Saudi Cultural Missions Theses & Dissertations
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Item Restricted Evaluation of Acute Cardiorespiratory Disease: Integrating Metabolite-wide Analysis and Lung Mechanics Pathophysiology(Leicester University, 2024-01-30) Aljaroof, Masarrah Yousif; Greening, NeilChallenges in studying acute life-threatening events and a knowledge gap in biomarker exploration for overlapping cardio-respiratory conditions necessitate further investigation. This thesis aims to bridge the gap by identifying additional biomarkers using metabolomics and physiological measures in acute cardio-respiratory conditions. Our hypotheses aim to test the differentiation power of plasma metabolomic profiles, characterize ventilation heterogeneity, and identify of metabolic dysfunction in lipid mediators in acute cardiorespiratory conditions. Methods: We employed a multidimensional approach using LC-MS and GC-MS platforms to analyze plasma, breath, and sputum samples from the same population. The following studies were conducted: (1) Metabolite analysis in blood plasma samples of n = 54, in which n = 20 acquired from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients and n = 20 acquired from acute heart failure (AHF) patients, compared to n = 14 samples acquired from healthy volunteers. (2) Breath data analysis for ventilation heterogeneity involved 310 subjects using the FOT test, with a subgroup of 208 with published VOC measurements (1, 2), The analysis aimed to investigate the association between identified VOC metabolomics disturbances and respiratory impedance. (3) Prospective study using n = 141 sputum samples of AECOPD, acute asthma, pneumonia patients, and healthy control group targeting 13 metabolomic markers of inflammation resolution and comparing the results to a sub-cohort of n = 45 during stable status. Results: (I) Mass spectral analysis identified 2193 compounds in plasma samples of AECOPD, AHF, and healthy subjects. Biomarker scores of 19 metabolites (9 features associated with AECOPD and 10 with AHF) demonstrated ≥70% sensitivity and specificity in distinguishing between ACOPD, AHF, and health. (II) Resistance at 5 and 5-19 Hz as well as reactance at 5 Hz, area under the reactance AX, and resonant frequency were significantly different (p <0.000) between all groups; moreover, (p <0.05) indicated the significant impact of respiratory system compliance on the recovery of O, N, and S VOCs in exhaled breath. (III) Group comparisons revealed significant differences in lipid mediator PGE2 levels (p <0.01), with no significant differences observed in stable cohorts. Correlation analysis showed a negative association between eosinophil count and PGE2 levels (coefficient = -0.21, p <0.05) and a positive association between neutrophil count and PGE2 levels (coefficient = 0.24, p <0.05). Conclusion: This research highlights the potentials of metabolomics, both in targeted and untargeted approaches, along with the integration of bioinformatic statistical models in effectively differentiating between conditions with an overlapping pathology in an acute exacerbation’s events and healthy volunteers. Additionally, the study demonstrates the feasibility of utilizing handheld FOT as a valuable tool for assessing respiratory system mechanics in the acute care setting. Furthermore, examining the relationships between the analysed metabolites and other clinical observations adds to our understanding of acute cardio-respiratory conditions. These findings provide valuable insights that can contribute to the development of improved diagnostic strategies in the future.21 0Item Restricted Investigating the mechanisms underpinning antipsychotic-mediated pneumonia(Saudi Digital Library, 2023-11-01) Howsawi, Alanood; Caroline, Copeland; Athanasios, SekerisBackground: The mechanisms behind the association between antipsychotics and pneumonia risk remain inadequately understood. Existing studies propose that antipsychotics might attenuate the immune response through cytokine modulation. The present study aimed to explore the impact of olanzapine and quetiapine on surface markers expression and cytokines released by CD4+ lymphocytes. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from four healthy volunteers. Olanzapine doses (6, 20, and 60 ng) and quetiapine doses (15, 50, 150 ng) were employed. The cells were stimulated with Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). Stimulated cells were treated with olanzapine or quetiapine and compared to control cells. Flow cytometry was used to analyse CD25, CD28, CD127 (IL-7R-a), CD152 (CTLA4), CD274 (PD-L1), CD279 (PD-1) markers, and cytokines IL-2, IL-10, and IFN-Y. Statistical analyses were performed with GraphPad Prism 9.0, employing one way- analysis of variance (ANOVA) and Friedman tests (P < 0.05 for significance). Results: Olanzapine and quetiapine increased CD25 expression, with olanzapine 20 ng reached statistical significance in PA-stimulated cells. PD-L1 expression exhibited an upward trend in SA-stimulated cells treated with both drugs, with quetiapine 15 ng being significant. Both drugs significantly increased CD28 expression in the stimulated cells. CD152 decreased slightly with therapeutic doses of both drugs in PA-stimulated cells. CD127 and PD-1 expressions remained unchanged. Regarding cytokines, olanzapine 6 ng significantly reduced IL-2 release in stimulated cells, while quetiapine caused a mild IL-2 release in PA-stimulated cells. IFN-Y release slightly dropped in PA-stimulated cells in both drugs. Quetiapine slightly lowered IFN-Y release in SA-stimulated cells, whereas olanzapine left IFN-Y unchanged. IL-10 release decreased significantly with olanzapine 6 ng and 20 ng in PA and SA-stimulated cells, and quetiapine led to a slight reduction in IL-10 release. Conclusions: This in vitro study revealed how olanzapine and quetiapine affect CD4+ markers and cytokines. It emphasizes immune reduction via elevated CD25 and PD L-1 markers, known to decrease activated T-cells. Reduced immune response is evidenced by lower cytokine levels from activated T-cells, possibly increasing infection susceptibility, including pneumonia. Immune stimulation via CD28 and CD152 modulation might induce immunosuppression over time, exacerbating infection risk. Further studies are warranted to investigate the impact of antipsychotics on immune cells surface markers to better understand their immunomodulatory effects.5 0