Saudi Cultural Missions Theses & Dissertations
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Item Restricted Role of IDO1 in the Spiral Artery remodeling during pregnancy(Drexel University, 2024-07) Ghaban, Dema; Muller, AlexanderDuring gestation, the trophoectoderm, the outer layer of the blastocyst, engages with the uterine wall to form the placenta, a temporary organ at the maternal-fetal vascular interface. To increase blood flow through the placenta, uterine spiral arteries transform into large, dilated, low-resistance vessels in which the endothelial layer has been replaced by infiltrating extravillous trophoblasts that invade the uterine myometrium. While it has been widely assumed that these invasive trophoblasts drive the spiral artery remodeling (SAR) process, careful temporal analysis has established that SAR initiation occurs prior to trophoblast arrival. Rather, it is decidual immune cells that are implicated in causing the disorganization of vascular cells and separation of smooth muscle layers characteristic of early-stage SAR. Mouse studies have shown that uterine natural killer (uNK) cells, which expand rapidly in the decidua at mid-gestation, are required for SAR to proceed normally and that this activity is dependent on the inflammatory cytokine interferon-gamma (IFNγ). It therefore has been clearly established that inflammation plays a fundamental role in this complex, physiological process, but thus far a detailed understanding of the specific factors involved downstream of IFNγ has remained elusive. Addressing the unresolved role of inflammation in the reshaping the vasculature at this key stage of gestation has been the core focus of my research project. To better understand how the inflammatory microenvironment established by decidual immune cells promotes SAR, it is important to have an assay that quantifiably assesses the remodeling process. To this end, I describe the development of a method whereby sections of mid-gestation mouse embryos are prepared for comparative assessment of SAR initiation based on confocal microscopy-based immunofluorescence quantification of staining for smooth muscle alpha actin (SMA) within individual arterial vessels (Chapter 2). This technique provides a reproducible and objectively quantifiable methodology for monitoring this initial stage of the SAR process for any perturbations that might result from modifications to the inflammatory microenvironment. Trophoblasts must next migrate to the spiral arteries for SAR to proceed, and I further describe the use methods for assessing trophoblast invasiveness as a later aspect of the SAR process using both in vitro human cell and in vivo mouse-based experimental models (Chapter 3). The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) is an IFNγ-inducible protein that is highly expressed in the placenta at mid-gestation. Through its well-established capacity to promote T cell tolerance, IDO1 has gained widespread recognition as a mechanism for protecting hemi-allogeneic fetus from maternal immunity. More recently, our laboratory has determined that a specific myeloid subpopulation that protects neovasculature from IFNγ due to IDO1 mediated activation of the integrated stress response through general control non-derepressible 2 (GCN2) that results in elevated production of interleukin 6 (IL6). Research studies have reported that IDO1 deficiency can induce symptoms akin to preeclampsia in both mice and humans. While these findings suggest a role of IDO1 in decidual vascularization during pregnancy, this has yet to be explored. Altered expression of IL6 and its receptor in decidua have likewise been reported in cases of sporadic miscarriage and in vitro assays have identified IL6 as a potential factor driving trophoblast invasion. Based on our findings in settings of pathological neovascularization, I have investigated the hypothesis that the initiation of SAR similarly runs through IFNγ/IDO1/IL6. In line with previous reports, vessel wall SMA remained significantly elevated in mice lacking IFNγ, and consistent with our hypothesis lack of either IDO1 or GCN2 resulted in a similar retention of SMA. However, in contrast to IDO1 or GCN2 deficiency which only partially attenuated SMA loss, IL6 deficiency blocked SMA loss almost completely, suggesting that IDO1 is not the sole input driving IL6 in this context. IFNγ expression was unaffected in mice lacking IDO1, GCN2 or IL6 despite the defects in vessel wall remodeling observed in these mice while IL6 expression was impaired in mice lacking IFNγ, IDO1 or GCN2 consistent with IFNγ being an upstream driver and IL6 a downstream effector in the SAR process. In addition to these effects on the vessel wall, IL6 was confirmed to promote trophoblast migration in vitro and loss of IFNγ, IDO1, GCN2 or IL6 all compromised trophoblast invasiveness in vivo. Thus, two key features of the SAR process, vessel wall remodeling