http://hdl.handle.net/2440/5865 2013-06-19T02:12:38Z http://hdl.handle.net/2440/78406 Title: Neonatal exendin-4 reduces growth, fat deposition and glucose tolerance during treatment in the intrauterine growth-restricted lamb Author: Gatford, Kathryn Leanne; Sulaiman, Siti Aishah; Mohammad, Saidatul Naziah; De Blasio, Miles Jonathon; Harland, Margaret Lyn; Simmons, Rebecca; Owens, Julie Anne Abstract: BACKGROUND IUGR increases the risk of type 2 diabetes mellitus (T2DM) in later life, due to reduced insulin sensitivity and impaired adaptation of insulin secretion. In IUGR rats, development of T2DM can be prevented by neonatal administration of the GLP-1 analogue exendin-4. We therefore investigated effects of neonatal exendin-4 administration on insulin action and β-cell mass and function in the IUGR neonate in the sheep, a species with a more developed pancreas at birth. METHODS Twin IUGR lambs were injected s.c. daily with vehicle (IUGR+Veh, n = 8) or exendin-4 (1 nmol.kg-1, IUGR+Ex-4, n = 8), and singleton control lambs were injected with vehicle (CON, n = 7), from d 1 to 16 of age. Glucose-stimulated insulin secretion and insulin sensitivity were measured in vivo during treatment (d 12–14). Body composition, β-cell mass and in vitro insulin secretion of isolated pancreatic islets were measured at d 16. PRINCIPLE FINDINGS IUGR+Veh did not alter in vivo insulin secretion or insulin sensitivity or β-cell mass, but increased glucose-stimulated insulin secretion in vitro. Exendin-4 treatment of the IUGR lamb impaired glucose tolerance in vivo, reflecting reduced insulin sensitivity, and normalised glucose-stimulated insulin secretion in vitro. Exendin-4 also reduced neonatal growth and visceral fat accumulation in IUGR lambs, known risk factors for later T2DM. CONCLUSIONS Neonatal exendin-4 induces changes in IUGR lambs that might improve later insulin action. Whether these effects of exendin-4 lead to improved insulin action in adult life after IUGR in the sheep, as in the PR rat, requires further investigation. 2012-12-31T13:30:00Z http://hdl.handle.net/2440/78392 Title: Antibiotics for treating bacterial vaginosis in pregnancy Author: Brocklehurst, Peter; Gordon, Adrienne; Heatley, Emer Mellett; Milan, Stephen J. Abstract: BACKGROUND Bacterial vaginosis is an imbalance of the normal vaginal flora with an overgrowth of anaerobic bacteria and a lack of the normal lactobacillary flora. Women may have symptoms of a characteristic vaginal discharge but are often asymptomatic. Bacterial vaginosis during pregnancy has been associated with poor perinatal outcomes and, in particular, preterm birth (PTB). Identification and treatment may reduce the risk of PTB and its consequences. OBJECTIVES To assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2012), searched cited references from retrieved articles and reviewed abstracts, letters to the editor and editorials. SELECTION CRITERIA Randomised trials comparing antibiotic treatment with placebo or no treatment, or comparing two or more antibiotic regimens in pregnant women with bacterial vaginosis or intermediate vaginal flora whether symptomatic or asymptomatic and detected through screening. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trials for inclusion, trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS We included 21 trials of good quality, involving 7847 women diagnosed with bacterial vaginosis or intermediate vaginal flora. Antibiotic therapy was shown to be effective at eradicating bacterial vaginosis during pregnancy (average risk ratio (RR) 0.42; 95% confidence interval (CI) 0.31 to 0.56; 10 trials, 4403 women; random-effects, T² = 0.19, I² = 91%). Antibiotic treatment also reduced the risk of late miscarriage (RR 0.20; 95% CI 0.05 to 0.76; two trials, 1270 women, fixed-effect, I² = 0%). Treatment did not reduce the risk of PTB before 37 weeks (average RR 0.88; 95% CI 0.71 to 1.09; 13 trials, 6491 women; random-effects, T² = 0.06, I² = 48%), or the risk of preterm prelabour rupture of membranes (RR 0.74; 95% CI 0.30 to 1.84; two trials, 493 women). It did increase the risk of side-effects sufficient to stop or change treatment (RR 1.66; 95% CI 1.02 to 2.68; four trials, 2323 women, fixed-effect, I² = 0%). In this updated review, treatment before 20 weeks' gestation did not reduce the risk of PTB less than 37 weeks (average RR 0.85; 95% CI 0.62 to 1.17; five trials, 4088 women; random-effects, T² = 0.06, I² = 49%). In women with a previous PTB, treatment did not affect the risk of subsequent PTB (average RR 0.78; 95% CI 0.42 to 1.48; three trials, 421 women; random-effects, T² = 0.19, I² = 72%). In women with abnormal vaginal flora (intermediate flora or bacterial vaginosis), treatment may reduce the risk of PTB before 37 weeks (RR 0.53; 95% CI 0.34 to 0.84; two trials, 894 women). One small trial of 156 women compared metronidazole and clindamycin, both oral and vaginal, with no significant differences seen for any of the pre-specified primary outcomes. Statistically significant differences were seen for the outcomes of prolongation of gestational age (days) (mean difference (MD) 1.00; 95% CI 0.26 to 1.74) and birthweight (grams) (MD 75.18; 95% CI 25.37 to 124.99) however these represent relatively small differences in the clinical setting. Oral antibiotics versus vaginal antibiotics did not reduce the risk of PTB (RR 