Background: Corticosteroids (CS) are highly recommended in the treatment of asthma and COPD. CS act via binding to the glucocorticoid receptor (GR). Upon activation, GR translocates into the nucleus, an essential prerequisite for CS function. Two groups of nuclear receptors, importin and exportin mediate RanGTPases-dependent transport across the nuclear membrane. In an in vitro nuclear import assay, importin-7 resulted in the nuclear import of the nuclear localisation signal fragment of GR. We therefore hypothesised, Importin-7 is crucial for corticosteroid-induced GR nuclear translocation. Method: We initially investigated whether GR binds to Importin-7 in U937 monocytes, followed by the effects of Importin-7 siRNA knockdown on fluticasone propionate (FP) induced GR nuclear localisation and suppression of IL-1β induced CXCL8. siRNA Importin-7 knockdown was achieved via electroporation and results were compared to a negative siRNA control. Statistical analysis was performed using non-parametric analysis. Results: Cytoplasmic and nuclear levels of Importin-7 protein expression were significantly decreased by 38.4%±19.9 and 42.7%±28.6, respectively, post 36h siRNA Importin-7 transfection. Additionally, 36hr post siRNA Importin-7 transfection, FP (10 –9 M) increase in nuclear GR levels at 2h and suppression of IL-1β induced CXCL8 secretion at 16h were significantly decreased by 39.3%±12.3 and 32.4%, respectively. Conclusions: Importin 7 knockdown reduced FP induction of GR nuclear localisation and FP suppression of IL-1β induced CXCL8. Importin-7 is a potential therapeutic target that maybe manipulated to improve CS function and activity.
Theophylline has been used for several decades in the treatment of asthma and remains the most widely prescribed anti-asthma drug worldwide, although the development of newer anti-asthma medications, especially inhaled steroids, has resulted in declining use of theophylline in industrialized countries. Theophylline is now considered to be a bronchodilator, but it is increasingly recognized that theophylline has other anti-asthma activities, which may be more important. Theophylline, even at low plasma concentrations, inhibits the late asthmatic reaction following allergen challenge. These clinical pharmacological observations are substantiated by experimental animal and in vitro data showing that theophylline has several anti-inflammatory activities relevant to asthma. These include the inhibition of cytokine synthesis and release, the inhibition of inflam- matory cell activation and microvascular leakage, and the prevention of airway hyperresponsiveness induced by airway inflammation. Theophylline appears to have immunomodulatory effects, even at relatively low plasma concentrations. Based on these considerations, theophylline can be regarded as a useful altern- ative to other anti-inflammatory drugs for the chronic treatment of mild to mod- erate asthma. Theophylline should be used at lower doses to achieve plasma concentrations of 5-10 mg·l-1, which will avoid the risk of side-effects. Further studies are required to evaluate the role of low-dose theophylline as an adjunct to low-dose inhaled steroids in the management of chronic asthma. It may now be appropriate to re-evaluate the role of theophylline in asthma management.
Asthma is usually easy to manage, but approximately 5% of patients are not controlled even on high doses of inhaled corticosteroids. It is important to assess these patients carefully in order to identify whether there are any correctable factors that may contribute to their poor control. It is critical to make a diagnosis of asthma and to exclude other airway diseases, particularly chronic obstructive pulmonary disease (COPD), and vocal cord dysfunction ("pseudo-asthma"). Poor adherence to therapy, particularly inhaled corticosteroids, is a common reason for a poor response. There may be unidentified exacerbating factors, including unrecognized allergens, occupational sensitizers, dietary additives, drugs, gastro-oesophageal reflux, upper airway disease, or other systemic diseases, that need to be identified and avoided or treated. Psychological factors may be important in some patients, but it is difficult to know whether these are causal or secondary to troublesome disease. Some patients have instability of their asthma, with resistant nocturnal asthma, premenstrual exacerbations or chaotic and unpredictable instability (brittle asthma). A few patients are completely resistant to corticosteroids, but more patients are relatively resistant and require relatively high doses of corticosteroids to control their symptoms (steroid-dependent). Some patients develop progressive loss of lung function, as in patients with COPD. Management of patients with difficult asthma should be supervised by a respiratory specialist and should involve careful assessment to confirm a diagnosis of asthma, identification and treatment of exacerbating factors, particularly allergens, and recording of peak expiratory flow patterns. A period of hospital admission may be the best way to assess and manage these patients. Treatment involves optimizing corticosteroids therapy, assessing additional controllers such as long-acting inhaled or subcutaneous beta2-agonists or subcutaneous, theophylline and antileukotrienes. In some patients, the use of immunosuppressive treatments may reduce steroid requirements, although these treatments are rarely effective and have side-effects. In the future, the nonsteroid anti-inflammatory treatments now in development may be useful in these patients.
