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Biomedical subjects

T M Wright

Publications and source records attributed to T M Wright.

At least 55 records · Page 3Linked to original sources
PubMed1995

Combined effects of FK506 (tacrolimus) and cyclophosphamide on atypical B220+ T cells, cytokine gene expression and disease activity in MRL/MpJ-lpr/lpr mice.

Groups of female MRL/MpJ-lpr/lpr mice received either saline or FK506 (tacrolimus; 2 mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20 mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY-treated mice was 26 weeks, and for FK506- and FK506 + CY-treated groups was > or = 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to < or = 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3+ B220+ and CD3+CD4-CD8- T cells. Neither FK506 nor CY affected the reduction in IL-2 and IL-4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL-2 mRNA levels, IL-4 mRNA transcripts were increased six-fold compared with saline-treated controls. IL-10 and interferon-gamma (IFN-gamma) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti-dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell-directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL-4 within the affected lymphoid tissue.

Animals↗
PubMed1995

T cell proliferative response induced by DNA topoisomerase I in patients with systemic sclerosis and healthy donors.

The in vitro T cell proliferative response to DNA topoisomerase I (topo I) was examined in 26 systemic sclerosis (SSc) patients with anti-topo I antibody, 10 SSc patients without anti-topo I antibody, and 21 healthy donors. Using recombinant fusion proteins encompassing the entire human topo I amino acid sequence, a topo I-specific proliferative response was detected in PBMC cultures from 25 (96%) anti-topo I-positive SSc patients, 4 (40%) anti-topo I-negative SSc patients, and 13 (62%) healthy donors. Molecular typing at MHC class II loci revealed that all SSc patients and healthy donors having either DRB1*1501,2 (DR15), DRB1*1101,3,4 (DR11), or DRB1*07 (DR7) were responders. Characterization of the topo I-induced T cell proliferative response showed that (a) the responding cells were CD4+ T cells; (b) antigen-presenting cells were necessary for the response; (c) the response was restricted by HLA-DR, and to a lesser extent by HLA-DQ; and (d) the estimated frequency of the responding T cells determined by limiting dilution analysis was 1/9,277-1/24,853. PBMC cultures from anti-topo I-positive SSc patients showed a high T cell proliferative response after only 3 d of culture with topo I. Anti-topo I-negative SSc patients and healthy donors had no proliferative response after 3 d, but did respond after 7 d of culture. T cell proliferative responses to six truncated topo I fragments tested individually showed different patterns of T cell proliferation that were dependent upon the responder's HLA-DR alleles. These results indicate that T cells reactive with topo I are components of the normal T cell repertoire, and that the topo I-specific T cell proliferative response is not associated with the presence or absence of SSc or anti-topo I antibody, but is restricted by MHC class II alleles.

Adult↗
PubMed1995

Nonconsolidated polyethylene particles and oxidation in Charnley acetabular cups.

Nonconsolidated particles of ultra high molecular weight polyethylene are believed to be defects that adversely can affect the wear performance of total joint prostheses. The present study was done to determine the number, size, and distribution of these particles and to determine if their presence correlated with wear performance, as well as with other clinical and implant parameters. Forty retrieved and 7 new, never-implanted acetabular components were examined using light microscopy on thin cross sections. Particles were found in 92% of retrieved components and in all the new components. Particles in the retrieved components were either randomly distributed (32 components) or banded (with particles localized in regions approximately 1 mm below the outer surface of the component). No correlations were found between the number or area of particles and the wear performance or any of the clinical or implant variables. The presence of particles in the new implants was found to correlate with the length of time since the components had been radiation sterilized. For retrieved components, the density (and, therefore, the level of oxidative degradation) was high in the areas of banded particles. For new components, the density was higher the longer the time since sterilization. Nonconsolidated polyethylene particles are prevalent in total replacements but their source and cause are unknown. The results of this study show that they do not appear to affect or correlate with the length of implantation of acetabular cups. However, they still may be expected to adversely affect performance in cases where large numbers of particles are banded together near articulating surfaces of high stress environments such as found in the knee.

