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Biomedical subjects

T M Wright

Publications and source records attributed to T M Wright.

At least 37 records · Page 2Linked to original sources
PubMed1998

Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages.

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM). Recent evidence has suggested that fragments of the ECM component hyaluronan play a role in chronic inflammation by inducing macrophage expression of chemokines. Interferon-gamma (IFN-gamma), an important regulator of macrophage functions, has been shown to induce the C-X-C chemokines Mig and IP-10. These chemokines affect T-cell recruitment and inhibit angiogenesis. The purpose of this investigation was to determine the effect of hyaluronan (HA) on IFN-gamma-induced Mig and IP-10 expression in mouse macrophages. We found a marked synergy between HA and IFN-gamma on Mig and IP-10 mRNA and protein expression in mouse macrophages. This was most significant with Mig, which was not induced by HA alone. The synergy was specific for HA, was not dependent on new protein synthesis, was not mediated by tumor necrosis factor-alpha, was selective for Mig and IP-10, and occurred at the level of gene transcription. These data suggest that the ECM component HA may influence chronic inflammatory states by working in concert with IFN-gamma to alter macrophage chemokine expression.

Animals↗
PubMed1998

Residual stresses in ultra-high molecular weight polyethylene loaded cyclically by a rigid moving indenter in nonconforming geometries.

The characterization of stress and deformation fields that incorporate moving cyclic loads and nonlinear material response in ultra-high molecular weight polyethylene components for total knee replacements is required to quantify mechanisms of surface damage. A simulation of stresses in polyethylene components for total knee replacement subjected to cyclic moving loads was performed with use of nonlinear finite element analysis. Convergence to a steady-state cycle of stress and deformation was observed within five cycles of loading. Differential plastic deformation under the surface of the polyethylene led to horizontal residual stresses that were tensile at the surface and compressive in the subsurface. The magnitudes of the residual stresses indicate their importance in surface failure mechanisms. Horizontal residual tensile stresses at the surface are consistent with the initiation and propagation of surface cracks that could cause pitting in polyethylene. Horizontal residual compressive stresses under the surface could cause such cracks to arrest or turn and thus limit damage to a region just beneath the surface. The results emphasize the importance of incorporating nonlinear effects to simulate long-term stress fields associated with surface damage in polyethylene.

Arthroplasty, Replacement, Knee↗
PubMed1998

Role of polyethylene oxidation and consolidation defects in cup performance.

Quality factors such as particle consolidation and oxidation have been claimed to impair the performance of ultrahigh molecular weight polyethylene implants, but no definite data estimate their real effect. To assess the influence of these quality determinants in wear, wear rate, and time in service at a single, well proven design, the percentage area of polyethylene sections occupied by nonconsolidated polyethylene particles, the presence of a white band, and the amount of polyethylene oxidation (through density curves) were evaluated in 92 retrieved Charnley acetabular components with available clinical data. The average percentage area of nonconsolidated polyethylene particles in cup sections was 3.1%. There were 11 cups showing a subsurface white band. The authors observed an average density in the deep polyethylene of 0.9420 g/cc after an average in vivo use of 9.8 years (range, 0.08-20.3 years). Banded cups showed significantly higher subsurface densities. When studying the relationship among clinical and material factors with performance variables, wear measurements (obtained through radiographic methods and direct measurements of polyethylene thickness in the collected implants) correlated with age at implantation, activity, and time in service. Weight was a determinant of the wear rate. None of the studied polyethylene quality factors showed a definite association with wear performance or time to failure in this series. Implant survivorship was not significantly impaired in the 22.225-mm Charnley low friction replacement by a subsurface white band or by a higher area occupied by nonconsolidated particles. Fewer nonconsolidated particles were not associated with longer survivorship. This design proved tolerance to polyethylene quality variations, in the signaled ranges, without a significant effect in the system performance.

