Stephen G Matthews

..Furthermore, these effects can pass across generations. The race is now on to understand the mechanisms involved and to find ways to prevent or reverse the effects of an "adverse" early environment in human populations...

..This is important given the widespread use of sGC in the management of women in preterm labor...

..These data support the hypothesis that prenatal sGC exposure leads to broad changes in critical components of the epigenetic machinery and that these effects can pass to the next generation...

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..In conclusion, hypothalamic OT mRNA increases at term and OT can stimulate ACTH output from fetal corticotrophs. Together, these data indicate that OT may be involved in the regulation of ACTH secretion in fetal sheep in late gestation...

..Permanent changes in endocrine function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging...

..Permanent changes in HPA function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid has been linked to the premature onset of pathologies associated with aging...

..The decreases in GR mRNA levels in the PVN in late gestation likely facilitate the simultaneous increases in ACTH and cortisol that occur near term, and which are critical for the delivery of viable young...

..Understanding these mechanisms could hold the key to the development of therapeutic interventions aimed at reversing the impact of an adverse intrauterine or neonatal environment...

..Understanding these fundamental biological processes will allow for development of intervention strategies that prevent or reverse adverse programming of the stress response...

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..This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone...

..Paradoxically, these novel investigations suggest some types of occasional stress may limit development of diabetes...

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..Protection against epinephrine defects, both without and with antecedent hypoglycemia, is associated with enhancement of adrenal catecholamine-synthesizing enzyme levels...

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..In females, this effect may be attributed, in part, to increased fetal adrenal steroidogenic activity...

..In diabetes, this ability is impaired; hence, maximal HPA activation is greatly diminished. This is a novel observation that may have important implications in the treatment of impaired counterregulatory mechanisms in human diabetes...

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..This study reveals sex-specific effects of prenatal exposure to sGC on LTP in the presence of elevated cortisol, a situation that would occur in vivo during stress...

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..In contrast, the increase in basal pituitary-adrenal activity with repeated sham exercise appears to be associated with decreases in hippocampal MR and PVN GR mRNA expression...

..In contrast, 24-h catecholamines were unaltered. Thus, rather than playing a causal role, intermittent stress delayed deteriorations in glycemia and ameliorated HPA hyperactivity in the ZDF rat...

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..In conclusion, improved beta-cell compensation through increased beta-cell function and mass occurs in exercised but not sedentary ZDF rats and may be in part responsible for improved glucoregulation...

..Thus, preservation of beta-cell mass with adaptation to intermittent stress is related to beta-cell hyperplasia, maintenance of insulin responses to glucose, and reductions in alpha-cell mass that do not occur with food restriction...

..In conclusion, repeated antenatal glucocorticoid treatment programs HPA function in a sex-specific manner, and these changes are associated with modification of corticosteroid receptor expression in the adult brain and pituitary...

..These data have clinical implication given the widespread use of repeat course glucocorticoid therapy in the management of preterm labour...

..Furthermore, impaired epinephrine counterregulation in diabetes is associated with reduced adrenal TH mRNA, whereas the additional epinephrine defect after recurrent hypoglycemia is associated with decreases in both TH and PNMT mRNA...

..Developmental changes in limbic SRC-1 expression probably have important consequences on steroid receptor signaling, which is known to be critical for brain maturation in late gestation...

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..In summary, both exercise and sham treatment delay the progression of type 2 diabetes mellitus in the male ZDF rat by distinct mechanisms related to pancreatic function and improvements in peripheral glucose disposal...

..No sex differences were observed. Understanding the regulation of ABCB1 function will facilitate the development of treatment strategies for human fetal protection against maternally derived endobiotics and xenobiotics...

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..Further, these changes are dependent on the timing of the maternal stressor, a pattern that is emerging in human studies...

..Permanent changes in endocrine function will ultimately impact on health in both human and animal populations...

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..Synthetic glucocorticoid exposure can modify expression and function of multidrug-resistance in the fetal brain, and this will likely have clinical implication given the extensive use of synthetic glucocorticoid in the management of PTL...

..In conclusion, prenatal glucocorticoid exposure affects growth and HPA function as well as limbic and hypothalamic GR expression in juvenile offspring, and these effects are highly sex-specific...

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..Furthermore, we have shown there are considerable difference in phenotypes between the Beta- and Dex-exposed females and the specific endocrine and maternal outcome is contingent on the specific sGCs administered during pregnancy...

..These changes in oxidative stress markers and inflammation are associated with decreased hyperglycemia and insulin resistance and reduced expression of the main gluconeogenic enzyme phosphoenolpyruvate carboxykinase...

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..It is possible that these alter NMDA-dependent signaling at this time. Prenatal exposure to exogenous glucocorticoids modifies the trajectory of NMDAR subunit expression in females but not in males...

..These effects of CPEE, coupled with increased glutamate release and increased NMDA receptor expression, may predispose the near-term foetal hippocampus to GR and Glu-NMDA receptor-mediated neurodevelopmental toxicity...

