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Biomedical subjects

James A Martin

Publications and source records attributed to James A Martin.

At least 19 recordsLinked to original sources
PubMed2006

Intrinsic radiation resistance in human chondrosarcoma cells.

Human chondrosarcomas rarely respond to radiation treatment, limiting the options for eradication of these tumors. The basis of radiation resistance in chondrosarcomas remains obscure. In normal cells radiation induces DNA damage that leads to growth arrest or death. However, cells that lack cell cycle control mechanisms needed for these responses show intrinsic radiation resistance. In previous work, we identified immortalized human chondrosarcoma cell lines that lacked p16(ink4a), one of the major tumor suppressor proteins that regulate the cell cycle. We hypothesized that the absence of p16(ink4a) contributes to the intrinsic radiation resistance of chondrosarcomas and that restoring p16(ink4a) expression would increase their radiation sensitivity. To test this we determined the effects of ectopic p16(ink4a) expression on chondrosarcoma cell resistance to low-dose gamma-irradiation (1-5 Gy). p16(ink4a) expression significantly increased radiation sensitivity in clonogenic assays. Apoptosis did not increase significantly with radiation and was unaffected by p16(ink4a) transduction of chondrosarcoma cells, indicating that mitotic catastrophe, rather than programmed cell death, was the predominant radiation effect. These results support the hypothesis that p16(ink4a) plays a role in the radiation resistance of chondrosarcoma cell lines and suggests that restoring p16 expression will improve the radiation sensitivity of human chondrosarcomas.

Acridine Orange↗
PubMed2006

Rat spinal motion segment in organ culture: a cell viability study.

STUDY DESIGN: This study investigated tissue integrity and viability of cells in an organ culture system of intervertebral disc (IVD) with adjoining vertebral bodies. OBJECTIVE: The goal of this study was to design a methodology to maintain an IVD motion segment in organ culture, thereby preserving viability and tissue architecture. SUMMARY OF BACKGROUND DATA: Study of IVD mechanobiology in vitro necessitates availability of vertebral bodies for controlled application of complex loads. METHODS: IVD motion segments were dissected from rat lumbar segments and maintained in organ culture and cell viability was evaluated histochemically using NitroBlue Tetrazolium. Tissue integrity and morphology were evaluated using conventional histologic techniques. RESULTS: The in vitro organ culture of motion segments maintained the viability and tissue integrity for 14 days. More than 95% viability in all three regions of interest (anulus fibrosus, nucleus pulposus, end plates) was maintained for 14 days in culture. CONCLUSION: Our initial results suggest that long-term motion segment culture is practical, and the inclusion of vertebral bodies will facilitate anchoring during biomechanical stimulation. Thus, we expect the culture system to provide us with an excellent model for studying the pathomechanics of IVD degeneration and the effects of mechanical stimulation on the biology of IVD cells.

Animals↗
PubMed2006

Osteoarthritis.

Osteoarthritis (OA), the syndrome of joint pain and dysfunction caused by joint degeneration, affects more people than any other joint disease. In most instances joint degeneration develops in the absence of an identifiable cause, but increasing age, excessive joint loading, and joint abnormalities and insults increase the risk of OA. Articular surface contact stress that causes tissue damage and compromises that ability of chondrocytes to maintain and restore the tissue has an important role in the development of joint degeneration Current methods of attempting to restore an articular surface in osteoarthritic joints include penetrating subchondral bone, altering joint loading, osteotomies and insertion of soft tissue grafts. Dramatic advances in the prevention and treatment of OA are likely to stem from better understanding of the role of mechanical forces in the initiation and progression of joint degeneration.

Cartilage, Articular↗
PubMed2006

Loading and boundary condition influences in a poroelastic finite element model of cartilage stresses in a triaxial compression bioreactor.

BACKGROUND: We developed a poroelastic finite element (FE) model of cartilage in dynamic triaxial compression to parametrically analyze the effects of loading and boundary conditions on a baseline model. Conventional mechanical tests on articular cartilage such as confined and unconfined compression, indentation, etc., do not fully allow for modulation of compression and shear at physiological levels whereas triaxial compression does. A Triaxial Compression Bioreactor, or TRIAX, has been developed to study chondrocyte responses to multi-axial stress conditions under cyclic loading. In the triaxial setting, however, a cartilage explant's physical testing environment departs from the ideal homogeneous stress state that would occur from strict linear superposition of the applied axial and transverse pressure. METHOD OF APPROACH: An axisymmetric poroelastic FE model of a cartilage explant (4 mm diameter, 1.5 mm thick) in cyclic triaxial compression was created. Axial and transverse loads (2 MPa at 1 Hz.) were applied via a platen and containment sheath. Parameters of interest included the rise time and magnitude of the applied load, in addition to the containment sheath modulus and the friction coefficient at the cartilage/platen interfaces. Metrics of interest in addition to whole explant axial strain included axial (surface normal) stress, shear stress, pore pressure, and the fluid load carriage fraction within the explant. RESULTS: Strain results were compared to experimental data from explants tested in the TRIAX under conditions similar to the baseline model. Explant biomechanics varied considerably over numbers of load cycles and parameter values. Cyclic loading caused an increase in accumulated strain for the various loading and boundary conditions. CONCLUSIONS: Unlike what would be expected from linear superposition of the homogeneous stresses from the applied axial and transverse pressure, we have shown that the stress state within the TRIAX is considerably heterogeneous. Both the boundary influences (variation in the sheath modulus and friction coefficient) and the loading history (due to poroelastic material behavior) interact in a highly nonlinear manner to influence that heterogeneity.