Arthroplasty, Replacement, Hip↗
PubMed1997

Cytokines in acute and chronic inflammation.

Inflammation is mediated by a variety of soluble factors, including a group of secreted polypeptides known as cytokines. Inflammatory cytokines can be divided into two groups: those involved in acute inflammation and those responsible for chronic inflammation. This review describes the role played in acute inflammation by IL-1, TNF-alpha, IL-6, IL-11, IL-8 and other chemokines, G-CSF, and GM-CSF. It also describes the involvement of cytokines in chronic inflammation. This latter group can be subdivided into cytokines mediating humoral responses such as IL-4, IL-5, IL-6, IL-7, and IL-13, and those mediating cellular responses such as IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons, transforming growth factor-beta, and tumor necrosis factor alpha and beta. Some cytokines, such as IL-1, significantly contribute to both acute and chronic inflammation. This review also summarizes features of the cell-surface receptors that mediate the inflammatory effects of the described cytokines.

Acute Disease↗
PubMed1997

Highly restricted TCR-alpha beta usage by autoreactive human T cell clones specific for DNA topoisomerase I: recognition of an immunodominant epitope.

Autoantibody responses to DNA topoisomerase I (Topo I) are highly specific to patients with systemic sclerosis (SSc). We recently demonstrated that Topo I-specific T cells are components of the T cell repertoire of patients with SSc and healthy individuals. These autoreactive T cells were essential for the Ag-specific activation of B cells resulting in anti-Topo I Ab production in vitro and therefore are believed to play a central role in autoantibody production. To characterize the Topo I-specific T cell, 15 T cell clones reactive with Topo I were generated from two patients with SSc and three healthy donors, all of whom shared the MHC class II allele DR11. All clones expressed a CD3+CD4+CD8- phenotype and were restricted by HLA-DR. When eight rTopo I fragments were tested individually as Ags, all clones responded to F5, which encodes amino acids 209 through 386 of Topo I, but not to F10, which encodes amino acids 209 through 276, indicating that one or more immunodominant epitopes on Topo I is located between amino acids 276 and 386. Analysis of TCR gene usage showed that the predominant V(alpha) segment of the functionally rearranged TCR-alpha gene was Vdelta5, which was used by seven clones. Most strikingly, all except one T cell clone had functional rearrangements of TCR beta-chain genes using the Vbeta120.la and Jbeta1.1 gene segments. Comparison of the CDR3 sequences of the TCRs revealed limited diversity, and, of note, all clones contained the amino acid motif PGGN (or minor variations) in the CDR3 of their TCR beta-chains. Furthermore, identical beta-chain CDR3 amino acid sequences were encoded by cDNAs generated from T cell clones derived from multiple individuals, including patients with SSc and healthy donors.

Adult↗
PubMed1996

Cancellous bone screw thread design and holding power.

This study was designed to isolate and evaluate the parameters of host density, outer diameter (OD), root diameter (RD), and pitch in cancellous bone screw design and their effect on holding power. Special emphasis was placed on screw pitch, which has been evaluated infrequently in the literature. Three groups of stainless steel V thread screws (group I, OD 4.5 mm, RD 3.0 mm; group II, OD 6.4 mm, RD 3.5 mm; group III, OD 6.4 mm, RD 4.2 mm) were machined with progressive increases in pitch from 12 to 32 threads per inch (TPI). Two densities of synthetic cancellous bone material (Pedilen, Ottobock, Minneapolis, MN, U.S.A.), 0.15 g/ml and 0.22 g/ml, were then prepared and molded into sheets 1.9 cm thick and the screw threads completely engaged. Push-out tests were performed using a servohydraulic testing machine (MTS, Minneapolis, MN, U.S.A.). Fifteen trials of each screw were tested in each material. The effect on holding power of the different parameters of the custom screws in order of importance was (a) host material density, (b) OD (c) pitch, and (d) RD. The groups with a 6.4-mm OD had a much greater holding power than did the group with a 4.5-mm OD (p < 0.001). A decrease in screw pitch (increased threads per inch) did itself have a significant improved effect on fixation for all groups in both pedilen densities (p < 0.001). In the two 6.4-mm screw groups studied, the difference in the two root diameters (4.2 mm vs. 3.5 mm) showed the smaller root diameter to give a greater holding power in the less dense 0.15 g/ml pedilen (p < 0.001). In the more dense 0.22 g/ml pedilen there was no difference (p = 0.26) between the root diameters. To optimize holding power, cancellous screws may be designed with a decreased pitch (increased TPI) over those commercially available today. Cannulated screws must have a larger cancellous thread root diameter to leave room for the central cannulation; this may decrease their holding power in less dense cancellous bone but not in denser bone.

