Publications

Several mediators produced by various inflammatory cells have now been implicated in asthma. They may contribute to the pathology of asthma by contracting airway smooth muscle, stimulating mucus secretion, and promoting bronchial oedema and chemotaxis of inflammatory cells. Because many mediators interact, antagonism of any single mediator is unlikely to have a major clinical effect.

At present, asthma represents a substantial burden on health care resources in all countries so far studied. The costs of asthma are largely due to uncontrolled disease, and are likely to rise as its prevalence and severity increase. Costs could be significantly reduced if disease control is improved. A large proportion of the total cost of illness is derived from treating the consequences of poor asthma control-direct costs, such as emergency room use and hospitalizations. Indirect costs, which include time off work or school and early retirement, are incurred when the disease is not fully controlled and becomes severe enough to have an effect on daily life. In addition, quality of life assessments show that asthma has a significant socioeconomic impact, not only on the patients themselves, but on the whole family. Underuse of prescribed therapy, which includes poor compliance, significantly contributes towards the poor control of asthma. The consequences of poor compliance in asthma include increased morbidity and sometimes mortality, and increased health care expenditure. To improve asthma management, international guidelines have been introduced which recommend an increase in the use of prophylactic therapy. The resulting improvements in the control of asthma will reduce the number of hospitalizations associated with asthma, and may ultimately produce a shift within direct costs, with subsequent reductions in indirect costs. In addition, costs may be reduced by improving therapeutic interventions and through effective patient education programmes. This paper reviews current literature on the costs of asthma to assess how effectively money is spent and, by estimating the proportion of the cost attributable to uncontrolled disease, will identify where financial savings might be made.

The rise in life expectancy worldwide has been accompanied by an increased incidence of age-related diseases, representing an enormous burden on healthcare services and society. All vital organs lose function with age, and this is well described in the lung, with a progressive decline in pulmonary function after the age of about 25 years. The lung ages, like any other organ, with progressive functional impairment and reduced capacity to respond to environmental stresses and injury. Normal physiological ageing results in enlarged alveolar spaces and loss of lung elasticity in the elderly known as 'senile emphysema', whereas in COPD there is destruction of the alveolar walls and fibrosis of peripheral airways. However, COPD shows striking age-associated features, such as an increase in cellular senescence, stem cell exhaustion, increased oxidative stress, alteration in the extracellular matrix and a reduction in endogenous antiageing molecules and protective pathways such as autophagy. In this review we discuss the evidence showing how oxidative stress induces accelerated ageing by upregulating the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT/mechanistic target of rapamycin signalling pathway resulting in depletion of stem cells, defective autophagy, reduced antioxidant responses and defective mitochondrial function thus generating further oxidative stress. Understanding the mechanisms of accelerated ageing in COPD may identify novel therapeutic approaches.

Molecular biology: principles and applications Analysis of protein synthesis Methods for in situ hybridization Finding disease genes Protein and gene polymorphisms Site directed mutagenesis Tissue specificity Applications of molecular biology to lung disease: bacterial infection Molecular biology and respiratory disease Application to pathology Oncogenes, cancer and growth factors Molecular biology of lung receptors The regulation of collagen and elastin gene expression in normal lung and during pulmonary disease Transepithelial transport of secretory immunoglobulins Heat shock proteins Molecular cellular and genetic studies of atopic disease Interleukins in the pulmonary inflammatory response Gene therapy

The peak and critical state strengths of sands are linearly related to the stress level, just as the frictional resistance to sliding along an interface is related to the normal force. The analogy with frictional sliding has led to the use of a 'friction angle' to describe the relationship between strength and stress for soils. The term 'friction angle' implies that the underlying mechanism is frictional resistance at the particle contacts. However, experiments and discrete element simulations indicate that the material friction angle is not simply related to the friction angle at the particle contacts. Experiments and particle-scale simulations of model sands have also revealed the presence of strong force chains, aligned with the major principal stress. Buckling of these strong force chains has been proposed as an alternative to the frictional-sliding failure mechanism. Here, using an idealized abstraction of a strong force chain, the resistance is shown to be linearly proportional to the magnitude of the lateral forces supporting the force chain. Considering a triaxial stress state, and drawing an analogy between the lateral forces and the confining pressure in a triaxial test, a linear relationship between stress level and strength is seen to emerge from the failure-by-buckling hypothesis.