The role of complement and complement regulatory proteins in the progression of atherosclerosis

Whilst evidence from human studies suggests that complement activation is pro-atherogenic, studies using animals models of the disease, including the low density receptor deficient (ldlr-/-) and apolipoprotein E deficient (apoE-/-) mouse models, contradict one another. The hypothesis underpinning this thesis is that the complement system contributes to disease pathology in atherosclerotic plaques of apoE-/- mice. The work focussed on the membrane attack complex (MAC) of the terminal pathway and the central component of the complement system, C3. I have shown that in the absence of the MAC regulator CD59a, apoE-/- mice had accelerated atherosclerosis compared to controls, accompanied by increased MAC activation within the plaques. In accordance, C5 deficiency was protective against atherosclerosis in apoE-/- mice, a result of absence of MAC in these mice. However, MAC inhibition using an anti-C5 antibody in apoE-/- mice did not inhibit progression of atherosclerosis. Surprisingly, in the absence of CD55, apoE-/- mice had smaller atherosclerotic lesions together with an anti-atherogenic lipoprotein profile and increased C3 activation product, C3adesArg, in their plasma. The data reveal a novel role for CD55 during lipid metabolism and, together with published data on the metabolic role of C3adesArg, highlight the need for further investigations into the role of complement during lipid metabolism.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The role of complement and complement regulatory proteins in the progression of atherosclerosis

Whilst evidence from human studies suggests that complement activation is pro-atherogenic, studies using animals models of the disease, including the low density receptor deficient (ldlr<super>-/-</super>) and apolipoprotein E deficient (apoE<super>-/-</super>) mouse models, contradict one another. The hypothesis underpinning this thesis is that the complement system contributes to disease pathology in atherosclerotic plaques of apoE<super>-/-</super> mice. The work focussed on the membrane attack complex (MAC) of the terminal pathway and the central component of the complement system, C3. I have shown that in the absence of the MAC regulator CD59a, apoE<super>-/-</super> mice had accelerated atherosclerosis compared to controls, accompanied by increased MAC activation within the plaques. In accordance, C5 deficiency was protective against atherosclerosis in apoE<super>-/-</super> mice, a result of absence of MAC in these mice. However, MAC inhibition using an anti-C5 antibody in apoE<super>-/-</super> mice did not inhibit progression of atherosclerosis. Surprisingly, in the absence of CD55, apoE<super>-/-</super> mice had smaller atherosclerotic lesions together with an anti-atherogenic lipoprotein profile and increased C3 activation product, C3adesArg, in their plasma. The data reveal a novel role for CD55 during lipid metabolism and, together with published data on the metabolic role of C3adesArg, highlight the need for further investigations into the role of complement during lipid metabolism.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Flow rate and source reservoir identification from airborne chemical sampling of the uncontrolled Elgin platform gas release

An uncontrolled gas leak from 25 March to 16 May 2012 led to evacuation of the Total Elgin well head and neighbouring drilling and production platforms in the UK North Sea. Initially the atmospheric flow rate of leaking gas and condensate was very poorly known, hampering environmental assessment and well control efforts. Six flights by the UK FAAM chemically-instrumented BAe-146 research aircraft, were used to quantify the flow rate. Where appropriate, two different methods were used to calculate the flow rate: 1. Gaussian plume fitting in the vertical and 2. Direct integration of the plume. When both methods were used, they compared within 6 % of each other and within combined errors. Data from the first flight on 30 March 2012 showed the flow rate to be 1.3 ± 0.2 kg CH4 s−1, decreasing to less than half that by the second flight on 17 April 2012. δ13CCH4 in the gas was found to be −43 ‰, implying that the gas source was unlikely to be from the main high-pressure high-temperature Elgin gas field at 5.5 km depth, but more probably from the overlying Hod Formation at 4.2 km depth. This was deemed to be smaller and more manageable than the high-pressure Elgin field and hence the response strategy was considerably simpler. The first flight was conducted within 5 days of the blowout and allowed a flow rate estimate within 48 hours of sampling, with δ13CCH4 characterisation soon thereafter, demonstrating the potential for a rapid-response capability that is widely applicable to future atmospheric emissions of environmental concern. Knowledge of the Elgin flow rate helped inform subsequent decision making. This study shows that leak assessment using appropriately designed airborne plume sampling strategies is well suited for circumstances where direct access is difficult or potentially dangerous. Measurements such as this also permit unbiased regulatory assessment of potential impact, independent of the emitting party, on timescales that can inform industry decision-makers and assist rapid response-planning by government

Flow rate and source reservoir identification from airborne chemical sampling of the uncontrolled Elgin platform gas release

An uncontrolled gas leak from 25 March to 16 May 2012 led to evacuation of the Total Elgin well head and neighbouring drilling and production platforms in the UK North Sea. Initially the atmospheric flow rate of leaking gas and condensate was very poorly known, hampering environmental assessment and well control efforts. Six flights by the UK FAAM chemically-instrumented BAe-146 research aircraft, were used to quantify the flow rate. Where appropriate, two different methods were used to calculate the flow rate: 1. Gaussian plume fitting in the vertical and 2. Direct integration of the plume. When both methods were used, they compared within 6 % of each other and within combined errors. Data from the first flight on 30 March 2012 showed the flow rate to be 1.3 ± 0.2 kg CH4 s−1, decreasing to less than half that by the second flight on 17 April 2012. δ13CCH4 in the gas was found to be −43 ‰, implying that the gas source was unlikely to be from the main high-pressure high-temperature Elgin gas field at 5.5 km depth, but more probably from the overlying Hod Formation at 4.2 km depth. This was deemed to be smaller and more manageable than the high-pressure Elgin field and hence the response strategy was considerably simpler. The first flight was conducted within 5 days of the blowout and allowed a flow rate estimate within 48 hours of sampling, with δ13CCH4 characterisation soon thereafter, demonstrating the potential for a rapid-response capability that is widely applicable to future atmospheric emissions of environmental concern. Knowledge of the Elgin flow rate helped inform subsequent decision making. This study shows that leak assessment using appropriately designed airborne plume sampling strategies is well suited for circumstances where direct access is difficult or potentially dangerous. Measurements such as this also permit unbiased regulatory assessment of potential impact, independent of the emitting party, on timescales that can inform industry decision-makers and assist rapid response-planning by government

