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The present research was carried out to investigate the differential activation of caspases-3, -8 and -9 using the novel CaspTag^TM technique and flow cytometry together with examination of changes in mitochondrial transmembrane potential (<span style='font-family:Symbol'>D<span style='font-family:Symbol'>Ym) in human cultured eosinophils and an eosinophilic cell line, EoL-1 following mAb-dependent ligation of CD45, CD45 isoforms, CD95, and CD69. The membrane receptor expression and the storage of the eosinophil granule proteins major basic protein (MBP) and eosinophil cationic protein (ECP) in these cells were also studied. This study also established that airway epithelial cells could recognise and ingest apoptotic and not freshly differentiated EoL-1. Peripheral blood eosinophils (PBE), cultured eosinophils (CE), and differentiated EoL-1 express pan-CD45 and the isoforms RA, RB, and RO, CD95, CD69, cytokine and chemokine receptors. They also express and store the eosinophil granule proteins MBP and ECP. My findings suggest that although PBE, CE, differentiated EoL-1 have many phenotypic properties in common there are quantitative differences that may be a consequence of their immaturity and/or the influence of the cytokines used in cultured eosinophils or that most likely reflect the leukaemic nature of the EoL-1 cell line. Annexin-V fluroescein isothiocyanate binding to cultured eosinophils and differentiated EoL-1 revealed significant apoptosis induction in cells cultured with monoclonal antibodies (mAb) specific for CD45, CD45RA, CD45RB, CD95 and CD69 compared with isotope controls. In contrast, dexamethasone failed to induce significant apoptosis at all concentrations or time points examined in this study. The pan-caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone (fmk) or caspase-8 (Z-IIE-Glu-Thr-Asp-fimk) and caspase-9 (Z-Leu-Glu-His-Asp-fmk) inhibitors demonstrated a role for these caspases in membrane receptor ligation-reduced apoptosis in differentiated EoL-1 cells.  The study also demonstrated that apoptosis induction in CE or differentiated EoL-1 by mAb-dependent receptor ligation involved differential caspase activation.

Study 1:  Outcomes after superficial venous surgery 1a: Quality of life (QoL) after varicose vein (VV) surgery.  203 consecutive patients undergoing VV surgery completed the Aberdeen Varicose Vein Severity Score (AVSS) QoL questionnaire pre-operatively, 4 weeks, 6 months and 2 years post-operatively.  VV surgery leads to a significant improvement in AVSS, sustained at 2 years.  Patients having surgery for recurrent VV score worse at all time-points than patients with primary VV but still enjoy a significant improvement in QoL. 1b:  The effect of long saphenous vein (LSV) stripping on QoL.  66 of the 203 patients in study 1a had pre- and post-operative venous duplex.  Even in a specialised vascular unit where stripping is routinely attempted, only 25/66 (38%) had their LSV completely stripped to the level of the knee.  Complete (as opposed to incomplete) stripping to the knee was associated with an additional improvement in AVSS above that seen in study 1a.  In those with pre-operative deep venous reflux (DVR) complete stripping did not confer this additional advantage. 1c:  The effect of long saphenous vein stripping on deep venous reflux (DVR).  In 77 limbs of 62 patients from study 1b, complete stripping was associated with reversal of pre-operative superficial femoral and popliteal vein reflux.  Incomplete stripping was associated with the development of DVR in previously normal deep veins. Study 2:  Lower limb ulceration:  delivery of care and aetiology.  2a:  Delivery of care for lower limb ulceration.  128 patients were assessed at a one-stop leg ulcer clinic, 79% of whom had purely venous ulceration. 2b:  Aetiology of CVU:  thrombophilia<i>.  </i>41% of 88 patients with CVU had an identifiable thrombophilic abnormality.  Thrombophilia was 3-20 times more common than in the general population, but similar to rates reported in patients with a first episode of venous thrombosis.