While considerable progress has been made in development of drugs for asthma, there have been few advances in the treatment of chronic obstructive pulmonary disease (COPD). New therapeutic approaches to prevent disease progression are urgently needed and these will arise out of better understanding of the disease process at a cell and molecular level. The inflammatory response in COPD differs markedly from that of asthma, with differences in inflammatory cells, mediators and response to therapy. The neutrophilic inflammation is orchestrated by chemotactic factors, such as interleukin (IL)-8, other CXC chemokines and leukotriene B4; receptor blockers (CXCR1, CXCR2, BLT antagonists) or synthesis inhibitors (5'-lipoxygenase inhibitors) might be effective. Tumour necrosis factor (TNF) alpha may be an important amplifying cytokine and there are several strategies for blocking it (antibodies, soluble receptors, TACE inhibitors). IL-10 is effective in blocking the synthesis of IL-8 and TNF alpha as well as proteases. Oxidative stress and peroxynitrite may be important in COPD; more effective antioxidants are now in development. The inflammatory response in COPD is essentially steroid-resistant so that alternative anti-inflammatory treatments are needed. Phosphodiesterase 4 inhibitors look promising in early clinical studies. Nuclear factor-kappa B inhibitors and p38 MAP kinase inhibitors may also be effective. Several protease inhibitors are in development including those for neutrophil elastase, selective matrix metalloproteinase and cathepsin.
In this study the hypothesis is tested that the motion pattern of small anatomic landmarks, recognizable at the left ventricular endocardial border in the contrast angiocardiogram, reflects the motion of the endocardial wall. To verify this, minute metal markers were inserted in the endocardium of eight pigs with a novel retrograde transvascular approach. Marker motion was subsequently recorded with roentgen cinematography and compared with the motion of the landmarks on the endocardial contours detected from the contrast ventriculogram with an automated contour detection system. Linear regression analysis of the directions of the systolic metal marker and endocardial landmark pathways yielded a correlation coefficient of 0.86 and a standard error of the estimate of 10.3°. Landmark pathways were also measured in 23 normal human left ventriculograms. Normal left ventricular endocardial wall motion during systole, as observed in the 30° right anterior oblique view, is characterized by a dominant inward transverse motion of the opposite anterior and inferoposterior walls and a descent of the base toward the apex. The apex itself is almost stationary. On the basis of these observations, a widely applicable model for the assessment of left ventricular wall motion is described in mathematical terms.
No abstract is provided for this article.
A 22 year old woman had signs of rheumatic mitral and aortic valve disease early in pregnancy. Cardiac catheterization was performed during her third month of pregnancy under two-dimensional echocardiographic control without the use of ionizing radiation. Severe mitral stenosis with mild aortic stenosis was found. Five cubic centimeters of 5 percent dextrose in water were injected by hand to obtain left ventriculograms and supravalvular aortograms of sufficient quality to diagnose valvular regurgitation. The use of “echo-catheterization” may have significant advantages in selected clinical situations.