Acetabulum↗
PubMed1994

Fatigue crack propagation behavior of ultra high molecular weight polyethylene under mixed mode conditions.

Analytical studies of the stresses on and within ultra high molecular weight polyethylene joint components suggest that damage modes associated with polyethylene fatigue failure are caused by a combination of surface and subsurface crack propagation. Fatigue crack propagation tests under mixed mode loading conditions were conducted on center-cracked tension specimens machined from extruded blocks of sterilized polyethylene in an attempt to determine how fatigue cracks change direction in this material. Cyclic testing was performed using a sinusoidal wave form at a frequency of 5 Hz and an R-ratio (minimum load/maximum load) of 0.15. Specimens had the notch oriented perpendicular to the direction of applied load and at angles of 60 degrees and 45 degrees to the loading direction. Numerical analyses were used to interpret the experimental test and to predict the fatigue behavior of polyethylene under mixed mode conditions. It was found that all cracks eventually propagated horizontally, regardless of the initial angle of inclination of the notch to the direction of applied cyclic load. In fact, the extent of the curvilinear crack growth was quite limited. An effective range of cyclic stress intensity factor was calculated for correlation with the rate of crack growth. The results followed a Paris relation, with crack growth rate linearly related to a power of the range of stress intensity, for all three crack orientations. The numerical analyses adequately modeled the experimental fatigue crack growth results.

Materials Testing↗
PubMed1994

Fatigue testing of cerclage stainless steel wire fixation.

Because wire fixation continues to be used extensively in the practice of orthopaedic surgery, despite a high incidence of wire breakage, understanding the mechanism of this failure is of important clinical interest. The aim of this study was to investigate the failure of cerclage stainless steel wire using an in vitro cyclic loading device. A stainless steel testing fixture consisting of two half cylinders with a combined diameter of 2.5 cm was mounted in a servo hydraulic testing machine. Specimens of number 18 gauge (0.97 mm diameter) and number 16 gauge (1.22 mm diameter) 316L stainless steel wire were mounted around the two half cylinders in a cerclage manner using three different fastening methods: a uniform symmetrical twist, a knot twist, and a square knot. Single-load-to-failure and cyclic load tests were performed under controlled tensile displacement. The cerclage wire system fastened with a twist resulted in failure at loads significantly lower than systems fastened with the knot twist and the square knot. Cyclic loading of the wire fastened with twists also showed decreased fatigue properties when compared to those fastened with the knot twist and the square knot. In all tests, the 16-gauge wire was found to be clearly superior to the 18-gauge wire. For both wires, fatigue strengths at 100,000 cycles were only 30-37% of the static ultimate strength. These results show that wire diameter and fastening system are two important factors affecting the mechanical properties of the resulting fixation.

Bone Wires↗
PubMed1994

A unique palindromic element mediates gamma interferon induction of mig gene expression.

To define the molecular mechanisms involved in the action of gamma interferon (IFN-gamma), we have analyzed the transcriptional regulation of the mig (monokine induced by gamma interferon) gene, a member of the platelet factor 4-interleukin-8 cytokine family that is expressed in murine macrophages specifically in response to IFN-gamma. Analysis of mig/CAT chimeric constructs transiently transfected into the RAW 264.7 mouse monocytic cell line revealed a unique IFN-gamma-responsive element (gamma RE-1). The sequence of this cis regulatory element defined by deletion analysis contains an imperfect inverted repeat extending 27 bp. Examination of mig/CAT constructs with mutations in gamma RE-1 revealed that the palindromic positions in the element were essential for activity. Consistent with its function as an enhancer, a single copy of gamma RE-1 conferred IFN-gamma inducibility to a heterologous (herpes simplex virus thymidine kinase) promoter. Exonuclease III protection assays demonstrated symmetrical protection of a mig promoter fragment centered about the gamma RE-1 palindromic sequence. Using the gel electrophoretic mobility shift assay, we identified a factor (gamma RF-1) present in nuclear extracts prepared from IFN-gamma-stimulated RAW 264.7 cells which binds to gamma RE-1. The activation of gamma RF-1 occurred rapidly (within 1 min) in response to IFN-gamma and was independent of protein synthesis. Similar to the expression of mig mRNA, the formation of gamma RF-1 was selectively induced by IFN-gamma and not IFN-alpha. The regulation of gene expression through gamma RF-1 and gamma RE-1 may explain the preferential activation of a subset of interferon-inducible genes by IFN-gamma.