..Furthermore, juvenile males appear to be more vulnerable to the effects of prenatal glucocorticoid exposure than females...

..The latter likely reflects removal of circulating endogenous ligand (cortisol). These alterations may form the basis for permanently modified HPA activity in later life...

..These findings show that the foetal HPA axis remains highly sensitive to glucocorticoid feedback even as plasma adrenocorticotropic hormone and cortisol levels are elevated at the end of gestation...

..Further, it appears that, at the level of Abcg2 gene expression, the female-derived placentae are more susceptible to the effects of DEX than male placentae...

..The sex differences in the pattern of GR and MR expression during development may indicate different windows of vulnerability to prenatal glucocorticoid exposure in fetal life...

..In conclusion, CMS leads to modification of growth trajectory, locomotor activity and adrenocortical responses to stress in juvenile offspring. Further, males appear considerably more vulnerable to these effects than females...

..Further, the nature of the effect is dependant on the timing of the maternal stress during pregnancy...

..In conclusion, 48 h of maternal nutrient restriction during pregnancy has a long-term effect on HPA function in adult offspring, and this effect is highly sex specific, but does not result in alteration of blood pressure...

..We conclude that 1) recurrent hypoglycemia may increase the risk of subsequent hypoglycemia by increasing insulin sensitivity, and 2) epinephrine counterregulation is particularly sensitive to impairment by recurrent hypoglycemia...

..This model will allow us to determine the mechanisms that underlie the association between prenatal stress and altered learning strategy and ability...

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..A comprehensive understanding of the acute and long-term impact of sGC exposure in utero is necessary to begin to develop recommendations and treatment options for pregnant women at risk of preterm delivery...

..We conclude that synthetic and endogenous glucocorticoids, as well as serotonin, can influence neuronal levels of GR mRNA during hippocampal development. However, whether these effects are permanent remains to be determined...

..We conclude that synthetic and endogenous glucocorticoids, as well as serotonin, can influence GR expression during hippocampal development and in this way may act to permanently programme HPA function...

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..Permanent changes in endocrine function will impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging...

..This study provides new information to begin to address the mechanism underlying the interplay between prenatal stress, gonadal steroids and postnatal behaviours...

..Furthermore, there is a dose-, sex-, and age-dependent effect of DEX on Abcg2 mRNA in the fetal brain in vivo, indicating a complex regulatory role of glucocorticoid during development...

..In conclusion, we have successfully sequenced the coding sequence of the guinea pig CRH gene, and have shown that a short period (48 h) of maternal nutrient restriction inhibits CRH mRNA expression in the fetal hypothalamus...

..Further, synthetic GCs (administered to pregnant women at risk of preterm delivery) may increase the protective capacity of the developing fetal blood-brain barrier, depending on the timing of GC exposure...

..Thus, women who experience infection and take prescription medication during pregnancy may expose the developing fetal brain to greater amounts of exogenous compounds - many of which are considered potentially teratogenic...

..This suggests that P-gp regulation by sertraline is tissue specific. These findings have important clinical implications with respect to fetal protection during maternal drug therapy in pregnancy...

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..05 for all)) markers of syncytiotrophoblast differentiation. These findings suggest that DEX stimulates system A activity and promotes syncytiotrophoblast differentiation and maturation...

..We conclude that E2 may affect CRH-stimulated fetal sheep pituitary corticotroph function late in gestation, but only within a narrow, physiological range of concentration...

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..While the latter is somewhat reassuring with respect to antenatal use of glucocorticoids for management of preterm labour, further studies are required to understand regulation of these important drug transporters in the placenta...

..Notwithstanding, the data reviewed below indicate that caution should be exercised in the use of multiple course glucocorticoid therapy during pregnancy...

..Thus, the level of fetal HPA activity is crucial not only for determining gestation length, but may also predict pathophysiologic adjustments in later life...

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..Understanding the mechanisms involved in neuroendocrine programming will facilitate the development of interventions aimed at reversing or ameliorating the impact of an adverse intrauterine environment...

..We aimed to find out whether multiple courses of antenatal corticosteroids would reduce neonatal morbidity and mortality without adversely affecting fetal growth...

..Thus, insulin apparently restored HPA activity at and below the pituitary but, surprisingly, not above it...

..Further investigations are essential for understanding poor counterregulation in insulin-treated diabetes and may lead to new strategies for preventing hypoglycaemia...

..A better understanding of these mechanisms may be important in developing new treatment modalities for patients with diabetes mellitus...

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..These changes may represent a protective mechanism to maintain appropriate thyroid hormone action in the face of fetal hypothyroxinaemia in order to optimize brain development...

..In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations...

..This research emphasizes the diversity of such prenatal mechanisms and the need to expand our understanding of how, when altered, they may lead to disordered development, the signs of which may not appear until long after birth...