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Timothy M Wright

Publications and source records attributed to Timothy M Wright.

26 records · Page 2Linked to original sources
PubMed2003

Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis.

OBJECTIVE: To investigate correlations between serum levels of topoisomerase I-specific antibody (anti-topo I) and clinical features of systemic sclerosis (SSc), including disease severity (the total skin score [TSS]) and disease activity. METHODS: Using highly sensitive enzyme-linked immunosorbent assays, we measured the levels of anti-topo I antibody, including total IgG, individual IgG subclasses, and IgA, and analyzed their correlations with the TSS in 59 patients with SSc, all of whom had diffuse cutaneous involvement. Serial serum samples were obtained from 11 of these patients. RESULTS: The titers of anti-topo I antibody, including IgG and IgA, were positively correlated with the TSS, a measure of SSc disease severity. In 8 of the 11 patients from whom serial serum samples were obtained, changes in the levels of both IgG and IgA, when detectable, paralleled changes in the TSS. In 3 patients, an increasing anti-topo I IgG level preceded an increase in the TSS. The level of each IgG subclass also correlated with and tended to parallel the TSS. The patients with very active disease had higher mean IgG (P < 0.001) and IgA (P < 0.05) titers than did those with inactive disease. CONCLUSION: Serum levels of anti-topo I antibody correlate positively with disease severity and disease activity in SSc.

Autoantibodies↗
PubMed2003

Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies.

OBJECTIVE: To examine concordance for systemic sclerosis (SSc) in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: MZ and DZ twins were recruited nationwide. Zygosity was confirmed by DNA fingerprint analysis. The presence of antinuclear antibodies (ANAs) was determined using indirect immunofluorescence with HEp-2 cells as substrate. Identification of SSc-associated serum autoantibodies was performed by immunoprecipitation and double immunodiffusion. Major histocompatibility complex class II alleles were identified by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Concordance for SSc was found to be similar in MZ and DZ twins. Overall concordance for SSc was low in the twins (4.7%). Concordance for the presence of ANAs was significantly higher in MZ twins compared with DZ twins. SSc-associated serum autoantibodies occurred exclusively in patients with SSc. The distribution of SSc-associated serum autoantibodies was similar to that observed in our large database of SSc patients. Increased HLA allele sharing was detected in DZ twins, irrespective of disease concordance. CONCLUSION: These results indicate that inherited genetic factors are not sufficient to explain the development of SSc. Rather, these data indicate that inheritance may play a role in the development of serum autoantibodies in the "healthy" twin sibling of an SSc patient.

Adult↗
PubMed2003

Mechanical performance of ceramic acetabular liners under impact conditions.

Although new generation alumina ceramics have exhibited a reduced incidence of fracture, concern still persists about the behavior of ceramic acetabular liners under impact conditions. The objective of this study was to explore whether fracture of a new generation alumina ceramic liner was likely to occur in vivo. Ceramic liners were impacted with forces of 23, 21, 15, and 12 kN (n = 3 at each force). At 23 kN, all 3 ceramic liners fractured on the first impact; at 12 kN none of the ceramic liners fractured after 20 impacts. The threshold force of 12 kN is large in comparison with estimated physiologic forces on the hip during falls or stumbling, suggesting that ceramic liner fracture is not a definite consequence of liner impact.

Aluminum Oxide↗
PubMed2003

The implications of constraint in lumbar total disc replacement.

Lumbar total disc replacement (TDR) is an evolving technique that has the potential to replace arthrodesis as the gold standard surgical treatment of degenerative disc disease. The interaction between host anatomy and physiology and the biomechanical properties of TDR implants will determine the quality of long-term clinical results. However, there is scant literature addressing this subject. The purpose of this article is to discuss the implications of biomechanical constraint in TDR. Based upon available data for normal motion segments and the design of two TDRs currently in clinical trials, unconstrained designs appear to have a kinematic advantage. They are more likely to provide a physiologic mobile instantaneous axis of rotation (IAR), which may explain why they display greater range of motion in vivo. Their lack of constraint may prevent excessive facet joint or capsuloligamentous loads in the extremes of flexion and extension. Furthermore, since the IAR is mobile, they may be less sensitive to small errors in implant placement. On the other hand, constrained devices appear to have an advantage in protection of the posterior elements from shear loading. Spinal shear loads of considerable magnitude occur during activities of daily living. Whether the transference of stresses to the implant and implant-bone interface is clinically significant is unknown. Although this article focuses on two specific TDR designs, future designs will need to account for the same kinematic and loading concerns regarding constraint. We hope this discussion will assist clinicians and researchers in the design, selection, and clinical comparison of present and future TDR implants.

