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Reproduction is a crucial process, required for bringing the next generation into the world. In preparation for pregnancy, and throughout pregnancy itself, reproductive tissues recruit specific populations of immune cells that are thought to contribute in a variety of ways to successful reproduction. Pregnancy culminates in parturition, an inflammatory process characterised by an influx of inflammatory cells into reproductive tissues. Effective healing of reproductive tissues in the post-partum period is vital for continued reproductive success, and it too is thought to involve specific populations of immune cells. For leukocytes to effectively perform their functions in the reproductive system and elsewhere, migration to the right place at the right time is crucial. Key regulators of leukocyte homing are the chemokine family of chemoattractants and their G-protein coupled receptors. The chemokine network is complex and controls migration of leukocytes from the Bone Marrow (BM) into the blood and from the blood into tissues. Chemokines influence leukocyte position within tissues, and orchestrate their departure. Very little is known about the types of leukocytes present within reproductive tissues in the post-partum period, or the chemokines and receptors that could be involved in their migration. Exploring these processes is critical for an understanding of how tissues are repaired in readiness for subsequent pregnancies. In this thesis I have examined the leukocyte populations in reproductive and peripheral tissues of mice during the post-partum period and compared them to those found in Non-Pregnant (NP) mice. This analysis has encompassed a range of myeloid cell types, and also the complex populations of CD3+ cells that exist in reproductive tissues. I was also interested in how these cells are instructed to enter reproductive tissues, and in particular on the role of CC chemokine Receptor 2 (CCR2), a receptor associated with the recruitment of monocytes and T cells into tissues. My work has clearly identified cells expressing CCR2 both in reproductive tissues and elsewhere, and defined the impact of the genetic deletion of this receptor on leukocyte populations during the post-partum period. These experiments exploited a variety of standard techniques including histology, quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR), Enzyme-Linked ImmunoSorbent Assay (ELISA) and Luminex, but they also required the development of challenging multiparameter flow cytometry protocols that allowed the simultaneous analysis, and definitive identification, of several leukocyte populations in various tissues and at specific reproductive time-points. Chapter 3 describes detailed experiments that focussed on characterising the myeloid cell populations across a variety of tissues in NP, 1 Day Post Partum (DPP) and 7DPP mice. Most strikingly, this revealed a profound accumulation of several myeloid cell populations in reproductive tissues at 1DPP, including inflammatory Ly6Chigh (hi) monocytes and neutrophils. Moreover, many of these myeloid cells expressed active CCR2 and remarkably CCR2 deletion was associated with a dramatic reduction in myeloid cell abundance in the uterine horn one day after birth. Thus, CCR2 appeared to be required for myeloid cell recruitment to the post-partum uterine horn. Chapters 4 and 5 describe changes in CD3+ cell populations over the post-partum period. Interestingly, the main finding from reproductive tissues was that the large majority of CD3+ cells lacked expression of CD4 and CD8, and were thus termed CD3+ Double-Negative (DN) cells. Three main CD3+ DN cell populations were described. CD3+CD25+NK1.1+TCRβ+ DN cells, likely to be Natural Killer T (NKT) cells, which were mainly found in reproductive tissues and blood. All tissues studied were found to contain CD3+NK1.1-TCRβ+ DN cells, likely to be ‘true’ DN T cells and CD3+NK1.1-TCRβ-TCRγδ+ DN cells, which were consistent with a γδ T cell phenotype. CD3+ DN cells were also found to increase in number at 1DPP, compared to NP tissues, driven by an increase in DN T cells. In contrast to myeloid cells CCR2 was not required for this change. However, at 1DPP there was a CCR2-dependent increase in the proportion of CD3+ DN cells in the blood. Finally, in Chapter 6, hormonal influences on leukocyte populations in reproductive and peripheral tissues were considered. This work had two major components: analysing sex differences in myeloid and T cell populations and exploring the effect that lactation has on these cell subsets over the post-partum period. Females were found to have an increased proportion of eosinophils in their blood, whereas males had a higher proportion of monocytes. I also found that female and male reproductive tissues, as well as peripheral tissues, have very similar CD3+ DN cell populations, suggesting that these cells serve roles in reproductive tissues that are not unique to one sex. Finally, CD3+ cell populations in the post-partum period were found to be controlled to some extent by lactation. Collectively, this work has significantly extended our understanding of leukocytes in various tissues in the post-partum period, and revealed the importance of chemokines in the regulation of these cells. It has laid the groundwork for future investigations aimed at dissecting the functions of these cells in reproductive tissues in the post-partum period.

