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51.
Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate‐to‐severe plaque psoriasis and non‐pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER‐1, UNCOVER‐2 and UNCOVER‐3)
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Richard G. Langley MD Kim Papp MD Robert Bissonnette MD Darryl Toth MD Robert Matheson MD Micki Hultquist MD Barbara White MD 《International journal of dermatology》2010,49(7):818-828
Several biologics targeting different cytokines and receptors, including T‐cell receptors, have been approved for psoriasis treatment. Siplizumab, a humanized anti‐CD2 monoclonal antibody, may potentially provide an alternative therapy for psoriasis. Its safety profile and immunogenicity was examined in adults with plaque psoriasis. Two multicenter phase II randomized, double‐blind, placebo‐controlled studies: one tested two intravenous (I.V.) doses (0.012 and 0.04 mg/kg) of siplizumab every 2 weeks × 8 doses (124 patients); the second study tested three subcutaneous (S.C.) dose regimens of siplizumab (5 mg × 12 weeks, 5 mg × 6 weeks + placebo × 6 weeks, 7 mg × 4 weeks + placebo × 8 weeks), and placebo × 12 weeks (420 patients). Adverse events (AEs) and laboratory values were monitored. Immunogenicity was determined by anti‐siplizumab antibodies quantification. In both studies, siplizumab exhibited an acceptable safety profile; most common AEs judged to be siplizumab related were lymphopenia, chills, and headache, reported at a higher frequency in the siplizumab‐treated vs. placebo group. Siplizumab‐related reductions in absolute lymphocyte count did not result in clinical evidence of immune suppression. Anti‐siplizumab antibodies were detected after exposure to siplizumab; however, there was no evidence of an association between antibody development and AEs. Siplizumab exhibited an acceptable safety profile in adult patients with plaque psoriasis when administered as multiple I.V. or S.C. doses. Higher, clinically relevant doses of siplizumab would need to be tested to fully assess its safety. 相似文献
55.
Jeff SW Wong Calvin SH Ng Tak Wai Lee Anthony PC Yim 《Canadian respiratory journal》2006,13(4):219-221
The present report describes a case of severe airway obstruction caused by endobronchial tuberculosis in an 11-year-old girl who was successfully treated by bronchoscopic balloon dilation. This case illustrates the insidious presentation and the increasingly important role of bronchoscopic intervention in the management of endobronchial tuberculosis. In addition, a brief literature review of the condition in the pediatric age group is included. 相似文献
56.
NADPH oxidase is an enzyme in the plasma membrane of the neutrophil that catalyzes the production of O2-, a species central to the oxygen- dependent killing mechanisms of this cell. The oxidase is dormant in resting cells and is activated upon the addition of a stimulus. Neutrophils of patients with chronic granulomatous disease (CGD) manifest no oxidase activity when stimulated. The possible role of protein phosphorylation in the activation of NADPH oxidase was examined in normal and CGD neutrophils by measuring the incorporation of 32Pi into proteins as determined by gel electrophoresis followed by autoradiography. Resting neutrophils from normal subjects exhibit at least 40 distinct phosphoprotein bands. The level of phosphorylation of these bands was examined after the addition of phorbol myristate acetate (PMA), opsonized zymosan, digitonin, N-formyl-methionyl- phenylalanine (FMLP), or NaF. PMA and opsonized zymosan increased the phosphorylation of a set of 6 protein bands. Digitonin and FMLP consistently caused the phosphorylation of 4 of these protein bands, while NaF failed to induce increased phosphorylation of any protein band. All activators tested caused the dephosphorylation of one specific protein band. The time course of phosphorylation (dephosphorylation) was examined using PMA as the activating agent. Increased phosphorylation of one protein band was evident by 12 sec after the addition of PMA. The most slowly phosphorylated protein band did not slow evidence of change until 5 min after the addition of PMA. Three of the phosphoproteins examined were phosphorylated either earlier than or concomitant with the activation of NADPH oxidase. CGD neutrophils were compared with normal cells for their ability to phosphorylate proteins in response to PMA. The phosphoprotein banding patterns of CGD neutrophils were identical with those of normal neutrophils in both the resting and activated states. The evidence presented shows that the phosphorylation of proteins is a prominent feature of neutrophil metabolism. The striking similarity of phosphorylation changes induced by the various activators tested suggests that protein phosphorylation may play a role in some aspects of neutrophil activation. Evidence was not obtained, however, regarding a link between protein phosphorylation and activation of NADPH oxidase. 相似文献
57.