and trophoblast invasion are subject to control by this inflammatory pathway. These data provide important elucidation of mechanism by which inflammation controls SAR an suggest potential pathways for interventional therapy to mitigate the effects when this process goes awry.9 0Item Restricted A systimatic review of the literature exploring experiences and perceptions of pregnant women regarding physical activity(Cardiff University, 2024-03-22) Hakami, Ghusun; Visser, KarenBackground: Physical activity during pregnancy has been widely acknowledged for its significant benefits to maternal health and fetal development. However, the engagement of pregnant women in physical exercise remains a complex issue, influenced by a myriad of factors ranging from personal beliefs to medical advice. Understanding the experiences and perceptions of pregnant women towards physical activity is crucial for developing interventions that are not only effective but also resonate with their needs and preferences. This systematic review aims to shed light on these perspectives by exploring the multifaceted relationship pregnant women have with exercise. By examining their personal viewpoints, experiences, and the challenges they encounter, this review seeks to provide valuable insights that can guide clinicians and healthcare providers in crafting more targeted and supportive physical activity programs for pregnant women. The ultimate goal is to enhance the well being of both mothers and their unborn children through informed and accessible exercise interventions. Objectives The aim of the review was to ascertain the most reliable evidence available to explore the experiences and perceptions of pregnant women regarding physical activity during pregnancy. This review sought to understand the perspectives of pregnant women towards engaging in physical exercise, focusing on their personal viewpoints and how these activities are integrated into their daily lives during pregnancy. Additionally, it aimed to investigate the specific challenges pregnant women face in participating in physical activity and to uncover any recurring themes arising from their experiences. By examining these aspects, the review intends to provide insights that could assist clinicians and healthcare practitioners in devising more personalized and effective physical activity interventions tailored to the needs of pregnant women. Inclusion criteria: The review focused on pregnant women from diverse backgrounds and at different stages of their trimesters, who had engaged in physical activity during their pregnancy. It concentrated on those participating in both structured exercise programs and informal physical activities. A comprehensive database search was initiated following the formulation of a search strategy, with a preference for studies that were qualitative in nature. A total of 671articles were retrieved, and 6 of these studies were considered appropriate for the critical appraisal process. Utilizing the Joanna Briggs Institute (JBI) guidelines, two reviewers employed a specially developed appraisal tool suitable for qualitative studies. Six studies were ultimately deemed suitable for final inclusion and data extraction. The data extraction was primarily undertaken by one reviewer, utilizing the JBI QARI Data Extraction Form for Interpretive & Critical Research, with a consensus reached on the findings. Meta aggregation was employed for data synthesis, creating categories based on similarities in the themes that emerged from the data. Results This systematic review synthesized qualitative studies to understand pregnant women's experiences and perceptions of physical activity, revealing significant insights across variousdimensions. Pregnant women from five countries reported a crucial need for clear, consistent guidance from healthcare professionals on safe exercise practices, often facing misinformation and inconsistency in advice that affected their engagement in physical activity. Psychological and social influences, including fear of harm to the fetus and cultural norms around rest, significantly impacted their physical activity levels. Barriers to exercise were multifaceted, encompassing both intrinsic fears related to pregnancy outcomes and extrinsic factors like time constraints and physical discomforts. Accessibility to suitable exercise facilities and motivation from social support circles were identified as key enablers, whereas safety concerns, particularly in shared facilities during the COVID-19 pandemic, posed additional challenges. Across the studies, the meta-aggregation synthesis created categories based on similarities, emphasizing the diverse yet common experiences that shape pregnant women's attitudes and behaviors towards physical activity, underscoring the importance of addressing these factors to promote healthier pregnancy outcomes12 0Item Restricted The Efficacy and Safety of