Novel mechanisms for increased cardiovascular risk in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a significant burden on individuals with the disease and on healthcare resources. By 2020 it is projected to be the third leading cause of death worldwide. COPD is a condition that is characterised by chronic lung inflammation and damage. However, it is now known that COPD not only affects the lungs, but also has systemic associations, effects and consequences. These include osteoporosis, skeletal muscle wasting and dysfunction, depression, anaemia, systemic inflammation and cardiovascular disease. Population based studies have identified that COPD is a risk factor for cardiovascular morbidity and mortality, independent of traditional risk factors including cigarette smoking. The mechanisms responsible for this association have yet to be established.In the studies in this thesis, I investigated a number of novel mechanisms that may contribute to the increased cardiovascular risk in COPD. It is thought that the lowgrade systemic inflammation associated with COPD may have a role to play. In addition, the enhanced systemic inflammatory response in exacerbations of COPD may predispose these individuals to cardiovascular events. Activation of platelets and interaction between platelets and monocytes are early processes in the pathogenesis of atherothrombosis. I therefore measured markers of platelet activation in patients with COPD and healthy controls. In a second study, platelet activation was measured in patients admitted to hospital with an exacerbation of COPD and in convalescence. Patients with COPD had higher platelet-monocyte aggregation in comparison to controls matched for age and cigarette smoke exposure. This was further increased during exacerbations.In addition to platelet activation, vascular dysfunction predisposes to cardiovascular morbidity and mortality. I undertook comprehensive assessments of vascular function (arterial stiffness, endothelial vasomotor function and endogenous fibrinolysis) in patients with COPD and healthy ex-smoking controls. I confirmed that patients with COPD have increased arterial stiffness independent of cigarette smoking. However, contrary to prior popular assumption, endothelial vasomotor and fibrinolytic function were not impaired in comparison to healthy controls matched for smoking history.We had previously reported an association between emphysema severity and arterial stiffness. I hypothesised that the mechanism for this association in COPD patients may be increased elastin degradation, not only in the lungs, but also in the large arteries. To test the hypothesis that COPD is a condition with systemic elastin degradation, I measured elastin degradation in skin biopsies from patients with COPD and healthy controls. There was increased cutaneous elastin degradation in COPD patients. In addition, there was increased expression of matrix metalloproteinases in COPD skin biopsies, which may be a mechanism for this observation. Furthermore, emphysema severity and arterial stiffness were associated with cutaneous elastin degradation.These studies have identified platelet activation and arterial stiffness as novel mechanisms for the development of cardiovascular disease in COPD. Platelet inhibition and improvement of vascular function represent plausible targets for the prevention of cardiovascular events in this population. In addition, I have provided evidence for elastin degradation as a systemic effect of COPD and that systemic upregulation of matrix metalloproteinases may be the unifying mechanism for this. Focus on inflammatory pathways that result in this will provide more insight into the pathogenesis of COPD and help direct future therapies

Reproductive and life history characteristics of a North American prairie orchid Spiranthescernua cernua (Linnaeus) L.C. Richard.

Introduction: Reproductive systems have a profound effect on the genetic structure of plant populations. How genes are passed from one generation to the next influences the amount and structure of genetic variation in succeeding generations (Clegg, 1980; Bell, 1982). Sexual reproduction increases the genetic variation within a population through recombination while asexual reproduction duplicates the maternal genome (Williams, 1975). A variety of systems have evolved in plants which combine both sexual and asexual reproduction (Lloyd, 1984 )

Obtaining tissue diagnosis in lung cancer patients with poor performance status and its influence on treatment and survival