Biomechanical Phenomena↗
PubMed1996

Catastrophic failure of a conforming type of total knee replacement: a case report.

A case study is presented to illustrate the concept of femoral component failure secondary to polyethylene wear in a 67 year old man, 13 years after he had conforming type total knee replacements. This case illustrates the theory that this observed problem may be a leading cause of failure in conforming and nonconforming total knee replacements in the future.

Aged↗
PubMed1995

Granulocyte colony-stimulating factor rapidly activates a distinct STAT-like protein in normal myeloid cells.

Binding of granulocyte colony-stimulating factor (G-CSF) to normal myeloid cells activates the protein tyrosine kinases Lyn and Syk and results in the immediate early upregulation of G-CSF receptor (R) mRNA. In our studies of the signaling pathways activated by G-CSF that are coupled to proliferation and differentiation of myeloid cells, we examined whether G-CSF activated a latent transcription factor belonging to the STAT protein family. Electrophoretic mobility shift assays (EMSAs) of nuclear extracts from G-CSF-stimulated human myeloid cells showed the rapid activation of a DNA-binding protein that bound to the high-affinity serum-inducible element (hSIE) and migrated with mobility similar to serum inducible factor (SIF)-A (Stat3 homodimer). The G-CSF-stimulated SIF-A complex (G-SIF-A) did not bind to duplex oligonucleotides used to purify and characterize other Stat proteins (Stat1-6). In addition, antibodies raised against Stat1-6 failed to supershift the G-SIF-A complex or interfere with its formation. Based on its binding to the hSIE and lack of antigenic cross-reactivity with other known STAT proteins that bind to this element, it is likely that G-SIF-A is composed of a distinct member of the STAT protein family. EMSAs of whole-cell extracts prepared from cell lines containing full-length and truncated mutants of the G-CSFR showed that activation of G-SIF-A did not correlate with proliferation; rather, optimal activation requires the distal half of the cytosolic domain of the G-CSFR that is essential for differentiation. Activation of G-SIF-A, therefore, may be an early G-CSFR-coupled event that is critical for myeloid maturation.

B-Lymphocytes↗
PubMed1995

IFN-gamma induces a p91/Stat1 alpha-related transcription factor with distinct activation and binding properties.

The 5' flanking region of the mig gene, a member of the chemokine family of small m.w. chemoattractant and growth regulatory factors, contains an IFN-gamma-responsive enhancer, gamma RE-1, consisting of an extended imperfect palindrome. In this report we show that a novel factor, gamma RF-1, which binds to the gamma RE-1 element, is rapidly activated in a variety of primary cell types and tumor cell lines treated with IFN-gamma. Our data indicate that gamma RF-1 is present in a latent form in unstimulated cells and its DNA-binding activity is dependent upon tyrosine phosphorylation. UV cross-linking studies revealed that gamma RF-1 consists of at least two proteins of approximately 95 and 130 kDa, which interact with the gamma RE-1 element. A comparison of gamma RF-1 and GAF, an IFN-gamma-activated transcription factor containing the p91/Stat1 alpha protein (Stat, signal transducer and activator of transcription), showed that these two factors exhibited differences in electrophoretic mobility, responsiveness to IFN-alpha, and kinetics of activation. Using anti-Stat Ab, however, we found that one or more subunits of gamma RF-1 are antigenically related to p91/Stat1 alpha. Our results indicate, therefore, that gamma RF-1 and GAF are distinct IFN-gamma-responsive transcription factors and probably contain closely related members of the Stat protein family.