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A number of women continue to smoke in pregnancy despite the associated risks to their health and that of their unborn child. Little is known about their attitudes towards the smoking cessation support which is available to them and this thesis used a Theory of Planned Behaviour (TPB) approach to investigate this further. Study One was a qualitative investigation designed to elicit pregnant women's views about NHS Stop Smoking Services and Nicotine Replacement Therapy (NRT). Interviews were conducted with 18 pregnant smokers, recent quitters and new mothers who smoked in pregnancy, and 18 health professionals working in smoking cessation services. A number of behavioural, normative and control beliefs were generated with respect to these behaviours. As there is evidence for inconsistent smoking cessation advice giving in pregnancy and a lack of confidence amongst health professionals in this area, a theory-based resource to facilitate the communication of smoking cessation information in pregnancy was developed in Study Two and tested in an exploratory randomised controlled trial. The 22 second year medical students who viewed the theory-based resource in preparation for a mock interview were not significantly better at eliciting the salient smoking cessation beliefs of the simulated patient (mean score 8.41) than the 18 second year medical students who received a standard information resource (mean score 7.67). However, the resource showed potential to facilitate the delivery of a more patient centred interview and is worthy of further testing. The themes generated in Study One were used to inform the development of a TPB questionnaire to predict NRT use in pregnancy (NRTP-LF) in Study Three. This questionnaire was completed by 100 pregnant smokers who were recruited from antenatal clinics and Stop Smoking Services. The NRTP-LF significantly predicted intention to use NRT in pregnancy, explaining 41.1% of the variance in the outcome variable, justifying the creation of a short form version of it (NRTPSF). In Study Four, the NRTP-SF was tested on a further sample of 204 pregnant smokers recruited from antenatal clinics and Stop Smoking Services and was also shown to have predictive validity with respect to intention to use NRT in pregnancy. It also significantly predicted interest in participation in a trial testing the efficacy and safety of NRT use in pregnancy. It is envisaged that the theory-based communication resource and the NRTP-SF could have practical utility in health care settings and the potential to increase smoking cessation service use and quit rates in pregnancy.

<p> Positive outcomes associated with traumatic stress have been gaining attention over the past 20 years. Posttraumatic growth (PTG) is one such outcome, characterized by changes resulting from struggling with trauma that leave an individual or community with improved wisdom, strengths, or skills in certain areas that they would not have gained without struggling with trauma. The current study looked at PTG among women in residential treatment for substance use and mental health concerns. All women were also pregnant or had a child under one year of age. Pregnant and new mothers are a particularly high-risk group for negative outcomes related to substance use. This was the first study to assess PTG among women who use substances. Participants were 104 women in a six-month residential treatment in central California from 2012-2015. Services included substance use recovery interventions, trauma interventions, parenting education, and individual and group counseling. Ninety-eight percent reported at least minimal PTG; the mean growth score was the equivalent of between a moderate and great degree of growth. Results demonstrated no relationship between trauma symptoms or change in substance use severity and PTG scores. However, consumer satisfaction was related to PTG, with greater satisfaction being related to higher levels of PTG.</p>

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Call number: LD2668 .T4 1957 H3 / Master of Science

Epidemiology has linked preeclampsia (PET) to vitamin D deficiency. To date, studies have focused upon serum 25-hydroxyvitamin D3 (25(0H. )D3) alone as the marker of vitamin D status. We provide strong evidence comprehensive analysis of vitamin D metabolites in pregnancy is highly informative, particularly within the context of PET. Uniquely, analysis of maternal urinary metabolites provides a novel insight into vitamin D and the kidney, with lower 25(0H)D3 and 24,25(0H)2D3 excretion early indicators of a predisposition towards PET. Since vitamin D is a potent regulator of immune function, and the decidua appears a key extra-renal site for vitamin D metabolism, we investigated effects of 1 ,25(0H)2D3 upon decidual uterine natural killer cells and macrophages. We show both express a functional vitamin-D system and demonstrate differential sensitivity to 1 ,25(0H)2D3 compared to their peripheral counterparts. To understand the functional impact of vitamin D, whole transcriptomic analysis of 1,25(0H)2D3-mediated effects upon uNK and macrophages was performed. We show the actions of vitamin D extend far beyond simple immuno-regulation, targeting major cellular functions including migration, adhesion and apoptosis. In particular, our data support effects highly relevant to decidualisation. We anticipate these findings to be highly relevant within the context of vitamin D deficiency, mal placentation and PET.

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