Animals↗
PubMed1994

Post-irradiation aging of ultra-high molecular weight polyethylene.

A study was performed to determine the time-course of oxidative degradation and the extent to which the degradation proceeded through the bulk of ultra-high molecular weight polyethylene joint components that had been irradiated and stored on a shelf. Standardized cylindrical samples, taken from a single batch of extruded polyethylene, were cleaned, packaged, and sterilized according to protocols used for commercial joint-replacement components. After sterilization, the samples were stored in the packages for time-periods of one day to more than one year. At each interval studied, thin sections were cut as a function of depth into the bulk of the sample and were used to determine the density and the infrared spectra. Marked alterations in the density and the infrared spectra consistent with continuing oxidative degradation occurred throughout the year of storage on the shelf. The alterations were most severe near the surface of the samples.

Drug Stability↗
PubMed1994

The natural history of ultra high molecular weight polyethylene.

Degradative changes occurring during the lifetime of ultra high molecular weight polyethylene total joint components made from 2 different starting resins were determined from retrieved tibial inserts. The inserts were manufactured in the Department of Biomechanics of the authors' institution, for intrahospital use by the hospital's surgical staff, allowing the ultra high molecular weight polyethylene properties to be traced from production, to sterilization, to shelf life, and to subsequent retrieval. Changes were found in the density and the infrared spectra. Density was greater after sterilization and at retrieval, when compared with the density of the virgin ultra high molecular weight polyethylene material, with a greater increase near the surfaces than within the bulk of the inserts. The inserts that had the longest life-times demonstrated the greatest increase in density. Density increases are important because they reflect increases in the elastic modulus of the ultra high molecular weight polyethylene. Such increases near the articulating surface of a total joint component would cause significant increases in the stresses associated with wear damage occurring on and near these surfaces. The infrared spectra were consistent with oxidative degradation.

Aged↗
PubMed1993

The effect of temperature, stress and microstructure on the creep of compact bovine bone.

Creep tests of 117 compact bovine bone specimens were conducted at three temperatures (25, 37, and 43 degrees C), with applied stresses between 71 and 115 MPa. Following testing, the amount of secondary haversian bone in the gage region of the specimens was estimated. The resulting steady-state creep rates (epsilon) were fit to an Arrhenius (e-Qc/RT) model (where Qc is the activation energy for the mechanism(s) controlling creep, R is the gas constant, and T is the absolute temperature) of the type used to describe the classic steady-state creep behavior of metals, ceramics, and metamorphic rocks. The empirical model developed was epsilon = 5.6 x 10(-9) e4.6F sigma 5.2 e-5330/T, where epsilon is the estimated mean steady-state creep rate, F is the volume fraction of secondary haversian bone, sigma is the applied stress, and T is the absolute temperature. There was a positive, significant association between the estimated mean steady-state creep rate and F, sigma, and T. Qc was determined to be 44.3 kJ mol-1, a reasonable value when compared to activation energies for creep in ceramics. It is hypothesized that permanent deformation during creep of compact bovine bone is primarily due to damage mechanisms associated with dislocations in the hydroxyapatite mineral lattice structure.

Animals↗
PubMed1993

Dislocation following THA: comparison of two acetabular component designs.

