Academic literature on the topic 'RC Internal medicine : RG Gynecology and obstetrics'

The mechanisms by which immune tolerance is maintained during human pregnancy are unclear but include a range of modifications to the local and systemic maternal immune system. There is considerable T cell infiltration of the maternal decidua during pregnancy, however, the functional properties of this T cell response remains poorly defined. We investigated the specificity and regulation of CD4+ and CDS+ T cells in human third trimester decidua and show that the ratio of highly differentiated effector to naive CD4+ and CDS+ T cells is increased markedly in comparison to peripheral blood. Decidual T cells were also found to display a unique functional profile with simultaneous production of interferon-y (IFN -y) and interleukin 4 (IL-4 ). Decidual T cells proliferated in response to fetal tissue, a function that was regulated by T regulatory cells, and HY -specific T cells with high levels ofProgrammed Death Protein 1 (PD-1) were detectable in the decidua of women with male pregnancies. Transcriptional analysis of CD4+ and CDS+ decidual T cells revealed a unique gene profile characterized by elevated expression of proteins associated with the response to interferon signaling. These data have considerable importance for the investigation of fetal-specific alloreactive immune responses within disorders of pregnancy.

Background: Research suggests that postnatal affective disorders such as anxiety, depression and post-traumatic stress disorder (PTSD) are associated with lower levels of maternal sensitivity. Understanding the mechanisms through which maternal affective disorders influence maternal sensitivity is important as it could lead to more tailored effective interventions to improve outcomes for women and their infants. One mechanism that is yet to be explored is the way in which mothers' process infant-related information. This thesis therefore developed a cognitive model that aimed to examine this mechanism. Aim: The aim of this thesis was to test this cognitive model of maternal sensitivity using a range of experimental, observational and questionnaire studies. The model proposed that maternal affective symptoms would be associated with maternal processing of infant-related information, which in turn would be associated with maternal sensitivity. Methods & Results: The aims were addressed through a systematic review and a study of women with (n = 23) and without (n = 47) affective symptoms and their infants (aged 2-8 months) after birth. The systematic review found that mothers with perinatal affective disorders are faster to disengage from sad infant faces and are more accurate at identifying sadness in infant faces (Article 1). To assess how mothers process infant-related information, validated pictures of infants' emotional faces were needed. Therefore, a validated set of infant emotional expressions was created and validated on student midwives and nurses and members of the general public. The images were found to have high criterion validity and good test-retest reliability (Article 2). Mothers processing of infant-related information and its relationship with maternal sensitivity was tested using a series of questionnaires, computerised and observational tasks. Results are reported in Articles 3, 4 and 5. Conclusion: Overall, the cognitive model of maternal sensitivity was only partly supported, in that maternal affective symptoms explained more of the variance of maternal sensitivity than maternal processing of infant-related information. Despite this, the work in this thesis provides a novel contribution to the literature by developing and testing a model based on previous research and by using robust measures such as eye-tracking technology and observational measures of mother-infant interaction. However, interpretation of the data is hindered due to methodological issues such as small sample sizes, homogeneous sample and demand characteristics. Therefore, more research is needed to test this model on a larger, more heterogenous sample.

This study reports on the analysis of 59 in-depth interviews conducted with people diagnosed with, or from families affected by, Spinal Muscular Atrophy (SMA). It focuses on attitudes towards, and actual uses of, prenatal testing and selective termination for SMA in reproductive decision making for this group of people, in order to focus on the role of experiential knowledge of SMA and its relationship to expert medical knowledge, within these highly complex decisions. Experiential knowledge has been described in the literature as knowledge derived from experience, whether ‘embodied’ (i.e. sensory) or ‘empathetic’ (i.e. based on the experiences of others). Experiential knowledge has frequently been positioned as being in opposition to, or even conflicting with, medical knowledge, particularly by feminists and disability rights supporters, for whom the tensions between experiential knowledge and medical knowledge have political significance. However, this research found the relationship between expert and experiential knowledge to be both fluid and dynamic, which had important implications for the way in which SMA was conceptualised, understood and responded to by families living with it. Whilst participants’ accounts of SMA were thoroughly grounded in their day-to-day realities with the condition, this knowledge always existed in and through a relationship with expert medical knowledge of SMA. The inherent uncertainties within and between experiential and expert knowledge, and the ways of conceptualising SMA that emerged from them, however, rather than alleviating, instead contributed to, and heightened, some of the social, ethical and moral dilemmas these families experienced around reproductive decision making. Indeed, many participants became trapped within these ways of knowing SMA and the internal contradictions they contained, whilst for others, the strategic privileging of one form of knowledge as ‘authentic’ over the other became the only way to escape some of these dilemmas, and clarify where their reproductive responsibilities lay.