Background: The hypothesis that paracetamol may increase the risk of asthma and other allergic disease has gained consistent support from epidemiological studies, but evidence from longitudinal cohort studies, particularly those looking at the timing and dose of exposure are lacking. Epidemiological studies have also reported an inverse relation between gastro-intestinal infections including Helicobacter pylori, commensal bacteria and geohelminths and asthma and allergic disease, however, data from longitudinal birth cohort study are scarce. This thesis has therefore investigated the effects of paracetamol, H. pylori and other gastro-intestinal infections on the incidence and prevalence of allergic diseases and sensitization in a low-income birth cohort in which confounding by social advantage and other medical interventions is unlikely to play a role. Methods: In 2005/6 a population based cohort of 1065 pregnant women from Butajira, Ethiopia was established, to whom 1006 live singleton babies were born, and these children have been followed-up from birth to age five. At ages one, three and five, the International Study of Asthma and Allergies in Children (ISAAC) questionnaires were administered to the mothers to obtain data on wheeze, eczema and rhinitis. Allergen skin tests to Dermatophagoides pteronyssinus and cockroach were performed at ages three and five. Data on child's use of paracetamol, and various early life putative risk factors, including levels of Der p 1 and Bla g 1 allergen in the child's bedding and symptoms of respiratory tract infections were also measured. Stool samples were collected at ages three and five for analysis of H. pylori antigen using a rapid test (Medimar immunocard), as well as for geohelminths (at ages one, three and five) and selected commensal bacteria (at age three). Multivariate logistic regression was used to determine the independent effects of various markers of paracetamol use on the incidence of each outcome between age one and five, as well as on prevalence at age five. Similar analyses were also carried out to determine the independent effects of H. pylori, geohelminths and commensals on the incidence and prevalence of each outcome. Results: Effects of paracetamol: Of the 1006 children in the cohort at birth, 863 children were successfully followed up at age five (94% of surviving mother-child dyads). Wheeze and eczema incidence between the ages of one and five were reported in 5.9% (40/676) and 5.8% (39/700) of children respectively, and rhinitis and sensitization incidence between ages three and five were found in 3.9% (31/798) and 2.0% (15/766) of children respectively. Paracetamol use in the first three years of life was common, with 18% reported use at age one but not three, 23% at age three but not one and 21% at both time points. Use in the first year of life was significantly associated with a dose-dependent increased risk of incident wheeze between ages one and three (fully adjusted ORs, 95% CI, 1.77; 0.96, 3.26 for 1-3 tablets and 6.78; 1.89, 24.39 for ≥ 4 tablets in past month versus never), but not eczema. The risk of incident wheeze, eczema, rhinitis and sensitization between ages three and five was increased in those exposed, significantly so for incident eczema (p=0.02) and borderline significant for rhinitis (p=0.07), with fully adjusted odds ratios (ORs), including for symptoms of respiratory tract infections, for persistent exposure (ages one and three) versus never of 3.82 (95% CI 1.36, 10.73) and 3.10 (1.00, 9.57) respectively. Borderline significant trends were also seen between paracetamol dose in the first three years of life and incident eczema and rhinitis, with adjusted ORs for heavy reported use compared to low of 1.59 (0.44, 5.74; p trend=0.06) and 2.31 (0.72, 7.46; p trend=0.07) respectively, but not with incident wheeze (fully adjusted OR=3.64; 1.34, 9.90, p trend=0.11). Cross-sectional analysis at age five resulted in significant positive dose-response effects of lifetime use (use at ages one, three and five) in relation to the prevalence of all outcomes. Effects of gastro-intestinal infection H. pylori infection was found in 17% of the children at age three but not five, 21% at age five but not three years, and 25% at both ages. In the longitudinal analysis, H. pylori infection at age three was significantly associated with a decreased risk of incident eczema between ages three and five years (adjusted OR, 95% CI, 0.31; 0.10, 0.94, p=0.02), but the associations with incident wheeze, rhinitis and sensitization were not significant. In cross-sectional analysis at age three, H. pylori infection was associated with a borderline significant reduced risk of eczema (adjusted OR, 95% CI, 0.49; 0.24, 1.01, p=0.05) and D. pteronyssinus sensitization (adjusted OR, 95% CI, 0.42; 0.17, 1.08, p=0.07), and a significant inverse association between current exposure to H. pylori, and any sensitization at age five (adjusted OR, 95% CI, 0.26; 0.07, 0.92, p=0.02). However, no significant associations were seen for wheeze and rhinitis. The prevalence and intensity of geohelminth infection (hookworm, Ascaris lumbricoides and Trichuris trichiura) were found to be low in this cohort, with only 4% of children infected at age one, 9% at age three and only 0.2% at both ages. The risk of new onset wheeze between ages one and three was lower in those infected at age one (3.6%) than uninfected (7.8%), but infection was insufficiently prevalent to compute estimates of effect. Exposure to geohelminth infections in the first three years of life was not significantly associated with the incidence of reported outcomes or sensitization. However, A. lumbricoides infection was associated with a borderline increased risk of incident eczema between ages three and five (adjusted OR, 95% CI, 2.86; 1.04, 7.86, p=0.07). Children at age three were commonly colonized with enterococci 38% (207/544), lactobacilli 31% (169/544) and bifidobacteria 19% (103/544). However, none of these commensal bacteria were associated significantly with either incidence or prevalence of allergic outcomes. Conclusions: This longitudinal study from a developing country birth cohort provides further support for an association between early life use of paracetamol and increased risk of wheeze and allergic disease, which is unlikely to be explained by aspirin avoidance, reverse causation or confounding by indication. Furthermore, among young children in this cohort, the study found novel evidence to support the hypothesis of a protective effect of H. pylori infection on the risk of allergic disease, but no evidence to support an etiological role for the microflora enterococci, lactobacilli or bifidobacteria. The power of the study to explore the role of geohelminth infection on wheeze and allergic disease was limited by few infected children, and therefore understanding on this particular relation has not been much further advanced.