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Sputum eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma 总被引:1,自引:0,他引:1
Duong M Subbarao P Adelroth E Obminski G Strinich T Inman M Pedersen S O'Byrne PM 《Chest》2008,133(2):404-411
BACKGROUND: The relationship between eosinophilic airway inflammation and exercise-induced bronchoconstriction (EIB), and the response to inhaled corticosteroid (ICS) therapy was examined. METHODS: Twenty-six steroid-na?ve asthmatic patients with EIB were randomized to two parallel, double-blind, crossover study arms (13 subjects in each arm). Each arm compared two dose levels of inhaled ciclesonide that were administered for 3 weeks with a washout period of 3 to 8 weeks, as follows: (1) 40 vs 160 microg daily; and (2) 80 vs 320 microg daily. Baseline and weekly assessments with exercise challenge and sputum analysis were performed. RESULTS: Data were pooled and demonstrated that 10 subjects had baseline sputum eosinophilia >or= 5%. Only high-dose ICS therapy (ie, 160 and 320 microg) significantly attenuated the sputum eosinophil percentage. Sputum eosinophil percentage significantly correlated with EIB severity, and predicted the magnitude and temporal response of EIB to high-dose therapy, but not to low-dose therapy (ie, 40 and 80 microg). Low-dose ICS therapy provided a significant reduction in EIB at 1 week, with little additional improvement thereafter, irrespective of baseline sputum eosinophil counts. In contrast, high-dose ICS therapy provided a significantly greater improvement in EIB in subjects with sputum eosinophilia compared to those with an eosinophil count of < 5%. The difference between the eosinophilic groups in the magnitude of improvement in EIB was evident after the first week of high-dose ICS therapy and increased with time. CONCLUSIONS: These results suggest that eosinophilic airway inflammation may be important in modifying the severity of EIB and the response to ICS therapy. Measurements of sputum eosinophil percentage may, therefore, be useful in predicting the magnitude and temporal response of EIB to different dose levels of ICSs. Trial registration: clinicaltrial.gov; Identifier: NCT00525772. 相似文献
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BACKGROUND: A pleural drainage system must be capable of efficiently evacuating the air or fluids from the pleural cavity so that adequate lung reexpansion can take place. The air flow and negative pressure of the system will depend on the particular design of each model. This experimental study analyzes the specifications and performance of the pleural drainage systems currently on the market. METHODS: Thirteen models of pleural drainage systems connected to wall suction were examined. The models were classified into the following three groups: dry systems; wet systems; and single-chamber systems. We determined the ambient air flow and the negative pressure generated according to the suction level. The components of each model are also described. RESULTS: Under normal conditions, dry (except for the Sentinel Seal; Sherwood Medical; Tullamore, Ireland), wet, and single-chamber systems reach similar air flow rates (17 to 30, 24 to 27, and 22 to 28 L/min, respectively). With higher wall suction levels, wet systems increase the air flow (26 to 49 L/min) but the negative pressure becomes unstable because of the water loss phenomenon, dry systems increase the air flow (29 to 50 L/min) without modifying the regulator pressure, and single-chamber systems also raise the air flow (45 to 51 L/min) but increase the negative pressure. When there is an air leak, dry systems (except for the Sentinel Seal) lose less negative pressure than the other systems. CONCLUSIONS: The functioning of these systems can be optimized only by applying a suitable wall suction level adjusted to each case. Although the three types of systems are capable of evacuating adequate air flow rates, the negative pressure and the capacity to maintain it in the presence of an air leak are different in each system. Being fitted with valves and not water compartments makes the dry systems the safest and the ideal for use when the patient has to be moved. 相似文献
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Aberrant removal of necrotic debris is considered a feature with inflammatory consequences in SLE. Herein, primary Sjögren's syndrome (SS) patients were investigated for the first time for the capacity of their sera to degrade secondary necrotic cell remnants (SNEC) and DNA (endonuclease DNase1 activity), as well as for uptake of SNEC by blood-borne phagocytes. For comparison, specimens from unselected SLE and RA patients and from healthy blood donors (HBD) were also studied. Compared to HBD, the sera from SS and SLE patients studied (but not RA) were found to exhibit significantly impaired capacity for degradation of SNEC (both for p = 0.007) and deficient DNase1 activity (both for p < 0.0001). The deficient DNase1 activity in SS and SLE sera did not owe to decreased DNase1 protein levels. It correlated inversely with increased serum levels of circulating nucleosomes and cell-free DNA (p < 0.0001), as well as with the disease activity indices of SS (r = −0.445, p = 0.0001) and SLE (r = −0.500, p = 0.013). In ex-vivo whole blood analyses, SS and SLE patients (but not RA) also manifested significantly increased SNEC-phagocytosis by monocytes and granulocytes (all for p < 0.0001) that also correlated with disease severity indices of SS (p = 0.001) and SLE (p = 0.01). In various cross-admixture experiments, such aberration was found to reside in the hyperfunctional activity of phagocytes, the impaired degrading activity of serum DNase1 and the SNEC-binding capacity of serum IgG of SS and SLE patients. The sera of SS and SLE patients (but not of RA) induced significant SNEC-phagocytosis by healthy monocytes that correlated inversely with the DNase1 activity (r = −0.634, p < 0.0001) of these sera. In line with this, the inhibition of DNase1 in HBD sera by G-actin was found to lead to significantly diminished SNEC degradation and increased SNEC uptake by healthy phagocytes (p = 0.0009), supporting the important physiologic role of serum DNase1 in the prevention of SNEC-phagocytosis. Purified serum IgG preparations from SS and SLE patients manifested increased binding to SNEC and were able to enhance significantly the engulfment of SNEC by healthy phagocytes both directly (under serum-free conditions, p ≤ 0.009) and via the prevention of physiologic degradation of SNEC by serum, most likely due to their “shielding” against endonuclease digestion (p = 0.0005). These data indicate that upon cell necrosis, the immune system of SS and SLE patients may be overly exposed to the necrotic debris, a fact that probably holds a key role in the pathogenesis of inflammatory and autoimmune reactions observed in these disorders. 相似文献
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Humoral immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp) is associated with failure to respond to common pathogens and high frequency of autoimmunity. Here we addressed the question how deficiency in WASp and the homologous protein N-WASp skews the immune response towards autoreactivity. Mice devoid of WASp or both WASp and N-WASp in B cells formed germinal center to increased load of apoptotic cells as a source of autoantigens. However, the germinal centers showed abolished polarity and B cells retained longer and proliferated less in the germinal centers. While WASp-deficient mice had high titers of autoreactive IgG, B cells devoid of both WASp and N-WASp produced mainly IgM autoantibodies with broad reactivity to autoantigens. Moreover, B cells lacking both WASp and N-WASp induced somatic hypermutation at reduced frequency. Despite this, IgG1-expressing B cells devoid of WASp and N-WASp acquired a specific high affinity mutation, implying an increased BCR signaling threshold for selection in germinal centers. Our data provides evidence for that N-WASp expression alone drives WASp-deficient B cells towards autoimmunity. 相似文献
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B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE. 相似文献