An enzyme-linked immunosorbent assay has been developed for the quantitation of activated Hageman factor-C1 inactivator (HF-C1 INH) complexes. Addition of increasing quantities of either of the major forms of activated Hageman factor (HFa or HFf) to normal plasma or to Hageman factor-deficient plasma leads to a dose-dependent increase in activated HF-C1 INH complexes. As little as 0.5 micrograms/mL of activated HF added to plasma can be detected, corresponding to activation of approximately 2% of plasma HF. The sensitivity of the assay is increased at least tenfold when complexes are formed in HF- deficient plasma, indicating competition between unactivated HF and activated HF-C1 INH complexes for binding to the antibody. Specificity is demonstrated in that addition of activated HF to hereditary angioedema plasma yields less than 1% of the activated HF-C1 INH complex formation obtained with normal plasma. Kaolin activation of HF- deficient plasma yields no detectable complex formation. Kaolin activation of prekallikrein-deficient plasma demonstrates a time- dependent increase in formation of activated HF-C1 INH complex consistent with the ability of HF in this plasma to autoactivate as the time of incubation with the surface is increased. Kaolin treatment of high-molecular weight (HMW) kininogen-deficient plasma yields an even more profound abnormality in the rate of formation of activated HF-C1 INH complexes reflecting the complex role of HMW kininogen in the initiation of contact activation. Although addition of corn inhibitor to plasma prevents activated HF-C1 INH complex formation, it does not inhibit activated HF sufficiently fast to prevent prekallikrein activation. 相似文献
58.
Prevention of degradation of human polymorphonuclear leukocyte proteins by diisopropylfluorophosphate 总被引:27,自引:0,他引:27
Proteases can complicate the characterization of proteins from cells, especially human polymorphonuclear leukocytes (PMN), which contain abundant neutral proteases. We tested the ability of agents to inhibit proteolysis, with special reference to the subunit polypeptides of the contractile proteins actin, myosin, and actin-binding protein (ABP). Phenylmethylsulfonyl fluoride (PMSF), O-phenanthroline, EGTA, EDTA, N- ethylmaleimide, alone or in combinations, failed to prevent extensive proteolysis of the PMN proteins during solubilization of cells with dodecyl sulfate. These inhibitors and also alpha-1-antitrypsin and soybean trypsin inhibitor similarly could not prevent proteolysis during homogenization of cells in cold isosomolar sucrose. Treatment of PMN with greater than or equal to mM diisopropylfluorophosphate (DFP) prior to solubilization or homogenization markedly inhibited proteolysis. PMSF and DFP were equally effective in inhibiting proteolysis in PMN extracts, suggesting that the efficacy of DFP may result from its permeation of intact cells and granules before barriers are disrupted by detergents or homogenization. Treatment of PMN with DFP under conditions inhibiting proteolysis did not affect their rate of phagocytosis. We recommend the use of DFP in future studies correlating functions and protein structure of PMN. 相似文献
59.
In this study we detected a factor that stimulates the proliferation of bone marrow-derived hematopoietic precursors in diffusion chambers implanted in mice. This factor, called diffusible colony-stimulating factor (D-CSF), was found in medium conditioned in the presence of spleen and peripheral blood cells from mice with B cell leukemia (BCL1). After the administration of D-CSF, the number of colonies formed in the plasma clot inside the chamber (CFU-DG) was increased, as were the number of hematopoietic precursors (CFU-MIX, CFU-S, CFU-C, and BFU-E) as judged by a subculture of diffusion chamber contents. Depletion of macrophages and T cells from the spleen cell suspension did not decrease the production of D-CSF, thereby indicating that it was derived from B cells. Neoplastic BCL1 cells appear to be the source because D-CSF could not be detected in medium conditioned with normal B cells. BCL1-conditioned medium (CM) did not enhance CFU-MIX, BFU-E, and CFU-C colony formation in vitro, which suggested that D-CSF is different from multi-CSF, EPA, or CSF. The addition of BCL1 CM to multi- CSF-, erythroid potentiating activity (EPA), and CSF (EL-4CM)- containing cultures had no effect on CFU-MIX, BFU-E, and CFU-C colony formation, thus indicating the absence of a synergistic or inhibitory activity. On the other hand, EL-4 CM, which stimulates CFU-MIX, BFU-E, and CFU-C in vitro, had no effect on CFU-DG in vivo. Biochemical characterization of BCL1 CM revealed that D-CSF is relatively heat stable and loses its bioactivity with protease treatments. It binds to lentil-lectin, according to gel-filtration chromatography has a relative molecular weight of approximately 43,000, and on reverse-phase high-performance liquid chromatography elutes with acetonitrile. These data also indicate that transformed B cells may serve as a source for hematopoietic regulators that act on hematopoietic precursors in vivo. 相似文献
60.
Anthony L Bui Rouselle F Lavado Elizabeth K Johnson Benjamin PC Brooks Michael K Freeman Casey M Graves Annie Haakenstad Benjamin Shoemaker Michael Hanlon Joseph L Dieleman 《Bulletin of the World Health Organization》2015,93(8):566-576D