Wiley
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Association of cold‐reactive antilymphocyte antibodies with lymphopenia in systemic lupus erythematosusAbstract In a prospective study 26 of 29 patients with systemic lupus erythematosus had cold‐reactive antilymphocyte antibodies cytotoxic for autologous lymphocytes and lymphocytes from normal subjects. The level of antilymphocyte antibodies was highly correlated, by linear regression analysis, with lymphopenia in these patients. The data suggested that both the avidity and the concentration of these antibodies were important determinants in this relationship. A clear association between increased antilymphocyte antibody activity and exacerbation of SLE was demonstrated. Apart from lymphopenia, however, neither type of clinical manifestation nor any particular serologic abnormality appeared to be related to the presence of antilymphocyte antibodies.
Wiley - Tập 18 Số 6 - Trang 587-594 - 1975
Measurement of increases in anti‐double‐stranded dna antibody levels as a predictor of disease exacerbation in systemic lupus erythematosusAbstract To evaluate the predictive power of changes in levels of antibodies to double‐stranded DNA (anti‐dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6–35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti‐dsDNA antibody (by the Crithidia luciliae assay, an enzymelinked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty‐seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti‐dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty‐four of these exacerbations were preceded by a significant increase in anti‐dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti‐dsDNA antibody levels preceded the exacerbation by 8–10 weeks. Significant increases in anti‐dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti‐dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P < 0.03). Serial assessment of anti‐dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.
Wiley - Tập 33 Số 5 - Trang 634-643 - 1990
Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double‐blind, methotrexate‐controlled study of patients with active rheumatoid arthritisAbstract Objective To determine the efficacy and safety of pamapimod (a selective inhibitor of the α‐isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA). Methods Patients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double‐blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs. Results Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50‐, 150‐, and 300‐mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300‐mg dose appeared to be more toxic than either the 2 lower doses or MTX. Conclusion The present results showed that pamapimod was not as effective as MTX in the treatment of active RA.
Wiley - Tập 60 Số 2 - Trang 335-344 - 2009
Distribution of HLA–B27 subtypes in Sardinia and continental Italy and their association with spondylarthropathies
Wiley - Tập 52 Số 10 - Trang 3319-3321 - 2005
Beneficial Effect of Artificial Tears Made with Autologous Serum in Patients with Keratoconjunctivitis Sicca
Wiley - Tập 27 Số 4 - Trang 459-461 - 1984
Cartilage repair using bone morphogenetic protein 4 and muscle‐derived stem cellsAbstract Objective Muscle‐derived stem cells (MDSCs) isolated from mouse skeletal muscle exhibit long‐time proliferation, high self‐renewal, and multipotent differentiation. This study was undertaken to investigate the ability of MDSCs that were retrovirally transduced to express bone morphogenetic protein 4 (BMP‐4) to differentiate into chondrocytes in vitro and in vivo and enhance articular cartilage repair. Methods Using monolayer and micromass pellet culture systems, we evaluated the in vitro chondrogenic differentiation of LacZ‐ and BMP‐4–transduced MDSCs with or without transforming growth factor β1 (TGFβ1) stimulation. We used a nude rat model of a full‐thickness articular cartilage defect to assess the duration of LacZ transgene expression and evaluate the ability of transplanted cells to acquire a chondrocytic phenotype. We evaluated cartilage repair macroscopically and histologically 4, 8, 12, and 24 weeks after surgery, and performed histologic grading of the repaired tissues. Results BMP‐4–expressing MDSCs acquired a chondrocytic phenotype in vitro more effectively than did MDSCs expressing only LacZ; the addition of TGFβ1 did not alter chondrogenic differentiation of the BMP‐4–transduced MDSCs. LacZ expression within the repaired tissue continued for up to 12 weeks. Four weeks after surgery, we detected donor cells that coexpressed β‐galactosidase and type II collagen. Histologic scoring of the defect sites 24 weeks after transplantation revealed significantly better cartilage repair in animals that received BMP‐4–transduced MDSCs than in those that received MDSCs expressing only LacZ. Conclusion Local delivery of BMP‐4 by genetically engineered MDSCs enhanced chondrogenesis and significantly improved articular cartilage repair in rats.