Vitamin D Supplementation during Pregnancy on the Incidence Rate of Pre-Eclampsia: a Systematic Review of Maternal and Infant Health Outcomes(Saudi Digital Library, 2023-12-01) Alanazi, Rehab; McCullough, FionaBackground: The aetiology of pre-eclampsia (PE) remains poorly understood, yet recent research suggests that an increase in inflammatory mediators produced by the placenta may be a potential causative mechanism. To date, studies published on vitamin D (Vit D) emphasise the association between its deficiency and the development of PE. However, data regarding the efficacy of Vit D supplementation in reducing PE risk are inconclusive. Objective: This systematic review aimed to evaluate the effect of Vit D supplementation on the incidence of PE, preterm delivery, Caesarean section (C- section), and 25(OH)-D serum levels, assess the safety of supplements for pregnant women, and determine the optimal supplementation strategy. Methodology: A systematic search of four databases (PubMed, Web of Science, Embase via Ovid, and Scopus) was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) of full-text English- language papers published from 2013 to 2023. Eligible studies were randomised controlled trials (RCTs) that examined the effects of Vit D supplementation on the incidence of PE and maternal and infant outcomes referring to birth weight, preterm delivery, C-section and 25(OH)-D levels. An independent t-test was performed to compare the mean difference between groups. Results: In total, six RCTs with a total sample size of 762 pregnant women were included and showed that prenatal Vit D supplementation was associated with a non- significant decrease in PE risk (8.47± 8.070 vs 15.59±9.522, P=0.193) and birth weight (BW) (2957.75±296.679 vs. 2819.47±313.248g, P= 0.545), preterm delivery (7.07 % vs 15.92 %, P=0.165) C-section (37.55 vs 42.80 %, P=0.464) and 25(OH)-D levels (46.11±7421 nmol/l vs 80±51.53 nmol/l. P=0.143). Moreover, no major side effects were reported. Conclusion: Vit D supplementation during pregnancy is a potential safe intervention strategy for preventing preeclampsia in pregnancy. However, the impact of the supplementation was not significant on PE odds, birth weight, preterm delivery C- section and 25(OH)-D levels; thus, more RCTs are needed to determine the optimal strategy in terms of population-specific dose recommendations and ideal timing.16 0Item Restricted Melanin Nanoparticles as a Potential Iron Chelation Therapy for Women with Beta Thalassemia during Pregnancy(2022-12-09) Bakhamis, Nahla; Townley, HelenThe main challenges in developing medications that are safe to use during pregnancy is to minimize foetal exposure to the drug, which has become increasingly challenging with the increased prevalence of chronic conditions among young women. In beta thalassemia, patients can now survive beyond puberty and achieve pregnancy. β-TM pregnancies, however, are at high risk of maternal morbidity due to the complication of iron overload. Current chelation medications are withheld during pregnancy as they can cross the placenta causing potential risk to the foetus. This thesis addressed this complicated challenge in which a chelation agent needs to be retained in the maternal circulation and not cross the placenta. Previous experiments in iron-overloaded mice have shown that melanin nanoparticles can effectively chelate iron. Since the interaction between nanoparticles and cells/tissues is determined by particle characteristics and functionalization that can manipulated at synthesis, it was hypothesized that a melanin nanoparticulates with appropriate characteristics could be restricted from movement across the placenta, and safely used to treat the mother. A library of melanin nanoparticles of different sizes was established, and functionalized. This was followed by particle characterization and imaging. Functional analysis confirmed that particles were able to chelate iron more effectively than the iron chelator desferroxamine at the same concentration. Haemocompatibility testing found that the particles did not cause red cell haemolysis or blood clots. Moreover, it was determined that a cut off size of 200 nm can be restricted from passing across the placental barrier in an in vitro model using a human choriocarcinoma cell line and ex vivo human placental perfusion. Finally, physiological changes during pregnancy such as the decrease in plasma albumin concentrations can alter the volume of distribution as well as the transport of drugs. Proteomics analysis was used to identify nanoparticle binding proteins in the serum from pregnant women, non-pregnant women, and women with beta thalassemia. 43 significantly different proteins between the three serum groups were identified, followed by the gene ontology analysis of cellular components that revealed the mediation of biological identity of the bio-inspired melanin in the biological system.22 0