Obstetrics and Gynaecology - Research Publications
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ItemPulmonary hemodynamic responses to in utero ventilation in very immature fetal sheep(BIOMED CENTRAL LTD, 2010-08-19)BACKGROUND: The onset of ventilation at birth decreases pulmonary vascular resistance (PVR) resulting in a large increase in pulmonary blood flow (PBF). As the large cross sectional area of the pulmonary vascular bed develops late in gestation, we have investigated whether the ventilation-induced increase in PBF is reduced in immature lungs. METHODS: Surgery was performed in fetal sheep at 105 d GA (n = 7; term ~147 d) to insert an endotracheal tube, which was connected to a neonatal ventilation circuit, and a transonic flow probe was placed around the left pulmonary artery. At 110 d GA, fetuses (n = 7) were ventilated in utero (IUV) for 12 hrs while continuous measurements of PBF were made, fetuses were allowed to develop in utero for a further 7 days following ventilation. RESULTS: PBF changes were highly variable between animals, increasing from 12.2 ± 6.6 mL/min to a maximum of 78.1 ± 23.1 mL/min in four fetuses after 10 minutes of ventilation. In the remaining three fetuses, little change in PBF was measured in response to IUV. The increases in PBF measured in responding fetuses were not sustained throughout the ventilation period and by 2 hrs of IUV had returned to pre-IUV control values. DISCUSSION AND CONCLUSION: Ventilation of very immature fetal sheep in utero increased PBF in 57% of fetuses but this increase was not sustained for more than 2 hrs, despite continuing ventilation. Immature lungs can increase PBF during ventilation, however, the present studies show these changes are transient and highly variable.
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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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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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ItemSocial theory and infant feeding.(Springer Science and Business Media LLC, 2011-06-15)Clinicians, public health advisors, nutritionists and others have been attempting to increase breastfeeding rates for the last few decades, with varying degrees of success. We need social science researchers to help us understand the role of infant feeding in the family. Some researchers in the area of food and nutrition have found Pierre Bourdieu's theoretical framework helpful. In this editorial, I introduce some of Bourdieu's ideas and suggest researchers interested in infant feeding should consider testing these theories.
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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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ItemPhase II biomarker trial of a multimarker diagnostic for ovarian cancer(SPRINGER, 2010-07)PURPOSE: The primary hypothesis to be tested in this study was that the diagnostic performance (as assessed by the area under the receiver operator characteristic curve, AUC) of a multianalyte panel to correctly identify women with ovarian cancer was significantly greater than that for CA-125 alone. METHODS: A retrospective, case-control study (phase II biomarker trial) was conducted that involved 362 plasma samples obtained from women with ovarian cancer (n = 150) and healthy controls (n = 212). A multivariate classification model was developed that incorporated five biomarkers of ovarian cancer, CA-125; C-reactive protein (CRP); serum amyloid A (SAA); interleukin 6 (IL-6); and interleukin 8 (IL-8) from a modelling cohort (n = 179). The performance of the model was evaluated using an independent validation cohort (n = 183) and compared with of CA-125 alone. RESULTS: The AUC for the biomarker panel was significantly greater than the AUC for CA-125 alone for a validation cohort (p < 0.01) and an early stage disease cohort (i.e. Stages I and II; p < 0.01). At a threshold of 0.3, the sensitivity and specificity of the multianalyte panel were 94.1 and 91.3%, respectively, for the validation cohort and 92.3 and 91.3%, respectively for an early stage disease cohort. CONCLUSIONS: The use of a panel of plasma biomarkers for the identification of women with ovarian cancer delivers a significant increase in diagnostic performance when compared to the performance of CA-125 alone.
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ItemNo Preview AvailableEarly Diagnosis of Werner's Syndrome Using Exome-Wide Sequencing in a Single, Atypical Patient.(Frontiers Media SA, 2011)Genetic diagnosis of inherited metabolic disease is conventionally achieved through syndrome recognition and targeted gene sequencing, but many patients receive no specific diagnosis. Next-generation sequencing allied to capture of expressed sequences from genomic DNA now offers a powerful new diagnostic approach. Barriers to routine diagnostic use include cost, and the complexity of interpreting results arising from simultaneous identification of large numbers of variants. We applied exome-wide sequencing to an individual, 16-year-old daughter of consanguineous parents with a novel syndrome of short stature, severe insulin resistance, ptosis, and microcephaly. Pulldown of expressed sequences from genomic DNA followed by massively parallel sequencing was undertaken. Single nucleotide variants were called using SAMtools prior to filtering based on sequence quality and existence in control genomes and exomes. Of 485 genetic variants predicted to alter protein sequence and absent from control data, 24 were homozygous in the patient. One mutation - the p.Arg732X mutation in the WRN gene - has previously been reported in Werner's syndrome (WS). On re-evaluation of the patient several early features of WS were detected including loss of fat from the extremities and frontal hair thinning. Lymphoblastoid cells from the proband exhibited a defective decatenation checkpoint, consistent with loss of WRN activity. We have thus diagnosed WS some 15 years earlier than average, permitting aggressive prophylactic therapy and screening for WS complications, illustrating the potential of exome-wide sequencing to achieve early diagnosis and change management of rare autosomal recessive disease, even in individual patients of consanguineous parentage with apparently novel syndromes.
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ItemNo Preview AvailableGenome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls(NATURE PORTFOLIO, 2010-04-01)Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.