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Biomedical subjects

W W Chatham

Publications and source records attributed to W W Chatham.

At least 19 recordsLinked to original sources
PubMed2006

Ultrasound appearance of knuckle pads.

OBJECTIVE: We describe the ultrasound appearance of knuckle pads. DESIGN AND PATIENTS: Retrospective analysis of imaging in a series of five patients initially referred for evaluation of periarticular soft-tissue swelling of the hands involving the dorsum of the PIP and MP joints. Two patients had associated Dupuytren's contractures. Ultrasound and radiographs of the hands in all patients were reviewed and correlated with clinical history and physical exams. RESULTS: Radiographs in four patients demonstrated dorsal soft-tissue thickening. Ultrasound exams showed increased dorsal subcutaneous thickening, with either diffuse or focal hypoechoic areas corresponding to the areas of soft-tissue fullness identified on physical exam. No erosions or synovial proliferation were identified either by radiographs or ultrasound of the underlying joints. CONCLUSIONS: Knuckle pads can sometimes be difficult to distinguish from synovitis on physical examination. Musculoskeletal ultrasound can quickly identify these superficial lesions and exclude underlying synovial proliferation.

Adult↗
PubMed2002

Immune function in patients with rheumatoid arthritis treated with etanercept.

Etanercept, a recombinant human tumor necrosis factor (TNF) inhibitor that binds both soluble and cell-bound TNF, has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis (RA). Because TNF receptors are found on many types of cells that modulate the immune response, we evaluated the general immune function of a subset of RA patients in a blinded clinical study. No significant differences were seen between patients treated with etanercept or placebo in the surface antigen phenotypes of peripheral blood leukocytes, T cell proliferative responses, neutrophil function, delayed-type hypersensitivity (DTH) reactions, serum immunoglobulin levels, or incidence of infections. Although this observational study was relatively small and could detect only major changes in immunological status, the stability of immune function over time in patients receiving etanercept corroborates the findings in clinical studies, which suggest that etanercept does not alter overall global immune function.

Adult↗
PubMed2001

Treatment of lupus with corticosteroids.

Through direct signals to the nucleus mediated by the glucocorticoid receptor, exogenous glucocorticoids impact a broad array of cellular functions. DNA binding of the glucocorticoid receptor, depending upon the specific promoter to which the receptor binds, affects gene expression by recruiting transcription factors to the promoter or by interfering with the function of co-factors required for gene transcription. Steroid effects on the adhesion functions and release of products by phagocytic cells are prompt, occurring within hours of administration. Administration of corticosteroids results in rapid depletion of circulating T-cells due to a combination of effects including enhanced circulatory emigration, induction of apoptosis, inhibition of T-cell growth factors, and impaired release of cells from lymphoid tissues. Corticosteroid effects on B-cell function and immunoglobulin production are more delayed. The broad, generally suppressive effects of corticosteroids on the immune response render them useful for the management of most organ system manifestations of lupus. Corticosteroid toxicity in lupus is notable for greater susceptibility to infections, osteoporosis, osteonecrosis and accelerated atherogenesis. Although use of corticosteroids for patients with severe disease manifestations is associated with higher numbers of deaths from infections, overall survival appears to be improved.

Adrenal Cortex Hormones↗
PubMed1999

Update on sarcoidosis.

The local inflammatory response in sarcoidosis appears to be a Th1-mediated process. Evidence exists that the systemic immune response, however, shows a Th2 predominance. Mycobacteria species, particularly cell wall-deficient forms, continue to be candidates for an infectious cause of the disease. Evidence for a possible role for human herpesvirus 8 has also been submitted. The relationship between sarcoidosis and infectious pathogens remains open to investigation. Both Sjögren's syndrome and common variable immunodeficiency display clinical and immunopathologic overlap with sarcoidosis. Blau's syndrome, a genetic disorder of autosomal dominant inheritance, may be confused with infantile sarcoidosis. Vasculitis in sarcoidosis may be underappreciated. Virtually any size vessel may be involved, thus adding to the multiplicity of clinical settings in which sarcoidosis can occur.

