The effect of platelet activating factor (PAF) on the generation of cyclo-oxygenase-derived arachidonic acid metabolites was examined on purified eosinophils harvested from the peritoneal cavity of male guinea pigs. PAF produced a concentration-dependent increase in the amount of immunoreactive thromboxane B2 (TXB2) and PGE1/E2 released from these inflammatory cells at a relative molar ratio of 30:1. The EC50 of PAF was 20 to 40 nM and maximum stimulation (4.5-fold) of both prostanoids occurred at 1 microM PAF. The ability of PAF to generate TXA2 was rapid (t 1/2 = 9 s), transient (40 s), noncytotoxic, and noncompetitively antagonized by the PAF-receptor blocking drug, WEB 2086. On an equimolar (100 nM) basis, PAF was significantly more effective than C5a, fMLP, and PMA at stimulating TXB2 release but markedly less potent than the calcium ionophore, calcimycin. Pretreatment of eosinophils with the cyclo-oxygenase inhibitor flurbiprofen (8 microM for 5 min) abolished the ability of PAF to promote both TXB2 and PGE1/E2 release. Likewise, dazmegrel (50 microM for 5 min), a selective inhibitor of thromboxane synthetase, abolished PAF-stimulated TXB2 release but markedly augmented the elaboration of PGE1/E2. Inhibition of cyclo-oxygenase with flurbiprofen affected neither the ability of PAF to elevate the intracellular calcium ion concentration (measured by fura-2 fluorescence) nor its appetency to generate superoxide anions at any PAF concentration examined. It is concluded that activation of guinea pig eosinophils by PAF is receptor-mediated and independent of the concomitant generation of cyclo-oxygenase-derived excitatory prostanoids. Inasmuch as TXA2 may contribute to the pathogenesis of bronchial hyperreactivity, then these data implicate the eosinophil as a potential source of this lipid mediator.
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Publisher Summary This chapter outlines a new approach to structural stainless steel design, which is based on exploiting the full deformation capacity of cross-sections, by adopting a continuous method of cross-section classification and member design coupled with more accurate material modeling. It presents recently generated laboratory test results, and shows how they are used in combination with existing test data to validate the proposed method. Average design advantages of around 20–25% are achieved. Significant improvements in performance may be achieved by basing the structural design of stainless steel members on the actual material behavior (rather than assuming an analogy with carbon steel). New test data on local buckling and plate element behavior is generated. Additional member tests on beams and pin-ended long columns are conducted. Using a new proposed design approach, average improvements of around 20%, that still produce safe side predictions of test data, are achieved. It is envisaged that the proposed design method will be incorporated into future revisions of Eurocode 3, bringing greater efficiency to structural stainless steel design and promoting more widespread use of the material.
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.
Functional studies suggest the presence of prejunctional muscarinic autoreceptors on cholinergic nerves in human airways. However, these studies are an indirect method of evaluating changes in neurally evoked acetylcholine (ACh) release. We have investigated the presence of muscarinic autoreceptors in human and guinea pig trachea by comparing the effects of the muscarinic receptor antagonists pirenzepine (M1), methoctramine (M2), 4-DAMP (M3), and rispenzepine (M1/M3) on cholinergic neural contractile responses evoked by electrical field stimulation (EFS) and [3H]ACh release. The M1, M1/M3, or M3 antagonists inhibited the EFS-evoked cholinergic contractile response in a concentration-dependent manner (4-DAMP > rispenzepine > pirenzepine), whereas methoctramine facilitated this response at low concentrations ( < 3 microM). In ACh release studies, the M3 antagonist had no significant effect, whereas pirenzepine, methoctramine, and rispenzepine significantly increased ACh release in guinea pig trachea. In contrast, ACh release was significantly inhibited by the muscarinic agonist oxotremorine M. Methoctramine and the nonselective antagonist ipratropium bromide, but not the M1, M1/M3, or M3 antagonists, significantly increased ACh release in human trachea. These data suggest the presence of an autoinhibitory receptor on cholinergic nerve terminals in human and guinea pig trachea. In addition, the action of ipratropium bromide at the autoinhibitory receptor may limit its use in the treatment of obstructive airways disease.
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.
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.