Base Sequence↗
PubMed1995

Ligand-dependent and -independent activation of the transcription factor gamma RF-1 in a cell-free system.

gamma RF-1 is a recently identified transcription factor induced by interferon-gamma (IFN-gamma) which binds to a unique palindromic enhancer, gamma RE-1, in the promoter of the mig gene. This paper describes the ligand-dependent and ligand-independent activation of gamma RF-1 in a cell-free system. gamma RF-1 activity was induced by IFN-gamma in a time-dependent manner from 5 to 60 min in lysates prepared from the human monocytic leukaemia line THP-1 and the human epidermoid carcinoma line A431. The activation of gamma RF-1 in vitro required both ATP and an inhibitor of tyrosine phosphatases (sodium orthovanadate or pervanadate). In the presence of limiting concentrations (micromolar) of ATP, activation was also dependent upon stimulation with IFN-gamma, whereas at millimolar concentrations of ATP, gamma RF-1 was activated by either sodium orthovanadate or pervanadate in the absence of ligand. Based on cell fractionation studies, both membrane and cytosol components were essential for activation of gamma RF-1 in vitro. Consistent with a role for one or more tyrosine kinases in the activation of gamma RF-1, its DNA binding activity was blocked by monoclonal anti-phosphotyrosine antibodies and by the tyrosine kinase inhibitors genistein, lavendustin A and herbimycin A. A comparison with recently described pathways of IFN-mediated transcription factor regulation indicates that the in vitro activation of gamma RF-1 is unique, requiring both membrane and cytosol fractions and inhibition of endogenous tyrosine phosphatase activity.

Adenosine Triphosphate↗
PubMed1995

T and B cell collaboration is essential for the autoantibody response to DNA topoisomerase I in systemic sclerosis.

To elucidate the mechanisms controlling anti-DNA topoisomerase I (topo I) antibody production in patients with systemic sclerosis (SSc), in particular the role of interactions between topo I-specific Th cells and B cells, we established an in vitro system for the analysis of anti-topo I antibody production. In vitro anti-topo I antibody synthesis in PBMC cultures was induced by recombinant topo I and PWM, and was measured by a topo I-specific ELISA. Anti-topo I antibody was detected in PBMC culture supernatants from 11 (61%) of 18 anti-topo I-positive SSc patients. In contrast, anti-topo I antibody was not detected in the PBMC culture supernatants from 4 anti-topo I-negative SSc patients or 10 healthy donors. Characterization of in vitro anti-topo I antibody production showed that 1) the anti-topo I antibody isotype produced was IgG; 2) the anti-topo I antibody levels in culture supernatants correlated with those in patients' sera; 3) CD4+ T cells were necessary for antibody synthesis; and 4) antibody synthesis was restricted by HLA-DR, but not by HLA-DQ or DP. In addition, separation of cultured T and B cells by a semipermeable membrane or culture with anti-CD40 ligand mAb blocked in vitro anti-topo I antibody production. These results indicate that a contact-mediated and HLA-DR-restricted collaboration between topo I-specific T and B cells is essential for in vitro anti-topo I antibody production in a subset of SSc patients.

Adult↗
PubMed1995

Cyclic compressive loading results in fatigue cracks in ultra high molecular weight polyethylene.