Sarcoidosis↗
PubMed1998

Ligation of CR1 attenuates Fc receptor-mediated myeloperoxidase release and HOCl production by neutrophils.

Surface adherent immunoglobulins are potent stimuli for inducing neutrophil release of myeloperoxidase and production of hypochlorous acid (HOCl), an oxidant that promotes activity of neutrophil proteases. Opsonization of surface adherent IgG (SAIgG) by complement results in attenuation of these responses, despite augmenting neutrophil production of superoxide and release of specific granule enzymes. The role of complement receptor ligation in modulating Fc receptor-triggered myeloperoxidase release and HOCl production by neutrophils was determined by incubating neutrophils with SAIgG in the presence of complement receptor ligating antibody reagents. Ligation of CR1 by F(ab')2 derived from CR1 specific monoclonal antibody (mAb 543) resulted in significant attenuation of surface-associated IgG (SAIgG)-induced release of myeloperoxidase and HOCl production but did not result in attenuation of SAIgG-induced superoxide or hydrogen peroxide production; ligation of CR1 by mAb 543 F(ab')2 also attenuated surface adherent IgA-induced myeloperoxidase release and HOCl production. HOCl production was not significantly attenuated when neutrophils were activated with SAIgG in the presence of surface adherent C1q or when CR3 was ligated by F(ab')2 derived from mAb having specificity for the CD11b (mAb M1/70) or CD18 (mAb TS1) subunits of CR3. These results indicate that ligation of CR1 on neutrophils by C3b fixed to IgG may alter signal transduction events linking ligation of neutrophil Fc receptors to cellular events required for release of myeloperoxidase and generation of HOCl.

Antibodies, Monoclonal↗
PubMed1996

Characterization of PepB, a group B streptococcal oligopeptidase.

Group B streptococci were recently reported to possess a cell-associated collagenase. Although the enzyme hydrolyzed the synthetic collagen-like substrate N-(3-[2-furyl]acryloyl)-Leu-Gly-Pro-Ala, we found that neither the highly purified enzyme nor crude group B streptococcal cell lysate solubilized a film of reconstituted rat tail collagen, an activity regarded as obligatory for a true collagenase. We cloned and sequenced the gene for the enzyme (pepB). The deduced amino acid sequence showed 66.4% identity to the PepF oligopeptidase from Lactococcus lactis, a member of the M3 or thimet family of zinc metallopeptidases. The group B streptococcal enzyme also showed oligopeptidase activity and degraded a variety of small bioactive peptides, including bradykinin, neurotensin, and peptide fragments of substance P and adrenocorticotropin.

Amino Acid Sequence↗
PubMed1995

Effects of tenidap on superoxide-generating enzymes. Non-competitive inhibition of xanthine oxidase.

The anti-rheumatic drug tenidap has been shown previously to attenuate superoxide production by activated neutrophils. Given the importance of leukocyte as well as endothelial cell derived superoxide in mediating inflammatory responses, the effects of tenidap on mammalian enzymes capable of generating superoxide were determined. Tenidap had no effect on the generation of superoxide by NADPH oxidase reconstituted from fractionated neutrophil lysates. However, significant inhibition of superoxide production by mixtures of hypoxanthine and xanthine oxidase was observed in the presence of 3-30 micrograms/mL tenidap. The kientics of xanthine oxidase inhibition by tenidap were non-competitive; the Ki of tenidap for xanthine oxidase was 11 micrograms/mL (34 microM). No inhibition of xanthine oxidase was observed in the presence of other known inhibitors of cyclooxygenase. Inhibition of xanthine oxidase may be a heretofore unrecognized mechanism of the antirheumatic effects of tenidap.