Arthroplasty, Replacement↗
PubMed2002

Critical requirement for professional APCs in eliciting T cell responses to novel fragments of histidyl-tRNA synthetase (Jo-1) in Jo-1 antibody-positive polymyositis.

Polymyositis (PM) is an autoimmune muscle disease characterized by oligoclonal T cell infiltrates mediating myocytotoxicity. Although antigenic triggers for this process remain undefined, clinically homogeneous subsets of PM patients are characterized by autoantibodies directed against nuclear and cytoplasmic Ags that include histidyl-tRNA synthetase (Jo-1). Available evidence suggests that formation of anti-Jo-1 autoantibodies is Ag-driven and therefore dependent on CD4(+) T cells that may also direct cytolytic CD8(+) T cells involved in myocyte destruction. To assess peripheral blood T cell responses to Jo-1, we first subcloned full-length human Jo-1 as well as novel fragments of Jo-1 into the maltose-binding protein expression vector pMALc2. Expressed proteins were then used in standard proliferation assays with either PBMC or autologous DCs as sources of APCs. Although PBMC-derived APCs and DCs both supported peripheral blood T cell proliferation when primed with full-length human Jo-1, only DCs promoted proliferative responses to a unique amino-terminal fragment of Jo-1. mAb blockade of different HLA Ags revealed that these responses were MHC class II dependent. Therefore, for the first time, these studies demonstrate anti-Jo-1 T cell responses in Jo-1 Ab-positive PM patients as well as in healthy control subjects. More importantly, this work underscores the critical importance of APC type in dictating T cell responses to a novel antigenic fragment of Jo-1.

Adult↗
PubMed2002

The CXC chemokine murine monokine induced by IFN-gamma (CXC chemokine ligand 9) is made by APCs, targets lymphocytes including activated B cells, and supports antibody responses to a bacterial pathogen in vivo.

Monokine induced by IFN-gamma (Mig; CXC chemokine ligand 9) is an IFN-gamma-inducible CXC chemokine that signals through the receptor CXCR3 and is known to function as a chemotactic factor for human T cells, particularly following T cell activation. The mig gene can be induced in multiple cell types and organs, and Mig has been shown to contribute to T cell infiltration into immune/inflammatory reactions in peripheral tissues in mice. We have investigated the expression and activities of Mig and CXCR3 in mouse cells and the role of Mig in models of host defense in mice. Murine (Mu)Mig functioned as a chemotactic factor for resting memory and activated T cells, both CD4(+) and CD8(+), and responsiveness to MuMig correlated with surface expression of MuCXCR3. Using mig(-/-) mice, we found that MuMig was not necessary for survival after infections with a number of intracellular pathogens. Surprisingly, however, we found that mig(-/-) mice showed reductions of 50-75% in Abs produced against the intracellular bacterium Francisella tularensis live vaccine strain. Furthermore, we found that MuMig induced both calcium signals and chemotaxis in activated B cells, and that B cell activation induced expression of MuCXCR3. In addition, IFN-gamma induced the expression of mumig in APCs, including CD8 alpha(+) and CD8 alpha(-) dendritic cells. Together, our data suggest that Mig and CXCR3 may be important not only to recruit T cells to peripheral inflammatory sites, but also in some cases to maximize interactions among activated T cells, B cells, and dendritic cells within lymphoid organs to provide optimal humoral responses to pathogens.

Animals↗
PubMedDate not supplied

Lack of hormonal influences on mechanical properties of sheep knee ligaments.

BACKGROUND: The number of anterior cruciate ligament injuries in female athletes exceeds that in male athletes at similar competitive levels. This difference has been attributed by some authors to hormone-mediated alteration in knee laxity in women. HYPOTHESIS: Sheep anterior cruciate and medial collateral ligament strength and stiffness are not altered by administration for 6 months of estrogen or a selective estrogen receptor agonist (raloxifene). STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-eight mature ewes were divided into five groups: sham operation (N = 6), ovariectomy (N = 9), ovariectomy and estradiol implant (N = 7), low-dose raloxifene (N = 9), and high-dose raloxifene (N = 7). After 6 months, the animals were sacrificed and ligaments were tested along with those from five rams' knees. RESULTS: No differences were found between treatment groups for maximum force, stiffness, energy to failure, or failure site. The ultimate stress of the rams' anterior cruciate ligaments was significantly higher than that of the ewes. CONCLUSIONS: Estrogen and estrogen receptor agonists at physiologic levels do not lead to decreased knee ligament strength. CLINICAL RELEVANCE: The female hormonal milieu may not be responsible for the increased incidence of anterior cruciate ligament injury in female athletes compared with their male counterparts.

Animals↗