Obstetrics and Gynaecology - Research Publications
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ItemHigh Bias Gas Flows Increase Lung Injury in the Ventilated Preterm Lamb(PUBLIC LIBRARY SCIENCE, 2012-10-08)BACKGROUND: Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI), leading to the development of bronchopulmonary dysplasia (BPD). It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. METHODS: Preterm lambs of 131 days' gestation (term = 147 d) were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13), 18 L/min (n = 12) or 28 L/min (n = 14). Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. RESULTS: High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. CONCLUSIONS: High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD.
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ItemMaternal adaptations and inheritance in the transgenerational programming of adult disease(SPRINGER, 2012-09)Adverse exposures in utero have long been linked with an increased susceptibility to adult cardio-renal and metabolic diseases. Clear gender differences exist, whereby growth-restricted females, although exhibiting some phenotypic modifications, are often protected from overt disease outcomes. One of the greatest physiological challenges facing the female gender, however, is that of pregnancy; yet little research has focused on the outcomes associated with this, as a potential 'second-hit' for those who were small at birth. We review the limited evidence suggesting that pregnancy may unmask cardio-renal and metabolic disease states and the consequences for long-term maternal health in females who were born small. Additionally, a growing area of research in this programming field is in the transgenerational transmission of low birth weight and disease susceptibility. Pathways for transmission might include an abnormal adaptation to pregnancy by the growth-restricted mother and/or inheritance via the parental germline. Strategies to optimise the pregnancy environment and/or prevent the consequences of inheritance of programmed deficits and dysfunction are of critical importance for future generations.
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ItemPLZF Mediates the PTEN/AKT/FOXO3a Signaling in Suppression of Prostate Tumorigenesis(PUBLIC LIBRARY SCIENCE, 2013-12-10)Promyelocytic leukemia zinc finger (PLZF) protein expression is closely related to the progression of human cancers, including prostate cancer (PCa). However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens. Interestingly, both PTEN rescue and phosphoinositide 3-kinase (PI3K) inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines. Further, luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a, a transcriptional factor phosphorylated by PI3K/AKT, could directly bind to the promoter of PLZF gene. These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a. Moreover, our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo. Taken together, our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer.
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ItemPatient-derived xenograft models to improve targeted therapy in epithelial ovarian cancer treatment(FRONTIERS MEDIA SA, 2013)Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer (OC) patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic. Patient-derived xenografts (PDXs) are renewable tumor models engrafted in mice, generated from fresh human tumors without prior in vitro exposure. PDX models allow an invaluable assessment of tumor evolution and adaptive response to therapy. PDX models have been applied to pre-clinical drug testing and biomarker identification in a number of cancers including ovarian, pancreatic, breast, and prostate cancers. These models have been shown to be biologically stable and accurately reflect the patient tumor with regards to histopathology, gene expression, genetic mutations, and therapeutic response. However, pre-clinical analyses of molecularly annotated PDX models derived from high-grade serous ovarian cancer (HG-SOC) remain limited. In vivo response to conventional and/or targeted therapeutics has only been described for very small numbers of individual HG-SOC PDX in conjunction with sparse molecular annotation and patient outcome data. Recently, two consecutive panels of epithelial OC PDX correlate in vivo platinum response with molecular aberrations and source patient clinical outcomes. These studies underpin the value of PDX models to better direct chemotherapy and predict response to targeted therapy. Tumor heterogeneity, before and following treatment, as well as the importance of multiple molecular aberrations per individual tumor underscore some of the important issues addressed in PDX models.
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ItemVariation in severe maternal morbidity according to socioeconomic position: a UK national case-control study(BMJ PUBLISHING GROUP, 2013)OBJECTIVES: This study aimed to explore the independent association between socioeconomic position, defined by occupation, and severe maternal morbidity among women in the UK. DESIGN: Case-control study. SETTING: The analysis was conducted as a case-control analysis, using data from a series of studies of direct causes of severe maternal morbidity undertaken through the UK Obstetric Surveillance System (UKOSS), with data collected throughout all consultant-let obstetric units in the UK. PARTICIPANTS: The analysis included 1144 cases and 2256 comparison women (controls). UKOSS studies from which data on case women were obtained included amniotic fluid embolism, acute fatty liver of pregnancy, eclampsia, peripartum hysterectomy, therapies for peripartum haemorrhage and uterine rupture. PRIMARY OUTCOME MEASURE: Odds of severe maternal morbidity by socioeconomic group, independent of ethnicity, maternal age, smoking, pre-existing medical condition, body mass index (BMI), multiple pregnancy and past pregnancy complications. Occupation was used to classify different socioeconomic groups. SECONDARY OUTCOME MEASURE: Odds of morbidity related to ethnic group, maternal age, smoking, pre-existing medical condition, BMI, multiple pregnancy and past pregnancy complications. RESULTS: Across the socioeconomic groups, compared with the 'managerial/professional' group, adjusted ORs were 1.17 (95% CI 0.94 to 1.45) for the 'intermediate group', 1.16 (95% CI 0.93 to 1.45) for 'routine/manual', 1.22 (95% CI 0.92 to 1.61) for 'unemployed' women and 1.51 (95% CI 1.18 to 1.94) for women with missing socioeconomic information. Women of non-white ethnicity, older maternal age (≥35 years), BMI ≥25 kg/m(2) and those with pre-existing medical condition/s, multiple pregnancy or past pregnancy complications were shown to have a significantly increased odds of severe maternal morbidity. CONCLUSIONS: This study suggests that socioeconomic position may be independently associated with an increased risk of severe maternal morbidity, although the observed association was not statistically significant. Further research is warranted to confirm this and investigate why this association might exist in a country where healthcare is universal and free at the point of access.
