Structure and function of human peripheral airways in obstructive airways disease

Obstructive airways diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma are characterized by airflow obstruction, and by structural changes in the airway wall associated with chronic inflammation. The degree to which these changes are related to airflow obstruction and hyperresponsiveness is not completely understood. The aims of the investigations carried out in this thesis were to relate peripheral airway dimensions, in vitro contractile properties, and muscle protein content, to pulmonary function measured before surgery in subjects who had varying degrees of airflow obstruction. The hypothesis was that an increase in airway smooth muscle (ASM) mass and contractility leads to exaggerated airway narrowing and airflow obstruction, and that the increased ASM is accompanied by dedifferentiation of the muscle during airway remodelling. Connective tissue deposition could also take place in the airway wall and lead to increased passive elastance and attenuation of bronchoconstriction. Airway dimensions of isolated human peripheral airways were measured by morphometry and the passive and active mechanical properties were measured in vitro by myography. The maximal isometric force (Fmax), stress (Fmax/ASM), airway diameter at Lmax (Dmax), maximal isotonic shortening (%Lmax), normalized airway smooth muscle (ASM/Dmax) were determined. Western blot analysis was performed to characterize the content and distribution of myosin and actin. The smooth muscle phenotype was assessed by the ratio of muscle (SM-MHC) to non-muscle (NM-MHC) myosin, and of α-actin to total actin. Pulmonary function was assessed prior to surgery. Fifteen airways were studied from nonobstructed (NOB), and 15 from obstructed (OB, FEV1/FVC<70%) patients (62±10 yrs, mean±SD). Thickening of the smooth muscle, and not the inner or outer wall area, was significantly related to pulmonary function parameters, FEV1 (forced expiratory volume in 1s of the forced vital capacity), FEV1/FVC (ratio of FEV1 to the forced vital capacity), FEF25-75 (forced expiratory flow at 50% of FVC), DFEV1 (change in FEV1 after bronchodilator administration) (p<0.03). There was a significant correlation between Fmax and FEV1 (%predicted) (r=-0.579, p<0.004), between Fmax and FEV1/FVC (%) (r=-0.720, p<0.003), and between stress and FEV1/FVC(%) (-0.611, p<0.002). There was no correlation between isotonic shortening and either measure of pulmonary function. Both force and stress were significantly increased (p<0.05) in OB (Fmax=0.87±0.80 g, stress=76±47 mN/mm²) versus NOB (Fmax=0.42±0.18 g, stress=51± 21 mN/mm²). ASM and ASM/Dmax were both significantly increased in the OB patient group (p<0.05). In addition, OB ASM exhibited decreased relaxation responses to MK886, a leukotriene biosynthesis inhibitor, and significant reduction in the force and shortening contractions when compared to NOB. These changes in contractility were not accompanied by alterations in the content of contractile and noncontractile proteins, or in the content or composition of connective tissue surrounding the muscle. These results suggest that obstructive airways disease is associated with an increase in the ability of the ASM to generate force. [Scientific formulae used in this abstract could not be reproduced.]Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat

Airway responsiveness to methacholine and airway smooth muscle in the guinea pig

The purpose of this study was two-fold: (1) to examine the relationship between the amount of airway smooth muscle and the airway responsiveness to inhaled aerosolized methacholine (MCh) in guinea pigs, and (2) to characterize the distribution of airway narrowing following MCh.In summary: (1) the quantity of airway smooth muscle (ASM) does not appear to determine differences in maximal bronchoconstriction among normal guinea pigs; the lack of a correlation between responsiveness and amount of ASM may be explained by the heterogenous distribution of bronchoconstriction among the airways studied or the modality of challenge; (2) the sensitivity to MCh appears to be related to differences in the amount of ASM in intraparenchymal cartilaginous airways; (3) variability in the EC$sb{50}$ may also reflect differences in airway cross-sectional area; (4) lung resistance appears to be a good measure of constriction since the morphometric measure of airway narrowing correlated well with resistance; (5) the heterogeneity of airway narrowing does not appear to be determined by differences in ASM

Incidence of Pulmonary Disease Caused by Mycobacteria other than Tuberculosis in British Columbia

CONTEXT: The incidence of pulmonary disease due to mycobacteria other than tuberculosis (TB) in Canada has not been documented

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011

Background Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. Methods Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. Results The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%). Conclusions No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

Additional file 4: Table S3. of Tumour stage distribution and survival of malignant melanoma in Germany 2002–2011

Relative 5-year survival of malignant melanoma patients diagnosed between 2002 and 2011, overall (UICC 0-IV, X) (N = 60 672) and for patients with invasive tumours (UICC I – IV, X) stratified by age, sex, UICC stage, ‘diagnosis during screening’ and place of residence (N = 49 351) (DOCX 39 kb

Additional file 3: Table S2. of Tumour stage distribution and survival of malignant melanoma in Germany 2002–2011

Malignant melanoma patients aged 35 years and above by age at diagnosis, sex, UICC stage, year of diagnosis, place of residence and ‘diagnosis during screening’, N = 34 739 (UICC 0 and X excluded) (DOCX 40 kb