Insulin resistance and androgen excess are the cardinal phenotypic features of polycystic ovary syndrome (PCOS). The severity of hyperandrogenism and metabolic dysfunction in PCOS are closely correlated. Aldoketoreductase type 1C3 (AKR1C3) is an important source of androgen generation in human adipose tissue, and may represent a link between androgen metabolism and metabolic disease in PCOS. We performed integrated in vitro studies using a human preadipocyte cell line and primary cultures of human adipocytes, coupled with in vivo deep phenotyping of PCOS women and age- and BMI-matched controls. We have shown that insulin upregulates AKR1C3 activity in primary female subcutaneous adipocytes. AKR1C3 mRNA expression increased with obesity. Androgens were found to increase lipid accumulation in human adipocytes. In clinical studies, androgen exposure induced relative suppression of adipose lipolysis in PCOS women, supporting a role for androgens in lipid accumulation. Androgens were detectable in adipose fluid from PCOS women, and correlated with systemic markers of androgen metabolism. Using comprehensive in vivo, ex vivo, and in vitro techniques, we have shown regulation of adipose androgen generation through AKR1C3, with evidence of a vicious circle of hyperinsulinaemia, adipose androgen generation and lipid accumulation. These data identify AKR1C3 as a promising therapeutic target in PCOS.

Hypertension is one of the most common medical conditions complicating pregnancy, with significant implications on maternal and perinatal morbidity and mortality. Abnormalities in placentation have been implicated as the primary pathology responsible for the development of hypertension during pregnancy and its effects such as pre-eclampsia and eclampsia. With advancing research, the focus is now gradually shifting towards abnormalities in the maternal vasculature, including endothelial damage/dysfunction and impaired repair as a probable cause for this, with the latter also being implicated in the development of cardiovascular disorders in later life in these women. Hypertensive disorders occur in 6-8% of pregnancies. They also determine and influence the development of cardiovascular disease (CVD) in the mother in later life. Hypertension, obesity, metabolic syndrome and CVD are commoner in women with pre-eclampsia and preterm deliveries, whereas the risk of cerebrovascular disease is much higher in those with recurrent spontaneous abortions. This research thesis is a study of the various processes occurring in the maternal vasculature, including angiogenesis, apoptosis, endothelial damage and regeneration/repair, the extra-cellular matrix and the haem oxygenase systems, the abnormalities that occur in them and their associations with hypertensive disorders of pregnancy and their complications.

The multiple pterygium syndromes are a heterogeneous group of conditions in which arthrogryposis (joint contractures), pterygia (webbing) and a variety of other developmental anomalies are present. It is caused by lack of fetal movement in the womb. Mutations in CHRNG, the embryonic subunit of the acetylcholine receptor (AChR), cause some of the cases. CHRNG mutation analysis was undertaken in a large patient cohort of 100 families and the mutations identified were included in a new Locus Specific Database. Genotype phenotype analysis showed that pterygia were almost invariably present in the CHRNG mutation positive patients. It was hypothesised that mutations in other genes necessary for fetal AChR function may cause fetal akinesia. Using a candidate gene approach a homozygous frameshift mutation in RAPSN was identified in one family and a homozygous splice site DOK7 mutation in second family. Mild mutations in both RAPSN and DOK7 have been previously identified in the congenital myasthenic syndromes (CMS). Thus, mild mutations in RAPSN and DOK7 cause CMS whereas severe mutations cause fetal akinesia. Finally, work was done to identify a novel cause of fetal akinesia in a consanguineous family using an autozygosity mapping approach. A region of homozygosity was located and candidate genes sequenced.

Environmental challenges during early life have been shown to result in greater risk of chronic diseases such as diabetes and coronary disease in later life. Factors such as unbalanced nutrition before birth result in metabolic and structural adaptations that lead to persistent modifications to offspring phenotype. There is evidence that respiratory disease is influenced by developmental environment. Reduced fetal growth is associated with impaired lung development, increasing risk of developing asthma and Chronic Obstructive Pulmonary Disease (COPD) in later life. To investigate the mechanisms underlying these effects, it is necessary to utilise animal models that emulate the phenotypes observed in human studies. The aim of this thesis was to investigate whether exposure to a maternal low protein diet in utero affects offspring lung morphology, bronchial hyperresponsiveness (BHR) and global methylation and/or gene expression in Wistar rats. Pregnant Wistar rats were allocated to either control (C, 18% casein) or protein restricted (PR, 9% casein) diet. Lung tissue was harvested (225 days) from male offspring (F1, (28 days, C=15; PR=10, 120 days, C=11; PR=7, 225 days: C=6; PR=6) F2, (28 days, C=24; PR=17) and F3 (21 days, C=16; PR=5)). Lungs were removed and the left lung was sectioned and haematoxylin and eosin stained, imaged at 10x magnification and using stereological methods, point counted to give volume fractionation of selected areas. Other morphological measurements were made to estimate surface area (10x magnification), and alveolar wall thickness (63x magnification). Primary bronchi were dissected out, mounted in a myograph and bronchoconstriction in response to a range of bronchoconstrictors and bronchodilators was assessed. RNA and DNA were extracted using TRIzol ® and global methylation assessed using MethylampTM Global DNA Methylation Quantification Ultra Kit. There was no significant difference in either lung volume or lung structure between the F1 or F2 offspring of control of PR exposed mothers except for a significant increase (p=0.046) in the amount of smooth muscle around blood vessels in the protein restricted group in the F1 225 day old group. However, in assessment of constrictor responses of isolated bronchi, a significant difference in response between groups was found with both carbachol, an acetylcholine mimetic, and U44619, A thromboxane mimetic, with the F1 offspring from protein restricted mothers exhibiting significantly increased BHR at 75 days of age (p=<0.001) compared to controls. No significant difference in global DNA methylation in lung tissue was found between F1 of F2 offspring of mothers exposed to the control of PR diet during pregnancy. Gene expression levels of selected candidate genes in lung tissue were then assessed using qPCR and again no differences were found between groups. In this study there is no evidence to suggest that in utero exposure to a maternal low protein diet has affected offspring lung physiology, structure, methylation patterns or gene expression. However, there could be differences in the amount of smooth muscle found around the vessels in response to this nutritional challenge as protein restricted animals appear to have more smooth muscle compared to controls. BHR was observed in the 75 day old rats indicating a possible shift towards a priming of asthma phenotype which could be induced with post natal allergen challenges.

