Thesis--Columbia University, 1974. / Facsimile. Includes bibliographical references (p. 97-101).

Thesis (M.P.H.)--Georgia State University, 2009. / Title from file title page. Michael P Eriksen, committee chair; Sheryl Strasser, committee member. Description based on contents viewed Feb. 22, 2010. Includes bibliographical references (p. 55-65).

Introduction: Lung cancer is the commonest cause of cancer related death in men and women in England. In 2004 the National Lung Cancer Audit (NLCA) was created, as a national non-mandatory contemporary dataset of clinical features of individuals with lung cancer in part to identify variations in clinical practice and outcomes. The main aims of this dissertation are to determine the validity and representativeness of this dataset and then to investigate what factors influence access to surgery and chemotherapy and subsequent survival. In addition I have taken the opportunity afforded by this large dataset to describe the natural history of lung cancer in young adults (20-40 years). Methods: In order to establish if the dataset was representative, I created a measure of case ascertainment at the level of an NHS Trust, and examined the distribution of patient features and outcomes for varying levels of case ascertainment. I have then quantified the impact of patient and NHS Trust level features on access to surgery in people with non-small cell lung cancer and access to chemotherapy in people with small cell lung cancer using multivariate logistic regression. I have also conducted a series of survival analyses using Cox regression. Results: I have found no evidence that patient features vary systematically according to levels of case ascertainment in the NLCA. Age, sex, performance status, stage and co-morbidity all influenced the likelihood of having surgery for people with non-small cell lung cancer. Those patients first seen in a thoracic surgical centre where more likely to receive surgery than patients seen at peripheral centres (adjusted OR 1.51, 95% CI 1.16, 1.97), and surgery had a significant benefit on mortality (adjusted HR 0.41, 95% CI 0.39, 0.44). Although the resection rate was higher for patients first seen at a surgical centre (17% v 12%) these patients did equally well after surgery suggesting they were not a higher risk group. Individuals with small cell lung cancer first seen in a hospital with a high participation in clinical trials, (>5% of expected lung cancer patients being entered into clinical trials), were more likely to receive chemotherapy (adjusted OR 1.42, 95% CI 1.06, 1.90). Chemotherapy was associated with an improvement in survival (adjusted HR 0.51, 95% CI 0.46, 0.56), and amongst those patients receiving chemotherapy, mortality was not affected by the trial status of the hospital where they were first seen. In limited stage small cell disease, those patients who had chemo-radiotherapy had an improved survival compared with those patients who received chemotherapy alone (adjusted HR 0.72, 95% CI 0.62, 0.84). This dataset of English patients with lung cancer contains one of the largest cohorts of young adults (20-40 years) with lung cancer (N=583). I have been able to demonstrate that the majority present with a good performance status (0 or 1 in 80% of those with PS recorded), but advanced (stage IV) disease at diagnosis (55% of those with stage recorded). Those who have surgery have a survival profile similar to their older counterparts. Conclusion: The National Lung Cancer Audit is a representative, contemporary cohort of people with lung cancer, which can provide valuable information for health service research in lung cancer. I have found evidence that there is variation in access to treatment based on the facilities or the performance of individual NHS Trusts. My results suggest that by improving access to thoracic surgery for those individuals with non-small cell lung cancer we may be able to raise the resection rate and improve five year survival. The pattern is similar for people with small cell lung cancer and access to chemotherapy. What this research cannot explain is the aetiology for this variation, and where in the diagnostic pathway changes need to be made to improve the active management and access to potentially curative regimes. As the audit matures with more detailed information on NHS Trust level care, further analyses will be possible to try and determine more clearly what explains these variations, and how we might intervene to reduce them.

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.