1.09; 95% CI 0.78 to 1.52; two trials, 264 women). Oral antibiotics had some advantage over vaginal antibiotics (whether metronidazole or clindamycin) with respect to admission to neonatal unit (RR 0.63; 95% CI 0.42 to 0.92, one trial, 156 women), prolongation of gestational age (days) (MD 9.00; 95% CI 8.20 to 9.80; one trial, 156 women) and birthweight (grams) (MD 342.13; 95% CI 293.04 to 391.22; one trial, 156 women). Different frequency of dosing of antibiotics was assessed in one small trial and showed no significant difference for any outcome assessed. AUTHORS' CONCLUSIONS Antibiotic treatment can eradicate bacterial vaginosis in pregnancy. The overall risk of PTB was not significantly reduced. This review provides little evidence that screening and treating all pregnant women with bacterial vaginosis will prevent PTB and its consequences. When screening criteria were broadened to include women with abnormal flora there was a 47% reduction in preterm birth, however this is limited to two included studies. 2012-12-31T13:30:00Z http://hdl.handle.net/2440/78391 Title: Investigating a cluster of vulvar cancers in young women: distribution of human papillomavirus and HPV-16 variants in vulvar dysplastic or neoplastic biopsies Author: Tan, Sarah E.; Garland, Suzanne M.; Rumbold, Alice Rosemary; Zardawi, Ibrahim; Taylor-Thomson, Debbie; Condon, John R.; Tabrizi, Sepehr N. Abstract: BACKGROUND: A high incidence of vulvar cancer, and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN) has been identified in young Indigenous women living in the Arnhem Land region of the Northern Territory (NT) of Australia. This clustering is restricted to women aged <50 years, suggesting that oncogenic human papillomavirus (HPV) is a key causal factor. This study compared the HPV genotype prevalence, HPV-16 variant distribution and p16(INK4a)expression in stored vulvar cancer and high-grade VIN biopsy specimens from women residing in Arnhem Land, with specimens taken from Indigenous and non-Indigenous women in other regions of NT where there is no observed increase in vulvar cancer incidence. METHODS: Twenty high-grade VIN and 10 invasive cancer biopsies were assessed from Arnhem Land along with 24 high-grade VIN and 10 invasive cancer biopsies from other regions of NT. RESULTS: Biopsies from Arnhem Land were similar to those from other regions in the detection of high-risk (HR) or possible HR HPV (VIN: 95% and 84% respectively for Arnhem Land and other regions, P = 0.356; invasive cancer: 100% and 80%, P = 0.473), HPV-16 (VIN: 60% and 80%, P = 0.364; invasive cancer: 70% and 70%, P = 1.0) and p16(INK4a) expression (VIN: 90% and 84%, P = 0.673; invasive cancer: 100% and 80%, P = 0.474). All HPV-16 variants were of the European prototype. CONCLUSION: Comparison of biopsies revealed no significant difference in the frequency of oncogenic HPVs or HPV-16 variant types between Arnhem Land and other regions, suggesting another cofactor in this cluster. 2012-12-31T13:30:00Z http://hdl.handle.net/2440/78380 Title: Characterisation of the maternal response to chronic phase shifts during gestation in the rat: implications for fetal metabolic programming Author: Varcoe, Tamara Jayne; Boden, Michael James; Voultsios, Athena; Salkeld, Mark David; Rattanatray, Leewen; Kennaway, David John Abstract: Disrupting maternal circadian rhythms through exposure to chronic phase shifts of the photoperiod has lifelong consequences for the metabolic homeostasis of the fetus, such that offspring develop increased adiposity, hyperinsulinaemia and poor glucose and insulin tolerance. In an attempt to determine the mechanisms by which these poor metabolic outcomes arise, we investigated the impact of chronic phase shifts (CPS) on maternal and fetal hormonal, metabolic and circadian rhythms. We assessed weight gain and food consumption of dams exposed to either CPS or control lighting conditions throughout gestation. At day 20, dams were assessed for plasma hormone and metabolite concentrations and glucose and insulin tolerance. Additionally, the expression of a range of circadian and metabolic genes was assessed in maternal, placental and fetal tissue. Control and CPS dams consumed the same amount of food, yet CPS dams gained 70% less weight during the first week of gestation. At day 20, CPS dams had reduced retroperitoneal fat pad weight (−15%), and time-of-day dependent decreases in liver weight, whereas fetal and placental weight was not affected. Melatonin secretion was not altered, yet the timing of corticosterone, leptin, glucose, insulin, free fatty acids, triglycerides and cholesterol concentrations were profoundly disrupted. The expression of gluconeogenic and circadian clock genes in maternal and fetal liver became either arrhythmic or were in antiphase to the controls. These results demonstrate that disruptions of the photoperiod can severely disrupt normal circadian profiles of plasma hormones and metabolites, as well as gene expression in maternal and fetal tissues. Disruptions in the timing of food consumption and the downstream metabolic processes required to utilise that food, may lead to reduced efficiency of growth such that maternal weight gain is reduced during early embryonic development. It is these perturbations that may contribute to the programming of poor metabolic homeostasis in the offspring. 2012-12-31T13:30:00Z