One hundred ninety-seven consecutive primary cemented total hip arthroplasties using 22 mm heads were evaluated for the rate of dislocation. All surgery was performed by one surgeon through a posterior approach. A Charnley type femoral component was used in each case. Patients were divided into three groups based on the acetabular component used. Group I had 60 Charnley HPW cups implanted between January 1985 and December 1986; group II had 70 Tibac cups implanted between January 1987 and August 1987; and group III had 67 Charnley HPW cups implanted between September 1987 and February 1988. The groups were similar with regards to age, sex, original diagnosis, and surgical technique. There was a total of 11 dislocations (5.6%), of which 8 (11.4%) occurred in group II (Tibac cup). Furthermore, 6 patients (3%) developed recurrent hip dislocations, 5 (7.1%) of which were from group II. Group II had a statistically significant increase in the dislocation rate (P < .05). The authors conclude that the dislocation rate with the 22 mm Tibac cup is unacceptably high and that the design of the Charnley cup affords greater stability to the artificial hip joint than the hemispherical design of the Tibac cup.

Adult↗
PubMed1992

Activation of phospholipase D by alpha-thrombin or epidermal growth factor contributes to the formation of phosphatidic acid, but not to observed increases in 1,2-diacylglycerol.

The receptor-mediated activation of a phosphatidylcholine-hydrolysing phospholipase D (PLD) has recently been described. We investigated the effect of alpha-thrombin and epidermal growth factor (EGF) on cellular PLD activity in order to determine the role of this enzyme in mitogen-induced increases in phosphatidic acid and sn-1,2-diacylglycerol. In the presence of ethanol, stimulation of [3H]myristic acid-labelled quiescent IIC9 cells with alpha-thrombin or EGF resulted in a rapid increase in radiolabelled phosphatidyl-ethanol which reached a plateau at 1 min, indicating the rapid and transient activation of PLD. We observed a concomitant decrease in the mitogen-stimulated increase of radiolabelled phosphatidic acid. In contrast, ethanol did not significantly effect the elevation of sn-1,2-diacylglycerol levels stimulated by alpha-thrombin or EGF as determined by measurement of sn-1,2-diacylglycerol mass or the appearance of [3H]1,2-diacylglycerol. A novel lipid, detected by two-dimensional t.l.c. analysis, was generated in [3H]myristic acid-labelled cells stimulated with alpha-thrombin, but not EGF, in the presence of ethanol. Treatment in vitro of cellular lipids isolated from [3H]myristic acid-labelled cultures with PLD in the presence of ethanol also resulted in the generation of this novel lipid species, supporting the role of this enzyme in its production. These data indicate that in quiescent IIC9 cells: (a) alpha-thrombin or EGF rapidly and transiently activates a PLD; (b) although this activation is responsible for part of the mitogen-induced increases in phosphatidic acid, it does not contribute to induced increases in sn-1,2-diacylglycerol; and (c) activation of this enzyme appears to be involved in the formation of a novel lipid generated in response to alpha-thrombin, but not EGF, in IIC9 fibroblasts.

Animals↗
PubMed1992

Wear of polyethylene in total joint replacements. Observations from retrieved PCA knee implants.

Observations of wear damage were performed on 12 retrieved porous coated anatomic (PCA) tibial components, all of which were removed because of excessive polyethylene wear. Density measurements of the remaining polyethylene were obtained as a function of depth from the surface of the components. Comparison to previous results from similar studies of total condylar type knee components and total hip acetabular components revealed distinct differences between the types and severity of damage, emphasizing the influence of design factors on the corresponding wear damage. These results confirm previous conclusions that nonconforming articulating surfaces on thin polyethylene components will be at higher risk of damage than more conforming surfaces on thicker components. It also appears that the high cyclic loads to which polyethylene implants are subjected in vivo are most responsible for the degradation in properties of the material near the articulating surface, although the heat pressing of the articulating surface of the PCA components may contribute to the problem.