Rationale: Current asthma guidelines recommend reducing inhaled corticosteroid (ICS) therapy dose by 50% in patients with mild to moderate asthma who have demonstrated three months of good symptom control however there is evidence to suggest that this does not occur. Objectives: We tested whether exhaled nitric oxide (FeNO) measurements or other clinical indices could be utilised to predict a safe reduction of ICS dose, without provoking loss of symptom control or exacerbation within 3 months. We also investigated relationships between airway inflammation and asthma symptoms in the mild to moderate asthma cohort. Methods: 191 patients with stable asthma were recruited from primary care. Patients had their FeNO level measured at baseline and then had their inhaled corticosteroid (ICS) dose reduced by 50%. FeNO measurements were reassessed seven days later. The primary outcomes were whether baseline FeNO or a change in FeNO following ICS dose reduction could predict asthma stability at 3 months. Results: 128/191 patients (67%) completed the ICS dose reduction successfully at three months. 63/191 patients (33%) suffered from either a loss of control or an exacerbation. Baseline FeNO, or change in FeNO (post step-down minus pre step-down) were not statistically significantly different between the two groups. Conclusion: 67% of patients with well-controlled asthma can safely reduce their ICS dose by half without suffering from a loss of control or exacerbation within three months; however neither baseline nor change in FeNO measurements or routine clinical indices can be used to predict which patients can or cannot successfully tolerate a reduction in ICS dose.

Background: Isolation of respiratory viruses routinely requires a panel of cell lines. Management of these cell lines is usually considered complex, cumbersome, long turnaround time and high cost. In order to improve the detection rate and cost, there is a need to evaluate any other cell line that could be as sensitive as the routine cell line for the detection of respiratory viruses. The human colon adeno-carcinoma (Caco-2) cell line has been shown to support the growth of enteroviruses, enteric viruses, and influenza A virus, and ability to grow coronavirus NL63 and SARS from culture isolates. In the present study, the isolation rate of respiratory viruses in Caco-2 from clinical specimens was studied and compared with the conventional panel of cell lines for the diagnosis of respiratory virus disease. Material and methods: The study was performed in two stages. In the first stage, one hundred and eighty-nine nasopharyngeal aspirates confirmed positive by direct immunofluorescence were used to inoculate onto Caco-2, and HEp-2, A549, MDCK, LLC-MK2 cell lines at the same time. In the second stage, fifty-six nasopharyngeal aspirates were randomly selected and cultured on Caco-2, HEp-2, A549, MDCK and LLC-MK2. Infected cells were examined daily for cytopathic effect for up to 10 days. Virus was further identified by performing direct immunofluorescence test for detection of eight common respiratory viruses (respiratory syncytial virus, influenza A and B viruses, parainfluenza type 1, 2, 3, 4 viruses and adenovirus). Results: Caco-2 (84%) was found to be the most efficient cell line to propagate the respiratory viruses from nasopharyngeal aspirate when compared with any positive by these conventional panel cells (78%) or individual cell line MDCK (38%), HEp-2 (21%), LLC-MK2 (27%) and A549 (37%). The latter differences were statistically significant (p = <0.000001). Furthermore, Caco-2 recovered 86% (36/42) viruses of conventional panel cells negative samples, while conventional panel cells recovered 80% (24/30) viruses of Caco-2 cells negative samples. Conclusion: Caco-2 is sensitive to a wide range of virus and can greatly simplify routine cell culture service for isolation of respiratory viruses. / published_or_final_version / Microbiology / Master / Master of Medical Sciences

No description available.

