The mechanical behaviour and design of fixed-ended unequal-leg angle section steel members subjected to axial compression are studied herein. The mechanical response of unequal-leg angle section columns is first described, with a particular emphasis on the relationship between torsional and local buckling, alongside the important transition from equal-leg to unequal-leg angle behaviour. Existing experimental data on unequal-leg angle section steel columns are then employed to validate numerical models developed within the commercial finite element package ABAQUS. A comprehensive parametric study is subsequently conducted that encompasses a broad spectrum of geometric configurations and global slenderness values. The mechanical behaviour and ultimate resistance of fixed-ended unequal-leg angle section columns are shown to be dependent on not only the global slenderness, but also on the ratio of the elastic torsional-flexural to minor-axis flexural buckling loads. The existing experimental data alongside the numerical parametric study results are employed to evaluate the resistance predictions given by the current Eurocode 3 design provisions, revealing an excessive level of conservatism. Finally, a new design approach for fixed-ended unequal-leg angle section steel columns, suitable for incorporation into future revisions of Eurocode 3, is proposed that significantly improves the accuracy and consistency of the resistance predictions. A reliability analysis of the proposed design approach is conducted in accordance with the procedure within EN 1990, resulting in a recommended partial safety factor γ M1 = 1 . 0 . • Description of critical and post-buckling behaviour of unequal-leg angle section steel columns. • Developed finite element models validated against existing experimental results and employed for a comprehensive parametric study. • High level of conservatism observed in the ultimate resistance predictions following current Eurocode design provisions. • Development of new design approach using generated numerical and collected experimental results. • Assessment and verification of reliability of the new design approach with EN 1990 procedure.
Nitric oxide can be detected in the exhaled air of animals and normal human subjects, is increased in patients with asthma and bronchiectasis, and may be modulated by inhaled corticosteroids. Nitric oxide may provide a noninvasive means of monitoring inflammation in the respiratory tract and the measurement of exhaled nitric oxide has attracted increasing interest. However, interpretation of exhaled nitric oxide measurements may be difficult and there is a wide variation in the reported levels of nitric oxide in exhaled air, suggesting that technical factors are important.
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In addition to classical cholinergic and adrenergic neural mechanisms, a third division of autonomic control has been recognised in human airways. Non-adrenergic inhibitory nerves are the dominant inhibitory neural pathway in human airway smooth muscle and there is increasing evidence that VIP and a related peptide, PHM, may be the neurotransmitters. These peptides are probably cotransmitters of acetylcholine in the airways and may modulate cholinergic effects. A defect in this system could occur in asthma because inflammation may more rapidly inactivate these neurotransmitter peptides. Non-cholinergic excitatory nerves have also been described in animal airways, although their existence in human airways is less certain. The neurotransmitter may be substance P or a related peptide neurokinin A, which could be released by axon reflex. Another peptide, calcitonin gene-related peptide, is colocalized with substance P and appears to be much more potent in human airways. Non-adrenergic non-cholinergic mechanisms may also regulate mucus secretion and the bronchial microvasculature. The role of this nervous system in health and disease is still uncertain as there are no specific blockers available.
Exacerbations of chronic obstructive pulmonary disease are of major importance in terms of their prolonged detrimental effects on patients, the acceleration in disease progression and high healthcare costs. There is still debate about how exacerbations should be defined and graded, and their mechanisms are poorly understood. The major causal agents are either bacteria or viral infections, or a combination of the two. Noninfective causes include air pollution and pulmonary embolus but, in some patients, no cause is identified. Exacerbations represent an increase in the inflammation that is present in the stable state, with increased numbers of inflammatory cells (particularly neutrophils), cytokines, chemokines and proteases in the airways, and increased concentrations of certain cytokines and C-reactive protein in the blood. There are presently no reliable biomarkers with which to predict exacerbations. Exacerbations have a long-lasting adverse influence on health status. High doses of bronchodilators are the mainstay of treatment and systemic corticosteroids have some benefit. The routine use of antibiotics remains controversial but they are of benefit with exacerbations of a bacterial origin. Noninvasive ventilation is beneficial in preventing the need for intubation and its important complications but it is not certain whether its use in stable patients prevents exacerbations. Although important advances have been made, more effective treatments are needed in the future for prevention and treatment of exacerbations.
1 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands, 2 Department of Immunology, Chronic Respiratory Disease Research Center and National Research Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 3 National Heart and Lung Institute, Imperial College, London, United Kingdom.
Background: The anti-ageing molecule Sirtuin-1 (SIRT1) has been reported to be decreased in COPD (Nakamaru Y et al, FASEB J, 2009). We have also reported an increase of osteoprotegerin (OPG) in COPD (To M et.al, CHEST 2011), which is b-catenin dependent. Our hypothesis is that the reduction of SIRT1 induced by oxidative stress may lead to increased b-catenin activation. Methods: U937 (human monocytic cell line), A549 (human alveolar epithelial cell line) and BEAS2B (human bronchial epithelial cell line) were grown until 70% confluent, starved for 24h and incubated with 2uM of sirtinol at 4 different time points (i.e. 1h, 4h, 8h, and 24h). The levels of b-catenin were measured in nuclear and cytoplasmic extracts by Western Blotting. Cells were also treated with H 2 O 2 for 24 hrs and sirt-1 protein level was also evaluated. Results: The level of b-catenin was higher in A549 and BEAS2B cells than U937 cells at baseline. In all three cell lines, nuclear b-catenin levels increased at 8h after treatment with 2uM of sirtinol by approximately 52% for the U937, 38% for the A549 and 25% for the BEAS2B cells. No difference was detected in cytoplasmic b-catenin levels in any cell line. Incubation with H 2 O 2 for 24h caused reduction in Sirt-1 levels in the A549 cells. Conclusions: This study shows that reduced SIRT1 protein leads to stabilization of β-catenin protein. This might give new insights in the understanding of COPD pathogenesis.