Introduction: 25% of patients with lung cancer have performance status 3 or 4. A pragmatic approach to investigative procedures is often adopted based on the risks and benefits in these patients and whether tissue diagnosis is necessary for anticipated future treatment. This cohort study investigated factors influencing a clinician's decision to pursue a tissue diagnosis in patients with lung cancer and performance status 3 and 4 and to examine the association of tissue diagnosis with subsequent management and survival. Methods: All patients with lung cancer diagnosed in North Glasgow from 2009 to 2012 were prospectively recorded in a registry. We investigated the relationships between achieving a tissue diagnosis, treatment and survival. Results: Of 2493 patients diagnosed with lung cancer, 490 patients (20%) were PS 3 and 122 patients (5%) were PS 4. Tissue diagnosis was attempted in 60% and 35% patients with PS 3 and PS 4 respectively. Younger age, better performance status and having stage 4 disease were independently associated with a diagnostic procedure being performed. Only 5% of patients with poor performance status received treatment conventionally requiring a tissue diagnosis. Age, stage and performance status were independent predictors of mortality. Achieving a tissue diagnosis was not associated with mortality. Receiving treatment requiring tissue diagnosis is associated with survival benefit. Conclusions: The majority of patients with poor fitness undergo a diagnostic procedure which does not influence further treatment or affect survival. However, the cohort of patients who do undergo therapy determined by tissue diagnosis have improved survival

Respiratory bronchiolitis-interstitial lung disease in first-degree relatives

SummaryThese two case reports examine the histories of a father and daughter with respiratory bronchiolitis-interstitial lung disease. This unusual condition occurs almost exclusively in smokers and has never previously been reported in first-degree relatives

Atomic Energy and Radioactive Substances: Licensing and Regulation of Sites: The Nuclear Installations Regulations, 1962

ERAF: A6 SI 1962.37These regulations, made by the Minister of Power and the Secretary of State for Scotland acting jointly, prescribe for the purpose of subsection (1)(b) of section one of the Nuclear Installations (Licensing and Insurance) Act, 1959, certain classes of installations designed or adapted for carrying out processes which are preparatory or ancillary to the production or use of atomic energy and which involve or might cause the emission of ionising radiations; the regulations also prescribe installations for storing irradiated nuclear fue

The relationship between 18F-FDG-PETCT-derived tumour metabolic activity, nutritional risk, body composition, systemic inflammation and survival in patients with lung cancer

The aim of this study was to examine the relationship between PET-CT derived tumour glucose uptake as measured by maximum standard glucose uptake (SUVmax) and total lesion glycolysis (TLG), nutritional risk as measured by the malnutrition universal screening tool (MUST), CT derived body composition as measured by skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD), the systemic inflammatory response as measured by the modified Glasgow prognostic score (mGPS) and the neutrophil to lymphocyte ratio (NLR) and survival in patients with lung cancer, treated with radiotherapy. In a retrospective cohort study, 119 patients were included in final analyses. The majority of patients were over 65 (86%), female (52%), had a performance status (ECOG-PS) of 0 or 1 (57%), were at nutritional risk (57%), were overweight (53%), had visceral obesity (62%), had a normal SMI (51%), had a low SMD (62%) and were systemically inflammed (mGPS 1/2, 51%). An elevated TLG was associated with sex (p < 0.05), TNM stage (p < 0.001), MUST (p < 0.01) and mGPS (p < 0.01). An elevated mGPS was associated with age (p < 0.05), NLR (p < 0.01), MUST (p < 0.01), and TLG (p < 0.01). On univariate survival analysis, TNM stage (p < 0.01), mGPS (p < 0.05), NLR (p < 0.01), MUST (p ≤ 0.001), Low SMD (p < 0.05), SUVmax (p ≤ 0.001) and TLG (p < 0.001) were associated with overall survival. On multivariate survival analysis MUST (HR: 1.49 95%CI 1.12–01.98 p < 0.01) and TLG (HR: 2.02 95%CI 1.34–3.04 p = 0.001) remained independently associated with survival. In conclusion, elevated tumour metabolic activity was associated with more advanced stage, greater nutritional risk, the systemic inflammatory response and poorer survival but not body composition analysis in patients with lung cancer. These results suggest that detrimental body composition is not directly determined by tumour metabolic activity but rather an ongoing systemic inflammatory response