Asthma is characterised by airway remodelling and an increase in airway resistance. A greater understanding of the mechanisms involved in airway inflammation and airway hyper-responsiveness (AHR) may highlight therapeutic opportunities for asthma. This study initially aimed to optimise the preparation of precision cut lung slices (PCLS) in mouse and pig to investigate the influence of calcium (Ca2+) homeostasis on airway smooth muscle (ASM) contraction as a prelude to human studies. The PCLS technique was then applied to a murine model of allergic airway disease to explore the inflammatory process and pathogenesis of airway hyper-reactivity in sensitised mice. Initial experiments using murine and porcine airways validated the PCLS model and demonstrated the significance of release and refilling of Ca2+ from internal stores to induce and maintain an airway contraction. Results also highlight interesting species differences in agonist sensitivity, with the porcine system sharing similar pharmacology to human airways. Using a murine model of allergic airway disease, agonist induced contractile responses in peripheral airways were measured in vitro using the PCLS technique. BALB/c mice underwent initial sensitisation by intraperitoneal administration of ovalbumin, receiving a 3 day challenge with aerosolised OVA l% (vlv), for varying periods of up to 3 weeks for acute, mid-chronic and chronic sensitisation protocols. To investigate the influence of the inflammatory environment, naive murine lung slices were incubated with selected inflammatory mediators. OVA sensitisation led to progressive structural remodelling and AHR to methacholine (MCh) challenge. However, this hyperresponsiveness was decreased 48 hours post lung removal. Of the inflammatory mediators selected for lung slice incubation, IL-33 significantly increased AHR to MCh. IL-33 is a proinflammatory cytokine with transcriptional repressor properties, playing a role in initiating the TH2 inflammatory response. In lung slices prepared from IL-33 receptor (ST2) KO mice IL-33 was unable to sensitise the contractile response. These data suggest the inflammatory environment promotes AHR and disassociates this airway sensitivity from structural remodelling. These data suggest a key role for IL-33 in mediating AHR in this murine model. Investigation of the mechanisms involved in airway hyper-reactivity revealed mRNA expression of IL-33 and the IL-33 receptor (ST2) in soluble and membrane bound forms were significantly increased in the mid-chronic and chronic ovalbumin sensitised murine lung tissue. Further quantitative analysis in human lung showed expression of IL-33 in epithelial and ASM cells. The human ST2 receptor (also known as IL-IRL-l) was expressed in mast cells. Together these results suggest IL-33 is a sensor of tissue damage; indirectly inducing AHR through further inflammatory cell activation to target ASM. This study demonstrates IL-33's role as an inflammatory marker of asthma and suggests a novel therapeutic intervention by targeting of the ST2 receptor.

No description available.

No safe and effective vaccine exists against respiratory syncytial virus (RSV), the main viral cause of lower respiratory tract infections in young children. Proteosome-based adjuvants, derived from the outer membrane proteins (OMP) of Neisseria species are potent inducers of mucosal and systemic immunity in humans and animals. RSV subunit vaccines based on enriched RSV proteins (eRSV) were formulated with proteosomes (Pro) or its S. flexneri LPS-supplemented derivative, Protollin (Prl). Administered intranasally (IN) in BALB/c mice, the vaccines elicited systemic and mucosal RSV-specific antibodies and fully protected against RSV challenge without enhanced pulmonary pathology or evidence of a Th2-biased response (eg: eosinophil infiltation or antigen-specific 1L-5 production by restimulated splenocytes or lung cells). Restimulation of cells from Prl-eRSV immunized mice elicited F peptide-specific CD8+ T cells producing IFNgamma and supernatant IFNgamma, TNFalpha, 1L-2 and IL-10. The Prl-eRSV vaccine was also studied in C57Bl/6 mice, to exploit the TLR2, TLR4 and MyD88-deficient (-/-) animals available on this background. Protection was significantly impaired in both TLR4-/- and MyD88 -/- mice, but not in TLR2 -/- mice following Prl- eRSV immunization and challenge. These studies revealed a role for the LPS component of Protollin in both initial (innate) cytokine release as well as dendritic cell maturation and Th1 polarization. Although antibody levels were sustained in MyD88-/- mice, the IgG1/IgG2a ratio was markedly higher in the absence of this pathway. The MyD88-/- mice also displayed elevated levels of pulmonary eosinophils following challenge, with concomitant reduction of neutrophils compared to wt mice. Using CD1d-iNKT cell-deficient mice (CD1-/-) in our BALB/c model, we also identified a significant role for the lipid component of both the Pro- and Prl-based vaccines. Responses to both vaccines in CD1-/- animals elicited lower antibody titers and reduced restimulated splenocyte supernatant cytokines (IFNgamma, IL-17 and IL-10), with concomitant augmentation of neutrophil recruitment (Prl only). Pro- and Prl-eRSV vaccines may therefore exert their powerful adjuvant effects by exploiting both CD1d-iNKT and, in the case of the Prlbased formulations the TLR4-MyD88-dependant signalling pathway. These pathways not only promote stronger Th1 immune responses but also act to control pulmonary eosinophil (MyD88-dependent) and neutrophil (MyD88 and CD1d-NKT-dependent) recruitment in a murine RSV challenge model.