Clinical science
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Editorial Review
Anti-inflammatory actions of glucocorticoids: molecular mechanisms.
1. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this anti-inflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents. 2. ⋯ This may be due to excessive formation of activator protein-1 at the inflammatory site, which consumes activated glucocorticoid receptors so that they are not available for suppressing inflammatory genes. 6. This new understanding of glucocorticoid mechanisms may lead to the development of novel steroids with less risk of side effects (which are due to the endocrine and metabolic actions of steroids). 'Dissociated' steroids which are more active in transrepression (interaction with transcription factors) than transactivation (GRE binding) have now been developed. Some of the transcription factors that are inhibited by glucocorticoid, such as nuclear factor-kappa B, are also targets for novel anti-inflammatory therapies.
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Comparative Study
CYFRA 21-1, a cytokeratin subunit 19 fragment, in bronchoalveolar lavage fluid from patients with interstitial lung disease.
1. It has been suggested that CYFRA21-1, a cytokeratin subunit 19 fragment, is potentially useful for diagnosis and monitoring of lung carcinoma. However, serum levels of CYFRA21-1 are also increased in a high proportion of patients with interstitial lung disease. ⋯ Serial bronchoalveolar lavage samples were obtained from six patients with clinically active pneumonitis after they had undergone systemic corticosteroid therapy. CYFRA21-1 levels were significantly lower after these patients exhibited clinical improvement (P < 0.05). 4. These findings suggest that the level of CYFRA21-1 in bronchoalveolar lavage fluid is a useful marker for the clinical diagnosis of pneumonitis, and is also adequate for the evaluation of disease activity, especially over the course of treatment.
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1. Fibroblast cultures were established from biopsies of hypertrophic scar and normal dermis taken from nine patients recovering from second- and third-degree burns. The capacity of these fibroblasts to synthesize the small proteoglycan decorin was assessed by quantitative Western blot analysis of conditioned medium collected from confluent cultures. ⋯ An increase in the length of the dermatan sulphate chain on decorin, a previously reported characteristic of this glycosaminoglycan in hypertrophic scar, was seen in all but two of the strains treated with transforming growth factor-beta 1. The depression of decorin synthesis by transforming growth factor-beta 1 was reversed on removal of the agent and passaging the fibroblasts. 3. The reduced capacity of fibroblasts in hypertrophic scar tissue to synthesize decorin may have implications for the development of the condition since this small proteoglycan is involved in tissue organization and may also play a role in modulating the activity in vivo of fibrogenic cytokines such as transforming growth factor-beta 1.
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1. The aetiology of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis, is uncertain. Studies of specific environmental factors and immune dysfunction have provided little insight into disease pathogenesis. 2. ⋯ Loci on chromosomes 3, 7 and 12 were linked to inflammatory bowel disease overall, whereas loci on chromosomes 2 and 6 were linked only in ulcerative colitis. Linkage with chromosome 16 was noted in Crohn's disease only. Fine mapping of these susceptibility loci is in progress, and may lead to gene identification with attendant clinical benefits.
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1. The impact of different genetic risk loads defined by HLA-DQB1 alleles on the autoimmune and clinical characteristics of 647 children and adolescents with recent-onset Type I diabetes was evaluated in a prospective population-based study. The subjects were divided into four groups based on HLA-DQB1 genotypes: DQB1*0302/0201 (high risk), *0302/x (moderate risk), *0201/y (low risk) and *z/z (decreased risk). 2. ⋯ Among ICA-negative subjects, those with the DQB1*0201/y genotype had higher serum C-peptide levels over the first 2 years after the diagnosis of Type I diabetes than those with other genotypes (P = 0.028). 3. Our data provide some evidence of HLA-DQB1-determined heterogeneity in the autoimmune and clinical characteristics of childhood Type I diabetes at the time of the clinical manifestation. This suggests differences between children with various HLA-DQB1 genotypes in the pace and/or intensity of the beta-cell destructive process leading to clinical Type I diabetes.