Adenosine Deaminase↗
PubMed1995

Progressive joint destruction in a human immunodeficiency virus-infected patient with rheumatoid arthritis.

This article reports the case of a 63-year-old patient with rheumatoid arthritis (RA) whose symptoms of RA improved after the occurrence of a secondary human immunodeficiency virus (HIV) infection; however, the HIV infection did not affect the histologic parameters of joint destruction to the same extent as it did the clinical symptoms. Histologic and immunohistologic joint examinations of this patient revealed an ongoing production of cartilage- and bone-degrading enzymes by macrophages and fibroblasts, without the presence of T cells. These findings demonstrate that progressive joint destruction in RA can occur in the absence of T cells. Moreover, our results support the hypothesis that both T cell-dependent and T cell-independent pathways play a significant role in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1995

Rheumatoid synovial fibroblast adhesion to human articular cartilage. Enhancement by neutrophil proteases.

OBJECTIVE: To determine if preexposure of human articular cartilage to activated neutrophils alters rheumatoid synovial fibroblast adhesion to human articular cartilage. METHODS: Human articular cartilage was exposed to either activated neutrophils, interleukin-1, or supernatants obtained from activated neutrophils that had been treated with different protease inhibitors. Radiolabeled rheumatoid synovial fibroblasts were then incubated with the cartilage and the number of counts associated with the cartilage was determined. RESULTS: Pretreatment of human articular cartilage with either activated neutrophils or supernatants obtained from activated neutrophils enhanced subsequent rheumatoid synovial fibroblast adhesion. In contrast, interleukin-1 treatment of cartilage did not alter the adhesion of synovial fibroblasts. The enhanced adhesion could be attenuated by pretreatment of the neutrophil supernatants with either diisopropylfluorophosphonate or EGTA and almost completely abolished by using both inhibitors. CONCLUSION: This study demonstrates that adhesion of rheumatoid synovial fibroblasts to human articular cartilage can be enhanced by exposing the cartilage to proteases released by neutrophils. These results suggest that neutrophil products may play a role in enhancing adhesion of rheumatoid synovium to cartilage in vivo.

Adult↗
PubMed1995

Activation of human neutrophils by surface-associated IgA is associated with the release of activated collagenase.

Neutrophils contain on their surface a receptor for the Fc portion of IgA. Cross-linking of this receptor in the fluid phase induces superoxide production and release of granule constituents, but the response to surface associated IgA has not been previously studied. Neutrophils incubated with surface-associated IgA (SAIgA) release significant amounts of activated collagenase in addition to the granule proteins myeloperoxidase and lactoferrin. This activation is associated with release of superoxide as well as hydrogen peroxide and hypochlorous acid. Although neutrophils incubated with soluble aggregates of IgA also release granule proteins and produce superoxide, soluble aggregates of IgA do not trigger the release of activated collagenase and do not generate hydrogen peroxide or hypochlorous acid. In summary, neutrophils activated by surface associated IgA respond differently than when cells are activated by soluble aggregates of IgA. These differences may be important in understanding the mechanisms of tissue injury in patients with inflammatory disorders.

Cells, Cultured↗
PubMed1994

HOCl production by human neutrophils activated by surface-associated IgG: requirement for influx of extracellular calcium.

Neutrophils produce large quantities of HOCl when stimulated by surface-associated immunoglobulin G, a result not seen when neutrophils are stimulated with soluble complexes of IgG. Compared with unactivated cells or cells stimulated with soluble aggregates of IgG, a significant influx of extracellular 45Ca2+ was observed in cells activated by surface-associated IgG. Removal of extracellular calcium with EGTA almost completely blocked HOCl production. Similarly, treatment of neutrophils with lanthanum, which has been shown to interfere with calcium channels, also effectively blocked HOCl production. These results were not secondary to an overall decrease in activation, as superoxide production and release of the specific granule protein lactoferrin and the azurophilic granule protein myeloperoxidase were not significantly altered by lanthanum or EGTA. Production of H2O2, the precursor of HOCl, was similarly decreased by both EGTA and lanthanum. Induction of extracellular calcium influx with a calcium ionophore in the presence of soluble aggregates of IgG resulted in HOCl production. Production of HOCl is not sensitive to inhibition by pretreatment of cells with pertussis toxin. These observations indicate that the differences in the biological responses of human neutrophils to surface-associated IgG compared with soluble aggregates of IgG are associated with differing signaling events, including influx of extracellular calcium.