Wiley - Tập 54 Số 2 - Trang 433-442 - 2006
Interleukin‐6 modulates production of T lymphocyte–derived cytokines in antigen‐induced arthritis and drives inflammation‐induced osteoclastogenesisAbstract Objective To determine the cellular mediators of antigen‐induced arthritis (AIA) and the relative contribution of members of the interleukin‐6 (IL‐6) family and tumor necrosis factor (TNF) in AIA. Methods AIA was induced in mice deficient in T and B lymphocytes, IL‐6 (IL‐6−/− ), TNF (TNF−/− ), IL‐11 receptor, and oncostatin M receptor, by immunization with methylated bovine serum albumin (mBSA) followed 7 days later by intraarticular injection of mBSA. Arthritis severity was assessed histologically, and T lymphocyte responses were assessed in vitro. Anti‐TNF neutralizing antibody was administered to wild‐type mice during AIA. Bone marrow osteoclasts were generated in vitro via culture with RANKL and macrophage colony‐stimulating factor. Results AIA was dependent on CD4+ T lymphocytes, but not CD8+ T lymphocytes or B cells. IL‐6−/− mice had reduced AIA severity and fewer osteoclasts at sites of bone erosion. This protective effect was not seen with a deficiency of other IL‐6 family members and was similar to that in TNF−/− mice or wild‐type mice receiving TNF blockade treatment. IL‐6−/− CD4+ T lymphocytes from draining lymph nodes had reduced antigen‐induced proliferation and produced less IL‐17 and less RANKL, relative to osteoprotegerin, than cells from wild‐type mice. Bone marrow from IL‐6−/− mice generated fewer osteoclasts in vitro than bone marrow from either wild‐type or TNF−/− mice. Conclusion AIA is driven by CD4+ T lymphocytes. IL‐6 is an important mediator of bone destruction in AIA because it regulates T lymphocyte production of key osteoclastogenic cytokines and inflammation‐induced bone marrow osteoclast differentiation. These findings have implications for reducing bone and joint damage in rheumatoid arthritis.
Wiley - Tập 54 Số 1 - Trang 158-168 - 2006
Cannabinoid‐mediated antinociception is enhanced in rat osteoarthritic kneesAbstract Objective To determine whether local administration of the cannabinoid 1 (CB1 ) receptor agonist arachidonyl‐2‐chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA). Methods OA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium mono‐iodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA. Results Local application of the CB1 agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n = 19) and up to 62% in OA knee joints (n = 29;P < 0.01). Coadministration of the CB1 receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV‐1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB1 receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint. Conclusion These findings indicate that activation of peripheral CB1 receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB1 receptor or the TRPV‐1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid‐mediated antinociception. The increased nerve activity observed following CB1 receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB1 receptors may be important targets in controlling OA pain.
Wiley - Tập 58 Số 1 - Trang 145-153 - 2008
Down‐regulation of myeloid cell leukemia 1 by epigallocatechin‐3‐gallate sensitizes rheumatoid arthritis synovial fibroblasts to tumor necrosis factor α–induced apoptosisAbstract Objective Overexpression of the antiapoptotic protein myeloid cell leukemia 1 (Mcl‐1) in rheumatoid arthritis (RA) synovial fibroblasts is a major cause of their resistance to tumor necrosis factor α (TNFα)–induced apoptosis. This study was undertaken to evaluate the efficacy of epigallocatechin‐3‐gallate (EGCG) in down‐regulating Mcl‐1 expression and its mechanism of RA synovial fibroblast sensitization to TNFα‐induced apoptosis. Methods EGCG effects on cultured RA synovial fibroblast cell morphology, proliferation, and viability over 72 hours were determined by microscopy and a fluorescent cell enumeration assay. Caspase 3 activity was determined by a colorimetric assay. Western blotting was used to evaluate the apoptosis mediators poly(ADP‐ribose) polymerase (PARP), Mcl‐1, Bcl‐2, Akt, and nuclear translocation of NF‐κB. Results In RA synovial fibroblasts, EGCG (5–50 μM ) inhibited constitutive and TNFα‐induced Mcl‐1 protein expression in a concentration‐ and time‐dependent manner (P < 0.05). Importantly, EGCG specifically abrogated Mcl‐1 expression in RA synovial fibroblasts and affected Mcl‐1 expression to a lesser extent in osteoarthritis and normal synovial fibroblasts or endothelial cells. Inhibition of Mcl‐1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts, which was mediated via down‐regulation of the TNFα‐induced Akt and NF‐κB pathways. Caspase 3 activation by EGCG also suppressed RA synovial fibroblast growth, and this effect was mimicked by Akt and NF‐κB inhibitors. Interestingly, Mcl‐1 degradation by EGCG sensitized RA synovial fibroblasts to TNFα‐induced PARP cleavage and apoptotic cell death. Conclusion Our findings indicate that EGCG itself induces apoptosis and further sensitizes RA synovial fibroblasts to TNFα‐induced apoptosis by specifically blocking Mcl‐1 expression and, hence, may be of promising adjunct therapeutic value in regulating the invasive growth of synovial fibroblasts in RA.
Wiley - Tập 60 Số 5 - Trang 1282-1293 - 2009
Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in ratsAbstract Objective To characterize the clinical and histopathologic changes in a rat model of broad‐spectrum matrix metalloproteinase (MMP)–induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans. Methods Male Lewis rats weighing 150–180 gm were administered 10–30 mg of the broad‐spectrum MMP inhibitor marimastat over a 2‐week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters. Results Marimastat‐treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high‐stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat‐treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans. Conclusion This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.
Wiley - Tập 48 Số 6 - Trang 1742-1749 - 2003
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