Aged↗
PubMed1991

Dissociation of protein kinase C activation and sn-1,2-diacylglycerol formation. Comparison of phosphatidylinositol- and phosphatidylcholine-derived diglycerides in alpha-thrombin-stimulated fibroblasts.

Diacylglycerols (DAGs) derived from phosphatidylcholine (PC) hydrolysis have been shown to activate protein kinase C (PKC) in vitro, but it is not known whether this event occurs in response to DAGs generated via agonist-induced PC hydrolysis in intact cells. In this report we have addressed this question directly, using alpha-thrombin stimulation of IIC9 fibroblasts. PKC activation in intact cells was assessed in two ways, by measuring: 1) PKC membrane association as determined by kinase activity and Western blot analysis and 2) the phosphorylation of an endogenous PKC substrate, an 80-kDa protein. Treatment with 500 ng/ml alpha-thrombin has been shown to stimulate both phosphoinositide and PC hydrolysis, whereas treatment with 100 pg/ml alpha-thrombin stimulates only PC breakdown. Using these two conditions, we show that DAG produced from phosphoinositide, but not PC hydrolysis, is associated with the activation of PKC.

Animals↗
PubMed1991

5' regulatory region of a novel cytokine gene mediates selective activation by interferon gamma.

A newly described member of the platelet factor 4 family of cytokine genes, mig, is selectively induced by interferon gamma (IFN-gamma), and not IFN-alpha, in the mouse macrophage-like cell line RAW 264.7. Treatment of RAW 264.7 cells with IFN-gamma activated mig gene transcription as determined by nuclear run-on assays. mig genomic clones were isolated, and constructs containing genomic fragments that included the mig promoter region and the CAT reporter gene were prepared. In RAW 264.7 cells transfected with these constructs, CAT activity was found to be selectively induced by IFN-gamma. A 278-bp genomic fragment containing 235 nucleotides 5' of the transcription start site was sufficient for IFN-gamma-selective induction of CAT activity. Analysis of 5' deletion mutants localized a region essential for activation by IFN-gamma to within 64 nucleotides extending from -235 to -172. A genomic fragment containing this sequence was capable of conferring IFN-gamma inducibility to constructs with a heterologous promoter.

Animals↗
PubMed1991

The biologic effects of implant materials.

The interaction between implant materials and the surrounding biological environment continues to be an area of intense research and clinical interest. This article presents the information presented in a symposium, held during the 36th Annual Meeting of the Orthopaedic Research Society, in which several important issues concerning the biologic effects of implant materials were discussed. These issues included the mechanisms by which implant materials are released to the surrounding tissues and the ways in which these tissues respond to implant materials. The problem of bone loss around cementless implants was discussed as a specific example of a biologic effect resulting in both bone remodelling and endosteal erosion.

Biocompatible Materials↗
PubMed1991

Mechanical characteristics of the stem-cement interface.

The mechanical characteristics of the interface between a metallic stem and the surrounding poly(methyl methacrylate) bone cement were determined from experimental tests and finite element analyses. Push-through-stem tests of straight and tapered titanium alloy stems, surrounded by cement columns, were performed and the resulting load-displacement behavior and strain distribution on the surface of the cement column were measured for loading, unloading, and reloading. Test geometries were modelled using nonlinear, axisymmetric, finite element analyses, which incorporated Coulomb friction elements at the titanium alloy-cement interface. Initial residual stresses, due to curing of the cement column, were modeled by thermal contraction of the cement. Good agreement was obtained between load-displacement curves and surface strains predicted from the nonlinear analysis and those obtained from experiments, when a coefficient of friction of 0.3 was assumed for the stem-cement interface. These results show that, in the absence of chemical adhesion, the load-displacement behavior of a stem-cement composite can be described completely in terms of the friction at the interface and the residual stresses normal to the interface.

Animals↗