Biological Transport↗
PubMed1994

Determinants of neutrophil HOCl generation: ligand-dependent responses and the role of surface adhesion.

Neutrophil (PMN) generation of HOCl, an oxidant important in mediating tissue injury by PMN proteases, requires PMN production of H2O2 and the catalytic activity of myeloperoxidase (MPO). Production of H2O2 and MPO release vary with the PMN activating ligand and are facilitated by cellular adhesion. Leukotriene B4, platelet-activating factor, heat-aggregated immunoglobulin G (HAIgG), tumor necrosis factor alpha (TNF-alpha), and f-Met-Leu-Phe (fMLP) all triggered significant superoxide production but negligible H2O2 or HOCl generation when added to suspended PMNs. Production of H2O2 was observed when fMLP, TNF-alpha, or HAIgG was added to PMNs adherent to bovine serum albumin (BSA)-coated wells, but significant production of HOCl was observed only when HAIgG was added to PMNs adherent to BSA-coated wells or when suspended PMNs treated with TNF-alpha were allowed to settle in BSA-coated wells. Even greater production of both H2O2 and HOCl was observed when PMNs were incubated in wells coated with IgG (SAIgG). HOCl generation, when observed, was accompanied by release of MPO. Nonadherent PMNs generated HOCl when treated with 50-100 ng/ml phorbol myristate acetate or when stimulated with fMLP following treatment with cytochalasin B; PMN activation under these conditions was also associated with MPO release but HOCl production was much less efficient relative to PMNs stimulated by SAIgG. These studies indicate that surface adhesion and ligand-induced responses that facilitate release of myeloperoxidase and dismutation of superoxide to H2O2 are required for production of extracellularly released HOCl; these responses are most efficiently utilized during PMN interaction with SAIgG.

Cell Adhesion↗
PubMed1993

Fixation of C3 to IgG attenuates neutrophil HOCl generation and collagenase activation.

Neutrophils stimulated with surface-associated monomeric IgG (SAIgG) release an activated collagenase in association with significant generation of hypochlorous acid (HOCl). To determine whether these neutrophil responses are modulated by IgG C fixation, neutrophils were incubated with SAIgG pretreated with normal or C-deficient sera. Treatment of SAIgG with normal sera did not attenuate neutrophil superoxide production, H2O2 generation, or extracellular release of latent collagenase and lactoferrin; however, serum treatment resulted in significant attenuation of SAIgG-induced HOCl generation (75%) and extracellular release of the azurophilic granule constituents myeloperoxidase and cathepsin G. Collagenase activity in supernatants of neutrophils incubated with SAIgG pretreated with normal sera (9.5 +/- 0.8 ng/min) was significantly less than activity in supernatants of neutrophils incubated with SAIgG not treated with sera (15.3 +/- 1.2 ng/min). Treatment of surface adherent monoclonal IgG1 and IgG2 with sera resulted in significantly greater attenuation of HOCl generation compared to serum treatment of IgG4. Attenuation of HOCl generation was not observed when SAIgG was pretreated with heat-inactivated sera, EDTA-chelated sera, or sera depleted of C3; treatment of SAIgG with C5-depleted sera yielded results comparable to treatment with intact sera. These results indicate that C3-derived ligands fixed to adherent Ig alter IgG-induced release of azurophilic granule constituents and HOCl generation by neutrophils.

