Synthetic glucocorticoids: antenatal administration and long-term implications

A clear relationship between intrauterine development and later life predisposition to long-term disease is well established. Weight at birth provides a surrogate measure for fetal development and low birth weight predicts changes in most endocrine axes in adulthood. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids, pre and periconceptional nutritional status and immediate postnatal development including catch-up growth all contribute substantially to the development of adult onset disease. Fetal exposure to high levels of glucocorticoids has direct clinical relevance. Synthetic glucocorticoids (betamethasone/ dexamethasone) are administered to women at risk of preterm delivery to advance fetal maturation and reduce neonatal morbidity and mortality. However, in human pregnancy, evidence suggests that fetal exposure to synthetic glucocorticoids has detrimental effects on birth outcome, childhood cognition and long-term behavior. Studies in animals have established a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development as well as changes in placental function. These developmental alterations appear to be permanent. Whether this is the case in humans awaits long-term follow-up of children enrolled in randomized controlled trials of prenatal glucocorticoid therapy. The research challenges in this field are now centered on uncovering the mechanisms by which glucocorticoids are involved in programming the fetus for its future life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced. The purpose of this mini-review is to provide a background into the use of antenatal synthetic corticosteroids and to highlight and summarize recently published clinical and animal-based studies.     

Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids

Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of Pomc-/- and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc-/- but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc-/- versus 14-fold in wild-type mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc-/- versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc-/- but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8-12 weeks. Thus, Pomc-/- mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc-/- mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state.     

Helping patients with Crohn's disease to stop smoking

Evidence shows that Crohn's disease in cigarette smokers runs a more aggressive course. Two nurses worked in collaboration to identify smokers with Crohn's disease in order to offer pharmacological and psychological support in quitting the habit. This paper provides the results of a pilot study on a smoking-cessation course targeted specifically at such patients.     

Influences of variation in force application on tibial displacement and strain in the anterior cruciate ligament during the Lachman test

OBJECTIVE: The purpose of this study was to examine the influence of Lachman test performance technique on tibial displacement and strain in the anterior cruciate ligament. DESIGN: Model simulation of experimental Lachman test performance by trained clinicians. BACKGROUND: Differences in clinician hand placement during Lachman test performance have been observed. METHODS: A two-dimensional computer sagittal plane model of the knee was designed to simulate experimentally observed Lachman test performance, and determine anterior cruciate ligament strain and tibial translation that occurred during variation in clinician hand placement and force magnitude. RESULTS: Anterior cruciate ligament strain and tibial translation were greater under conditions mimicking clinician hand placement utilizing a more proximal force application on the tibia. CONCLUSIONS: Tibial translation and strain behavior of the anterior cruciate ligament during the Lachman test appear to be influenced by clinician hand position used in the application of force to the tibia.     

Differential expression and regulation of microsomal prostaglandin E(2) synthase in human fetal membranes and placenta with infection and in cultured trophoblast cells

We have evaluated the effect of chorioamnionitis on the protein expression of microsomal and cytosolic prostaglandin E(2) synthases (mPGES and cPGES) in preterm human placentae (PL) and fetal membranes (FM), by Western blot and immunohistochemistry, as well as the regulatory effect of IL-1beta and TNF-alpha on mPGES, cPGES, and cyclooxygenase (COX)-2 expression in villous trophoblast (VT) and chorion trophoblast (CT) cell cultures. mPGES localized to the syncytiotrophoblast and vascular endothelium in PL and to the amnion epithelium, CT, and decidual cells in FM. cPGES protein was localized only to the syncytiotrophoblast in PL and had the same profile of expression as mPGES in FM. With infection, there was an increase in mPGES expression in PL and a decrease in the expression in FM. cPGES protein did not change in either PL or FM with infection. In VT cells in culture, IL-1beta up-regulated COX-2 protein expression but did not affect mPGES. However, TNF-alpha increased both mPGES and COX-2 protein expression in these cells. In CT cells in culture, IL-1beta and TNF-alpha increased both mPGES and COX-2 protein levels. Neither IL-1beta nor TNF-alpha affected cPGES in either VT or CT cells. We conclude that protein levels of mPGES, as well as COX-2, can be stimulated by cytokines, potentially contributing to the increased prostaglandin production at the time of infection-driven preterm labor. However, multiple mechanisms, which apparently are inductor- and cell-type-specific, exist for the regulation of these enzymes.