Airway dimensions in COPD:relationships with clinical variables

SummaryBackgroundCOPD patients have varying degrees of airways disease and emphysema. CT scanning can differentiate these pathological subtypes. We evaluated airway dimensions and emphysema severity with low dose CT scanning in COPD patients to determine relationships with clinical features of the disease.MethodsFifty six patients with COPD had a low dose thoracic CT scan. Airways were analysed using novel software as either proximal (1st and 2nd generation) or distal (3rd to 6th generation); the extent of emphysema was assessed as the percentage of pixels less than −950 Hounsfield units. CT measures were related to clinical features of COPD.ResultsThicker walls in the proximal airways were associated with clinical features that may represent a bronchitic phenotype (MRC Bronchitis Score; β = 0.20, p = 0.003, Frequent Exacerbations; β = 0.14, p = 0.017, Total St George’s Score; β = 0.50, p = 0.001 and body mass index [BMI]; β = 0.26, p = 0.049); these associations were independent of emphysema. BMI was negatively correlated with the degree of emphysema (β = −0.41, p = 0.001). Airway wall thickness was negatively correlated with CT measured emphysema for both proximal and more distal airways (r = −0.30, p = 0.025 and r = −0.32, p = 0.015).ConclusionsCT measured airway dimensions are associated with several clinical measures of COPD; these are related to a bronchitic phenotype and the effect is independent of emphysema

Transketolase catalysed upgrading of l-arabinose: the one-step stereoselective synthesis of l-gluco-heptulose

Conversion of biomass using biocatalysis is likely to become a technology that contributes significantly to the future production of chemical building blocks, materials and transport fuels. Here the synthesis of a value-added chemical from L-arabinose, a major component of the carbohydrates in sugar beet pulp (SBP), in a concise and sustainable manner has been investigated. Biocatalytic conversions using transketolase variants have been developed for the efficient, scalable synthesis of a rare naturally occurring ketoheptose, L-gluco-heptulose, from L-arabinose. New active E. coli TK mutants that readily accept L-arabinose were identified using a versatile colorimetric screening assay and the reaction was performed on a preparative scale

Forced Expiratory Volume in One Second Predicts Length of Stay and In-Hospital Mortality in Patients Undergoing Cardiac Surgery: A Retrospective Cohort Study

Objective: An aging population and increasing use of percutaneous therapies have resulted in older patients with more co-morbidity being referred for cardiac surgery. Objective measurements of physiological reserve and severity of co-morbid disease are required to improve risk stratification. We hypothesised that FEV1 would predict mortality and length of stay following cardiac surgery. Methods: We assessed clinical outcomes in 2,241 consecutive patients undergoing coronary artery bypass grafting and/or valve surgery from 2001 to 2007 in a regional cardiac centre. Generalized linear models of the association between FEV1 and length of hospital stay and mortality were adjusted for age, sex, height, body mass index, socioeconomic status, smoking, cardiovascular risk factors, long-term use of bronchodilators or steroids for lung disease, and type and urgency of surgery. FEV1 was compared to an established risk prediction model, the EuroSCORE. Results: Spirometry was performed in 2,082 patients (93%) whose mean (SD) age was 67 (10) years. Median hospital stay was 3 days longer in patients in the lowest compared to the highest quintile for FEV1, 1.35-fold higher (95% CI 1.20–1.52; p<0.001). The adjusted odds ratio for mortality was increased 2.11-fold (95% CI 1.45–3.08; p<0.001) per standard deviation decrement in FEV1 (800 ml). FEV1 improved discrimination of the EuroSCORE for mortality. Similar associations were found after excluding people with known pulmonary disease and/or airflow limitation on spirometry. Conclusions: Reduced FEV1 strongly predicted increased length of stay and in-hospital mortality following cardiac surgery. FEV1 is a widely available measure of physiological health that may improve risk stratification of complex patients undergoing cardiac surgery and should be evaluated for inclusion in new prediction tools