Antigen-Antibody Complex↗
PubMed1993

Degradation of human articular cartilage by neutrophils in synovial fluid.

OBJECTIVE: To determine whether surface-adherent immunoglobulins are capable of mediating synovial fluid (SF) neutrophil degradation of proteoglycan and collagen in intact, normal human articular cartilage, and to define the respective roles of neutrophil serine proteases and metalloproteases in degrading these cartilage constituents. METHODS: Pellet explants of normal human articular cartilage pretreated with bovine serum albumin (BSA) or IgG were incubated with polymorphonuclear cells suspended in SF (PMN-SF), or with supernatants derived from neutrophils stimulated with surface-associated IgG. Proteoglycan degradation was measured by assaying release of 35S-proteoglycan fragments from cartilage explants prelabeled with 35S-sulfate. Collagen degradation was measured by assaying hydroxyproline content in the PMN-SF preparations or neutrophil supernatants following their incubation with unlabeled explants. RESULTS: Significant release of both 35S fragments and hydroxyproline was noted following incubation of PMN-SF with IgG-treated pellets, compared with pellets treated with BSA. IgG preparations derived from pooled normal serum or rheumatoid arthritis SF were equally efficacious in mediating PMN degradation of cartilage collagens. Explant release of 35S fragments during incubation with PMN supernatant was completely inhibited when serine proteases were inactivated by diisopropyl fluorophosphate (DFP); however, release of 35S fragments was enhanced when metalloprotease activity was present in the supernatant. Release of hydroxyproline during incubation of explants with PMN supernatant was comparable in the presence of DFP or EDTA, but was markedly enhanced when both serine and metalloprotease activity were present in the supernatant. CONCLUSION: Neutrophils in SF are capable of degrading both proteoglycans and collagens in intact human articular cartilage. Degradation of these cartilage constituents is facilitated by immunoglobulins adherent to the cartilage surface and by the synergistic action of PMN serine and metalloproteases released during activation of neutrophils with surface-associated immunoglobulin.

Arthritis, Rheumatoid↗
PubMed1992

Additive enhancement of neutrophil collagenase activity by HOCl and cathepsin G.

Using preparations of latent collagenase derived from neutrophil specific granule extracts, the relative effects of cathepsin G and HOCl on activation of neutrophil collagenase were determined using a quantitative collagenase assay. Enhancement of collagenase activity by cathepsin G and physiologically relevant concentrations of HOCl were comparable, but HOCl mediated collagenase activation was reversible in the presence of HOCl scavenger. Collagenase activity in preparations treated with cathepsin G and HOCL simultaneously or sequentially was significantly greater than activity in preparations treated with HOCl or cathepsin G alone. The results indicated additive, yet independent enhancing effects of HOCl and cathepsin G on activity of neutrophil collagenase.

Cathepsin G↗
PubMed1991

Tenidap, in contrast to several available nonsteroidal antiinflammatory drugs, potently inhibits the release of activated neutrophil collagenase.

Neutrophils contain a collagenase that is stored in a latent form within the specific granule. With cellular activation, the latent enzyme is activated in association with the production of a variety of oxidants, including hypochlorous acid. We evaluated 4 nonsteroidal antiinflammatory drugs (NSAIDs) currently on the market and the new antiinflammatory/antirheumatic drug tenidap for their effects on the release of activated collagenase. In contrast to the 4 NSAIDs, tenidap profoundly inhibited the release of activated collagenase. This inhibition was predominantly due to interference with activation of the latent enzyme, rather than interference with enzyme release. The inhibition of collagenase activation was associated with a profound reduction in myeloperoxidase activity and in hypochlorous acid production. These observations demonstrate that tenidap has properties that set it apart from conventional NSAIDs and suggest that it may be a particularly useful agent in the treatment of inflammatory rheumatic disorders.

Anti-Inflammatory Agents, Non-Steroidal↗