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ItemAvoiding risk at what cost? Putting use of medicines for breastfeeding women into perspective.(Springer Science and Business Media LLC, 2012-10-17)Breastfeeding women often need to take medicines, and therefore health professionals need to consider the effects of medication on lactation and the breastfed infant, and any associated risks. This commentary discusses the tragic case of a young woman with a history of mental illness who committed suicide in the postpartum period. She was determined to be a 'good mother' and breastfeed, and to avoid any potential adverse effects of medication on her breastfed infant. The final outcome was fatal for both mother and child. We argue that if women require medication during lactation, all risks need to be considered - the risk of not treating the maternal medical condition may greatly outweigh the potential risk to the breastfed infant.
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ItemHypothenar hammer syndrome: case report and literature review.(Georg Thieme Verlag KG, 2013)Case report of a 69 year-old patient, with history of repetitive trauma events in the wrist, clinically simulating tenosynovitis, being held with Doppler Ultrasound and Magnetic Nuclear Resonance, which showed ulnar artery thrombosis. The accurate diagnosis of the hammer hypothenar disease through those tests enable an early intervention, improving the prognosis of patients affected by this rare disease.
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ItemRecommendations for fertility preservation in patients with lymphoma, leukemia, and breast cancer(SPRINGER/PLENUM PUBLISHERS, 2012-06)Fertility issues should be addressed to all patients in reproductive age before cancer treatment. In men, cryopreservation of sperm should be offered to all cancer patients in reproductive age regardless of the risk of gonadal failure. In women, the recommendation of fertility preservation should be individualized based on multiple factors such as the urgency of treatment, the age of the patient, the marital status, the regimen and dosage of cancer treatment.
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ItemNo Preview AvailableMedical retrieval and needs of infants with bronchiolitis: An analysis by gestational age(WILEY, 2013-03)AIM: Viral bronchiolitis is the most common lower respiratory tract infection in children less than 12 months of age. Prematurity is an independent risk factor for disease severity. Many infected infants require hospitalisation and those living in regional centres frequently require transfer to metropolitan hospitals capable of providing assisted ventilation. METHOD: We reviewed infants with bronchiolitis transported by the Victorian Newborn Emergency Transport Service between January 2003 and June 2007. We compared the clinical presentation and treatment required by infants born preterm with those of their term counterparts. RESULTS: Of the 192 infants transported, 92 were born preterm. Preterm infants were younger at time of transport (mean post-menstrual age 41 weeks vs. 45 weeks) and were more likely to require invasive ventilation (60% vs. 32%, P < 0.001) and to receive a fluid bolus (47% vs. 34%, P = 0.04) when compared with infants who had been born at term. Apnoea, either as a presenting symptom or in combination with respiratory distress, was more common in the preterm group (70% vs. 36%, P < 0.001). CONCLUSION: Higher illness severity should be anticipated in ex-preterm infants who present with bronchiolitis. Preterm infants with bronchiolitis are more likely to require invasive ventilation and fluid resuscitation than term infants, suggesting the need for a lower threshold for referral and medical retrieval.
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ItemContribution of Brain Size to IQ and Educational Underperformance in Extremely Preterm Adolescents(PUBLIC LIBRARY SCIENCE, 2013-10-09)OBJECTIVES: Extremely preterm (EP) survivors have smaller brains, lower IQ, and worse educational achievement than their term-born peers. The contribution of smaller brain size to the IQ and educational disadvantages of EP is unknown. This study aimed (i) to compare brain volumes from multiple brain tissues and structures between EP-born (< 28 weeks) and term-born (≥ 37 weeks) control adolescents, (ii) to explore the relationships of brain tissue volumes with IQ and basic educational skills and whether this differed by group, and (iii) to explore how much total brain tissue volume explains the underperformance of EP adolescents compared with controls. METHODS: Longitudinal cohort study of 148 EP and 132 term controls born in Victoria, Australia in 1991-92. At age 18, magnetic resonance imaging-determined brain volumes of multiple tissues and structures were calculated. IQ and educational skills were measured using the Wechsler Abbreviated Scale of Intelligence (WASI) and the Wide Range Achievement Test(WRAT-4), respectively. RESULTS: Brain volumes were smaller in EP adolescents compared with controls (mean difference [95% confidence interval] of -5.9% [-8.0, -3.7%] for total brain tissue volume). The largest relative differences were noted in the thalamus and hippocampus. The EP group had lower IQs(-11.9 [-15.4, -8.5]), spelling(-8.0 [-11.5, -4.6]), math computation(-10.3 [-13.7, -6.9]) and word reading(-5.6 [-8.8, -2.4]) scores than controls; all p-values<0.001. Volumes of total brain tissue and other brain tissues and structures correlated positively with IQ and educational skills, a relationship that was similar for both the EP and controls. Total brain tissue volume explained between 20-40% of the IQ and educational outcome differences between EP and controls. CONCLUSIONS: EP adolescents had smaller brain volumes, lower IQs and poorer educational performance than controls. Brain volumes of multiple tissues and structures are related to IQ and educational outcomes. Smaller total brain tissue volume is an important contributor to the cognitive and educational underperformance of adolescents born EP.