Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticosteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse steroid resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
Chronic hypoxaemia in chronic bronchitis and emphysema may lead to the development of pulmonary hypertension, and the occurrence of cor pulmonale remains a bad prognostic sign. This stage of the disease may be associated with a reduced respiratory drive, leading to hypercapnia and hypoxaemia. Long term oxygen treatment improves tissue oxyg?nation, reduces pulmonary hypertension, and prolongs survival in hypoxic cor pulmonale. Thus a controlled clinical trial of the Medical Research Council showed that 15 hours of continuous oxygen treatment a day was necessary and that an improvement was observed only after 500 days of treatment.l The use of chronic supplementary oxygen in this condition has been discussed previously.2 The introduction of oxygen concentrators has made home treatment with oxygen cheaper and more convenient,3 but it is essential that patients are adequately evaluated before this treatment is started and that they are supervised during treatment.4 Treatment of hypoxaemia solely with drugs, or in combination with oxygen treatment, remains a possibility. Interest has been shown in drugs that stimulate respiration and improve oxyg?nation in these patients, one particular drug being the peripheral chemo receptor stimulant almitrine. The use of pulmonary vasodilators to reduce the pulmonary hypertension of chronic obstructive airways disease is also being investigated.
Aluminum alloys are used in a wide range of engineering applications and are gaining increasing usage in the construction sector, offering high strength-to-weight ratios and good durability. In this paper, a series of stub-column tests on aluminum alloy box sections with and without internal cross stiffeners is carried out to investigate cross-section capacity and to explore the possible exploitation of strain hardening in design. All existing stub-column test results from the literature were also collected. A database containing the results from 346 tests on aluminum alloy stub columns of box, channel, and angle sections, with a wide range of cross-section slendernesses, was formed. The test strengths were compared with the design strengths predicted by the current American, Australian/New Zealand, and European specifications. Furthermore, the test strengths were compared with those predicted by the deformation-based continuous strength method (CSM). Following reliability analyses, the design strengths predicted by the three current design specifications were found to be generally conservative, whereas the CSM offered improved design capacities, owing to its allowance for strain hardening.
In current device trials, the values of angiographic late lumen loss (LLL) have become extremely low and the relationship between LLL and clinical endpoints has not been recently re-evaluated. The impact of LLL on target lesion revascularization (TLR) in a patient- and study-level analysis of contemporary coronary devices was investigated.We performed a patient-level meta-analysis of seven randomized controlled trials including 2426 patients treated with first- and second-generation drug-eluting stents (DES) and a study-level meta-analysis of 40 studies including 19 199 patients treated with CE-marked DES. In the patient-level analysis, the probability regression curve showed an exponential relationship between in-stent LLL and 2-year incidence of TLR. The optimal cut-off value of LLL based on Youden's index for 2-year TLR event was 0.50 mm. In the Cox proportional hazard model, LLL >0.50 mm was independently associated with an increased incidence of TLR up to 4 years after angiographic follow-up {adjusted hazard ratio (HR) 6.62 [95% confidence interval (95% CI) 4.67-9.39], P < 0.001}. In the meta-regression analysis of the DES studies, pooled mean value of LLL was as low as 0.23 mm (95% CI 0.20-0.26), and there was a moderate correlation between the 1- and 5-year incidence of TLR and the percentage of the lesions with LLL >0.50 mm (R2 = 0.44, P < 0.001 at 1 year, R2 = 0.40, P < 0.001 at 5 years).An angiographic LLL ≤0.50 mm was not predictive of the incidence of TLR whereas a LLL >0.50 mm was. Low LLL in contemporary device trials may not be a sufficiently discriminating parameter for the comparative evaluation of devices.