Wear damage to the articulating surfaces of total joint components made of ultra high molecular weight polyethylene is associated with a fatigue fracture mechanism, despite the fact that these surfaces are subjected to primarily compressive and compressive-tensile cyclic stresses. The question arises as to whether fatigue cracks will form under such loading conditions. In this study, we experimentally demonstrated that fatigue cracks could be initiated and propagated in notched ultra high molecular weight polyethylene specimens subjected to fully compressive and compressive-tensile cyclic loading. Under these loading conditions, growth of fatigue cracks was limited: the cracks arrested without catastrophic failure of the test specimens. The final length of the crack was dependent on the load ratio of the fatigue cycle; fatigue cracks propagated to greater lengths as the load ratio was increased.

Knee Prosthesis↗
PubMed1995

Detection of anti-DNA topoisomerase I antibody by an enzyme-linked immunosorbent assay using overlapping recombinant polypeptides.

Five recombinant fusion proteins with overlapping amino acid sequences encompassing the entire DNA topoisomerase I (topo I) molecule were generated, purified, and used as antigens for an enzyme-linked immunosorbent assay (ELISA). IgG, IgA, IgM, and "total" (total of IgG, IgA, and IgM isotypes) anti-topo I antibodies were measured using a mixture of these five fusion proteins in 73 systemic sclerosis (SSc) sera positive for anti-topo I antibody by double immunodiffusion (DID) and 184 control sera negative for anti-topo I antibody by DID. Fragment-specific anti-topo I antibodies were also measured by ELISA using each topo I recombinant protein as antigen. IgG, IgA, IgM, and total anti-topo I antibodies were detected in 67 (92%), 56 (77%), 16 (22%), and 70 (96%) of 73 SSc sera positive for anti-topo I antibody by DID, respectively. The specificity of the total anti-topo I ELISA was 99% when compared with DID. The total anti-topo I ELISA levels were strongly correlated with DID titers (r = 0.907, P < 0.0001). Three sera which recognized a conformational epitope on native topo I or had predominantly IgM anti-topo I antibody showed a false-negative result with the total anti-topo I ELISA. Three SSc sera negative for anti-topo I antibody by DID were positive by the total anti-topo I ELISA, and two were confirmed to recognize the N-terminus of topo I. IgG and IgA antibody levels to the N-terminal and central portion of topo I were correlated with each other, but those to the C-terminus were not. These findings indicate that the ELISA using recombinant fusion proteins is a highly sensitive and specific alternative to conventional DID for the detection of anti-topo I antibody.

Adult↗
PubMed1995

Coulomb frictional interfaces in modeling cemented total hip replacements: a more realistic model.

Loosening of cemented femoral hip stems could be initiated by failure of the cement mantle due to high cement stresses. The goals of this study were to determine if realistic stem-cement interface characteristics could result in high cement stresses when compared to a bonded stem-cement interface and to determine if stem design parameters could be chosen to reduce peak cement stresses. Three-dimensional finite-element models of cemented femoral hip components were studied with bonded or realistic Coulomb friction stem-cement interfaces. The results showed that the use of a non-bonded, non-linear Coulomb friction interface resulted in substantially different stress fields in the cement when compared to a bonded stem-cement interface. Tensile stresses in the proximal cement mantel for the Coulomb friction interface case (10.8 MPa) were greater than the fatigue strength of the cement. In contrast, the tensile stresses in the cement mantle were not greater than the fatigue strength for the bonded case (7.5 MPa). Failure of the cement mantle in the proximal femur could therefore be initiated by a lack of a bond at the stem-cement interface. The effect of different cross-sectional stem geometries (medial radii of 3.0, 4.9 and 5.5 mm and antero-posterior widths of 9.8 and 13.7 mm) and different elastic moduli (cobalt chromium alloy and titanium alloy) for the stem material were also evaluated for models with a Coulomb friction interface. Changes in the stem cross-section and elastic modulus had only limited effects on the stress distributions in the cement. Of the parameters evaluated in this study, the characteristics of the stem-cement interface had the largest effect on cement mantle stresses.

Alloys↗