Evaluation of FTIR Spectroscopy as a diagnostic tool for lung cancer using sputum

BACKGROUND: Survival time for lung cancer is poor with over 90% of patients dying within five years of diagnosis primarily due to detection at late stage. The main objective of this study was to evaluate Fourier transform infrared spectroscopy (FTIR) as a high throughput and cost effective method for identifying biochemical changes in sputum as biomarkers for detection of lung cancer. METHODS: Sputum was collected from 25 lung cancer patients in the Medlung observational study and 25 healthy controls. FTIR spectra were generated from sputum cell pellets using infrared wavenumbers within the 1800 to 950 cm(-1 )"fingerprint" region. RESULTS: A panel of 92 infrared wavenumbers had absorbances significantly different between cancer and normal sputum spectra and were associated with putative changes in protein, nucleic acid and glycogen levels in tumours. Five prominent significant wavenumbers at 964 cm(-1), 1024 cm(-1), 1411 cm(-1), 1577 cm(-1 )and 1656 cm(-1 )separated cancer spectra from normal spectra into two distinct groups using multivariate analysis (group 1: 100% cancer cases; group 2: 92% normal cases). Principal components analysis revealed that these wavenumbers were also able to distinguish lung cancer patients who had previously been diagnosed with breast cancer. No patterns of spectra groupings were associated with inflammation or other diseases of the airways. CONCLUSIONS: Our results suggest that FTIR applied to sputum might have high sensitivity and specificity in diagnosing lung cancer with potential as a non-invasive, cost-effective and high-throughput method for screening. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0089926

Complement activation in polycystic ovary syndrome occurs in the post-prandial and fasted state, and is influenced by obesity and insulin sensitivity

Objective: Polycystic ovary syndrome (PCOS) is associated with metabolic risk. Complement proteins regulate inflammation and lipid clearance but their role in PCOS‐associated metabolic risk is unclear. We sought to establish whether the complement system is activated in PCOS in the fasting and postprandial state. Design: Case‐control study. Patients: Fasting complement levels were measured in 84 women with PCOS and 95 healthy controls. Complement activation post‐oral fat tolerance test (OFTT) was compared in 40 additional subjects (20 PCOS, 20 controls). Measurements: Activation pathway (C3, C4, C3a(desArg), factor B, factor H, properdin, Factor D) and terminal pathway (C5, C5a, terminal complement complex [TCC]) proteins were measured by commercial or in‐house assays. Results: Fasting C3, C3a(desArg) and TCC concentrations were increased in insulin‐resistant (adjusted differences: C3 0.13 g/L [95%CI 0‐0.25]; C3a(desArg) 319.2 ng/mL [19.5‐619]; TCC 0.66 μg/mL [0.04‐1.28]) but not in insulin‐sensitive women with PCOS. C3 and factor H levels increased with obesity. Post‐OFTT, C3 and C4 levels increased to a similar extent in PCOS subjects and controls, whist factor H levels increased more in women with PCOS compared to controls (adjusted differences (area under the curve): 12 167 μg min/mL [4942‐19 392]), particularly in the presence of concomitant obesity. Conclusions: Activation and terminal complement pathway components are elevated in patients with PCOS, especially in the presence of insulin resistance and obesity

A Narrative Review of Chronic Kidney Disease in Clinical Practice: Current Challenges and Future Perspectives

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world's population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD

Transgenic wheat expressing a barley class II chitinase gene has enhanced resistance against Fusarium graminearum

Fusarium head blight (FHB; scab), primarily caused by Fusarium graminearum, is a devastating disease of wheat worldwide. FHB causes yield reductions and contamination of grains with trichothecene mycotoxins such as deoxynivalenol (DON). The genetic variation in existing wheat germplasm pools for FHB resistance is low and may not provide sufficient resistance to develop cultivars through traditional breeding approaches. Thus, genetic engineering provides an additional approach to enhance FHB resistance. The objectives of this study were to develop transgenic wheat expressing a barley class II chitinase and to test the transgenic lines against F. graminearum infection under greenhouse and field conditions. A barley class II chitinase gene was introduced into the spring wheat cultivar, Bobwhite, by biolistic bombardment. Seven transgenic lines were identified that expressed the chitinase transgene and exhibited enhanced Type II resistance in the greenhouse evaluations. These seven transgenic lines were tested under field conditions for percentage FHB severity, percentage visually scabby kernels (VSK), and DON accumulation. Two lines (C8 and C17) that exhibited high chitinase protein levels also showed reduced FHB severity and VSK compared to Bobwhite. One of the lines (C8) also exhibited reduced DON concentration compared with Bobwhite. These results showed that transgenic wheat expressing a barley class II chitinase exhibited enhanced resistance against F. graminearum in greenhouse and field conditions