For many centuries, malaria has remained the most common parasitic disease in sub-Saharan Africa potentially placing 32 million pregnancies at risk each year. Malaria in pregnancy (MiP) in malaria endemic Africa is mostly asymptomatic or paucisymptomatic, yet associated with maternal anaemia and intra-uterine growth retardation resulting in low birth weight (LBW) which is an important risk factor for infant mortality (chapter 1). In Mali, several observational studies have determined the risk and consequences of malaria in pregnancy. However, national estimates of the burden of MiP and its potential impact are lacking. This thesis describes the results of a series of surveys conducted in different malaria transmission settings countrywide from 2005 to 2010, to quantify the burden and consequences of MiP in Mali (chapter 2). Results demonstrate that the risk of malaria infection at delivery was generally high ([average prevalence 11.6%]) and showed marked diversity between regions and transmission settings. Coverage of intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) and impregnated treated bednets (ITNs) was low (30.4% and 60.7%) and indicated important miss opportunities for the control of PAM. To prevent the disease and its consequences in pregnancy, the World Health Organization recommends IPTp using SP and use of an ITN. For IPTp, the recommended regimen consists of at least 2 doses of SP given during the second and third trimesters for HIV negative women and at least 3 doses for HIV-positive women not receiving cotrimoxazole. However, there are concerns that the 2-dose regimen, which provides at most 12 weeks of prophylaxis, leaves many women unprotected for as much as half of the 20-26 pregnancy weeks after quickening. Re-infection with the 2-dose regimen is common, especially during the transmission seasons and amongst women who complete their last dose early in the third trimester. A trial was therefore conducted to compare the standard 2-dose regimen versus 3 doses using SP, hypothesizing that the third dose may add significant benefit over the 2-dose regimen in preventing placental malaria and other birth outcomes (chapter 3). The study concluded that IPTp-SP with 3-doses was superior to the standard 2-dose regimen and resulted in better birth outcomes. The results of this trial were then combined with 6 similar trials as part of a meta-analysis assessing if 3 or more doses of IPTp-SP are more effective than the current standard 2-dose regimen. The pooled results suggested a marked benefit of adding extra SP doses over the standard 2-dose regimen in both regions of high and low SP resistance as measured by the prevalence of dihydropteroate synthase K540E mutations (chapter 4). Although studies from western Africa favour the use of IPTp-SP, SP resistance is now a serious threat to the longevity of IPTp with SP in parts of eastern and southern Africa where the quintuple dihydofolate reductase (N51I, C59L, S108N) /dhps (A437G, K540E) mutation is saturated in many places. In order to get a better understanding of the impact of SP resistance on IPTp effectiveness, this thesis also determined the in vivo response of parasites in asymptomatic parasitaemic pregnant women who received IPTp-SP and the effectiveness of IPTp-SP on birth parameters in West-Africa (chapter 5 & 6) Overall, the study concluded that SP resistance in Mali and Burkina Faso is low and that the IPT-SP is associated with clinically relevant improvements in birth outcomes in Mali.

Embryo implantation represents a complex process vital in ensuring the normal development of pregnancy. Whether embryo implantation is the goal of natural conception or assisted reproductive treatment, the environment within the uterine cavity must be optimised in order to increase the chance of pregnancy. This thesis uses a mixture of research methods to investigate potential approaches to improving embryo implantation. Below are the key findings from this thesis: 1. The vitamin D status in women undergoing assisted reproductive treatment is important. An interventional trial would prove or disprove the merits of vitamin D deficiency treatment in these women. 2. There is not enough evidence to suggest a clear association between vitamin D and recurrent miscarriage, however there is a strong argument for biological plausibility. 3. The use of endometrial fluid collected at the time of embryo transfer in women undergoing assisted reproductive treatments for metabolomics analysis is possible. 4. Women with hydrosalpinx associated tubal infertility should be offered salpingostomy as a treatment option as the natural conception rates are similar to that achieved in in vitro fertilisation treatment.