperinsulinaemic-euglycaemic clamp at 65 days of gestation (term=147 days). Lamb growth rate was measured in late gestation by chronically implanted growth catheters and weight at 133 days of gestation. Ewes undernourished before or both before and after mating failed to develop the insulin resistance of pregnancy seen in normally nourished ewes. Ewes undernourished after mating showed intermediate insulin sensitivity. This was not related to plasma concentrations of pregnancy-related hormones, but was related to insulin kinetics. There was an inverse relationship between insulin sensitivity and fetal growth, with ewes that were most insulin sensitive having smaller, more slowly growing lambs (highest compared with lowest tertile for insulin sensitivity: fetal weight 3.5+/-0.3 compared with 4.5+/-0.1 kg, P=.02; growth rate 2.0+/-0.2 compared with 2.6+/-0.2 mm.day-1, P=.05). Maternal undernutrition before conception impairs adaptation of insulin-related metabolism during pregnancy in ways that affect fetal growth. This suggests a key mechanism whereby prepregnancy nutritional status influences pregnancy outcome.

There is increased prevalence of obesity and diabetes in offspring from mothers subjected to adverse conditions during pregnancy. Our previous work demonstrated that maternal undernutrition causes epigenetic changes in hypothalamic energy regulating networks in ...

Granulomatous amoebic encephalitis caused by Balamuthia mandrillaris is rare (63 human) cases reported worldwide) and fatal. We report a case in a five-year-old boy who had previously been well. For 18 months, he had had a slowly progressive, granulomatous mid facial lesion, but despite extensive investigation definitive diagnosis was made only with the acute onset of neurological signs in the last two weeks of life, when a brain biopsy specimen revealed amoebic trophozoites and cysts. Infection with B. mandrillaris should be considered in the differential diagnosis of chronic skin lesions with non-specific granulomatous histopathology and negative microbiological test results.

Embryo transfer of large sheep breed embryos (Suffolk) into small breed ewes (Cheviot) constrains birth size, but the maternal factors influencing fetal growth restriction are unknown. We hypothesized that reciprocal embryo transfer crosses between breeds of divergent size would affect pregnancy-related development of maternal insulin resistance in midgestation, thereby influencing fetal growth. Following superovulation, embryos were surgically collected 6 d postmating and transferred to recipients on the same day. Between- and within-breed transfers were performed. Between 60 and 70 d of pregnancy overnight-fasted ewes underwent hyperinsulinemic-euglycemic clamps for assessment of insulin sensitivity. Maternal insulin sensitivity did not vary with transferred lamb breed. Overall, Cheviot ewes tended to have higher fasting glucose (P = 0.068), fasting insulin (P = 0.052), and steady-state glucose (P = 0.065) concentrations than Suffolk ewes at the stage of pregnancy studied. As expected, transferred between-breed Suffolk lambs were born lighter (P = 0.014), and transferred between-breed Cheviot lambs tended to be heavier at birth (P = 0.056) than respective lambs transferred within breed. Midgestation insulin sensitivity does not appear to be a major factor constraining growth of large breed sheep fetus transferred into smaller breed or a factor in releasing constraint in growth of a small breed fetus within a larger breed ewe. However, as embryo size is already different between transferred groups by 19 d, factors other than maternal gestational insulin resistance may determine fetal growth in this embryo transfer paradigm.

Fetal growth is largely regulated by nutritional supply. The placenta is responsible for fetal nutrient supply for much of pregnancy, but in early pregnancy nutrition is histiotrophic. Both placental size and efficiency, and fetal growth, may be affected by maternal nutritional state before and during very early pregnancy. In contrast, manipulating maternal nutrition during later stages of pregnancy has a smaller than expected effect on fetal growth. Maternal nutrition before and during early pregnancy also has a greater effect on gestation length than maternal nutrition later in pregnancy, suggesting that nutritional status may regulate both fetal growth trajectory and gestation length and that these two outcomes may be linked. Thus, determination of the nutritional factors regulating fetal growth, and potentially postnatal growth and body phenotype, may lie with the maternal nutritional status even before conception.

Small size at birth is associated with increased risk of a variety of common chronic diseases in adulthood. Numerous experimental studies in animals have supported the observations in humans, demonstrating that changes in nutrition in early life can lead to altered long-term health. Importantly, these effects can be independent of size at birth, and can depend on the interaction between nutritional events before and after birth. Both macro- and micronutrient intake are important. Furthermore, these effects may vary according to the nature, timing, severity and duration of the nutritional insult. This review provides examples from animal studies of evidence of these long-term effects, and some possible underlying mechanisms whereby nutrition in early life can affect long-term health.

... SM Linton, L. Barrow, C. Davies and L. Harman pp. 14-14. 054. ... 36-36. 119. IDENTIFICATION AND CHARACTERISATION OF SURFACE PROTEIN COMPLEXES IN HUMAN SPERMATOZOA KA Redgrove, B. Nixon, EA McLaughlin, MK O'Bryan and RJ Aitken pp. 37-37. 120. ...

Poor maternal nutrition during pregnancy can result in increased disease risk in adult offspring. Many of these effects are proposed to be mediated via altered hypothalamo-pituitary-adrenal axis (HPAA) function, and are sex and age specific. Maternal undernutrition around the time of conception alters HPAA function in foetal and early postnatal life, but there are limited conflicting data about later effects. The aim of this study was to investigate the effect of moderate periconceptional undernutrition on HPAA function of offspring of both sexes longitudinally, from juvenile to adult life. Ewes were undernourished from 61 days before until 30 days after conception or fed ad libitum. HPAA function in offspring was assessed by arginine vasopressin plus corticotropin-releasing hormone challenge at 4, 10 and 18 months. Plasma cortisol response was lower in males than in females, and was not different between singles and twins. Periconceptional undernutrition suppressed offspring plasma cortisol but not adrenocorticotropic hormone responses. In males, this suppression was apparent by 4 months, and was more profound by 10 months, with no further change by 18 months. In females, suppression was first observed at 10 months and became more profound by 18 months. Maternal undernutrition limited to the periconceptional period has a prolonged, sex-dependent effect on adrenal function in the offspring.