No description available.

No description available.

Liver cirrhosis places an increasing burden on healthcare worldwide. Currently the only treatment is liver transplantation. Whilst liver transplant has a relatively good five-year survival, donor organ shortage costs many lives every year and results in lifelong immunosuppression. Alternative treatments are thus urgently needed. It is with this background that there is understandable interest for the development of stem cell therapies for liver regeneration. The identification of putative liver stem cells has brought closer the previously separate fields of liver ontology, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bio-artificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers. Human liver progenitor cells (LPCs) have therapeutic potential but their in vitro culture results in inadequate differentiation, function, and phenotypic instability reflecting an incomplete understanding of in vivo processes. LPCs can be robustly isolated from second trimester human foetal livers by immunoselection for EpCAM+/CD29+/CD49d+/CD49e–/CD235a–/CD45– cells. Expression profiling of mRNA and microRNA in human foetal LPCs was performed and compared with mature human hepatocytes and human embryonic stem cells undergoing hepatocytic differentiation. Foetal LPCs exhibit a distinct transcriptome profile consistent with a stem cell signature, cell division, and some liver-specific functions. Bioinformatic integration of microRNA and mRNA datasets revealed that microRNAs up-regulated in LPCs targeted genes involved in metabolic processes implying repression of the mature hepatocyte phenotype. Control of LPC gene expression therefore occurs at both transcriptional and, via microRNAs, post-transcriptional levels. Furthermore, transcription factor binding site analyses revealed enriched E2F1 motif in gene and microRNA promoters suggesting feedback control in determining LPC fate. Foetal LPCs were capable of differentiation to a hepatocytic phenotype in the presence of appropriate paracrine signals provided by EpCAM– non-parenchymal cells (NPCs), which consist mainly of endothelial cells and hepatic stellate cells. Fibronectin, despite being produced in abundance by EpCAM– NPCs, had no effect on LPC synthetic function in vitro. The expression of fibronectin in the perisinusoidal space suggests its potential role of modulating cross-talk between hepatoblasts/hepatocytes, liver sinusoidal endothelial cells, and hepatic stellate cells. Fibronectin expression in the portal vein mesenchyme and laminin α5 expression along the ductal plate suggest that both matrix molecules, located in close proximity to LPCs, may be important in supporting the LPC niche. Findings in this work provide insight into the regulation of the human foetal LPC functional phenotype, bringing stem cell-based therapies for liver disease one step closer.

Pericytes, progenitor cells embedded in the microvascular wall, are crucial for vascular homeostasis. Renin is the rate-limiting enzyme that regulates blood pressure and fluid/electrolyte balance. Previous work suggested the relationship between renin-expressing/ producing cells and pericytes, however human kidney pericytes have not been characterized in depth and the molecular switch controlling renin cell plasticity is not understood. Here, I describe a method of isolation of CD146+CD34-CD45-CD56- pericytes, putative progenitors for renin-producing cells, from the human foetal kidney and demonstrate their potential in vitro to express and produce renin. Co-staining of pericyte markers (CD146 and NG2) and renin showed coincidence in the juxtaglomerular region and along renal arterioles in the human foetal kidney. I have obtained primary cultures of renal pericytes from the developing human kidney that were purified via fluorescence-activated cell sorting. Primary cultures of renal pericytes exhibited tri-lineage mesodermal differentiation potential. Renin expression was triggered by cAMP induction (10μM forskolin and 100μM 3-isobutyl-1- methylxanthine [IBMX] and resulted in 64.3 fold increase of renin mRNA (p <0.01) and 41.5 fold increase in enzymatic activity of renin (p <0.05) over controls. Pericytes derived from non-renal tissues (placenta and foetal adrenal glands) also expressed renin in an inducible fashion. Renin positive cells following induction were confirmed to be CD146+/NG2+. Interestingly, alpha-smooth muscle actin expression was not always correlated with renin immunostaining. Wnt/β-catenin signalling plays a crucial role during kidney development and in disease, specifically; in pericyte modulation of the Wnt pathway has been shown to regulate cell differentiation. CHIR 99021, a specific inhibitor of glycogen synthase kinase 3, mimicking Wnt signalling, and C59, a potent Porcupine acyltransferase inhibitor that is required for Wnt biological activity, were tested in renin induction experiments. Preliminary data showed that renin expression was blocked by Wnt activation, whereas Wnt suppression increased renin mRNA levels above the level of stimulation achieved with cAMP inducers. These findings provide evidence that renin expression is an intrinsic feature of pericytes and can be regulated through the Wnt pathway.

Many midwives continue to use Continuous Electronic Foetal Monitoring (CEFM) on low risk women in labour, despite overwhelming clinical evidence that it is unnecessary. The use of CEFM on low risk labouring women has been linked to rising rates of medical intervention during labour and birth with no improvement in long term neonatal outcomes. This study examined the decision-making processes of midwives who used CEFM on low risk labouring women. Whilst a number of previous studies have examined various aspects of CEFM, none specific to midwives’ decision-making and CEFM on low risk labouring women. This study contributes to the literature in this specific area. The theoretical origins of Symbolic Interactionism and Grounded Theory (GT) methods underpin this study. SI, a sociological theory that emphasises meaning in human interactions and behaviours is used in this study to focus on the behaviours and interactions of five midwives’when deciding to use CEFM on low risk labouring women. Primary data were collected by conducting unstructured interviews and systematic analysis was undertaken using GT methods to generate a substantive theory of: Midwives’ CEFM decision-making despite evidence based guidelines. The midwives made the decision that led to CEFM at two key points in the woman’s labour care. Firstly, during the initial assessment of the woman and foetus, some midwives decided to use a baseline CTG rather than intermittent auscultation (IA). Secondly, following initial assessment, the midwives made an individualised assessment and decided whether to use CEFM as the method to monitor the foetus during labour. Trust was identified as the core variable, having a profound effect on the midwives’ decision-making at these two points. Another significant factor that impacted on decision-making was staff workload. Recommendations relating to these findings promote that labouring women be central and intimately involved in decisions about foetal monitoring. Workplace reforms, such as the introduction of midwifery led models of care for women within a community setting are recommended to address professional trust and workload issues. Through the implementation of these recommendations it is expected that midwives will embrace the notion of woman centred care and that the unnecessary use of CEFM on low risk labouring women will be reduced.

Mémoire de Sage-femme : Médecine : Nantes : 2007. / Bibliogr.

Mémoire de Sage-femme : Médecine : Nantes : 2007. / Bibliogr.

x, 101 leaves : ill., tables, graphs ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.1981) from the Dept. of Obstetrics and Gynaecology, University of Adelaide

Thesis (Ph.D. 1981) from the Department of Obsetetrics and Gynaecology, University of Adelaide.

This study was conducted to document the size of primigravid women and their infants and placentas born at term in the Coloured community of Cape Town. It also explored the relationship between maternal, infant and placental size at birth. One thousand nine hundred and fifty seven firstborn infants delivered at term to Coloured women by the Peninsula Maternity Service during 1975 and 1976 were examined. The birth weight, crown-heel length and head circumference of each infant were measured, the gestational age assessed and the ponderal index of weight to length calculated. In addition the standing height, delivery weight and postdelivery weight of 395 of their mothers were measured and the Quetelet index of weight to height determined. The trimmed weight and chorionic plate area of 992 of the study infants' placentas were also measured and the placental thickness calculated.