Bioreactors↗
PubMed2006

Perspectives on chondrocyte mechanobiology and osteoarthritis.

Osteoarthritis, the clinical syndrome of joint pain and dysfunction due to joint degeneration, is among the most frequent and symptomatic medical problems for middle aged and older people, and it is the most common cause of long term disability in most populations of people over 65. Currently there are no effective methods of preventing or curing osteoarthritis. Post-traumatic OA, the joint degeneration, pain and dysfunction that develop following joint injury, is the form of OA that is most directly related to elevated articular surface contact stress. However, mechanical stress that exceeds the tolerance of the articular surface can cause or accelerate the progression of joint degeneration in all individuals and in all synovial joints. In some patients, decreasing mechanical forces on degenerated joint surfaces stimulates formation of a new biologic articular surface. The advances in understanding of the effects of mechanical forces on chondrocytes and cartilage presented and discussed at the 4th Symposium on Mechanobiology: Cartilage and Chondrocyte will help in the efforts to develop new methods of preventing and treating osteoarthritis.

Aged↗
PubMed2005

Enhanced photoluminescence from group 14 metalloles in aggregated and solid solutions.

The unusual photoluminescence characteristics of a series of six group 14 metalloles (1,1-dimethyl-2,3,4,5-tetraphenylmetalloles and 1,1-diphenyl-2,3,4,5-tetraphenylmetalloles) containing silicon, germanium, or tin have been investigated. Although the compounds are weakly luminescent in dilute fluid solution at room temperature, they undergo a substantial enhancement of photoluminescence when forced to aggregate, as in mixed solvent systems. The compounds also exhibit considerable emission when incorporated into rigid room-temperature glasses of sucrose octaacetate. Absorption and emission characteristics of the compounds, including luminescence quantum yields, in fluid solution, solution-phase aggregates, and room-temperature glasses are reported. Quantum yields increase by as much as 2 orders of magnitude in the aggregates and glasses, compared to fluid solution. Experimental evidence supports the conclusion that the aggregation-induced enhancement of luminescence results from restricted intramolecular rotations in the packed metalloles. The unusual aggregation-induced enhancement of these compounds makes them potentially useful for the fabrication of a variety of electrooptical devices and sensors. In addition, the X-ray crystal structure of hexaphenylgermole is reported.

Journal Article↗
PubMed2004

Effects of oxidative damage and telomerase activity on human articular cartilage chondrocyte senescence.

Senescence compromises the ability of chondrocytes to maintain and repair articular cartilage. We hypothesized that oxidative stress and telomere loss contribute to chondrocyte senescence. To test this hypothesis, we compared the growth of human articular cartilage chondrocytes incubated in 5% O2 and 21% O2. Cells grown in 5% O2 reached 60 population doublings (PD) before senescing, but growth in 21% O2 induced DNA damage and premature senescence at less than 40 PD. Human telomerase reverse transcriptase (hTERT)-transduction failed to prevent chondrocyte senescence in 21% O2, but allowed 1 of 3 chondrocyte strains to exceed 90 PD in 5% O2. These results show that oxidative stress causes premature chondrocyte senescence. They may help explain the increased risk of osteoarthritis with age and after joint trauma and inflammation, and suggest that minimizing oxidative damage will help produce optimal results for chondrocyte transplantation.

Aging↗
PubMed2004

Telomerase reverse transcriptase subunit expression is associated with chondrosarcoma malignancy.

Expression of the telomerase reverse transcriptase subunit telomerase reverse transcriptase gene is associated with most human malignancies. Because telomerase reverse transcriptase is rarely expressed in normal tissue, its presence in pathologic specimens is considered a marker of transformed cells. Moreover, high levels of expression have been correlated with poor prognosis in many cancers. Although telomerase activity has been found in chondrosarcomas, its prognostic significance in these malignant cartilage tumors is unknown. Malignancy in cartilage-derived tumors is assessed routinely by histomorphologic grading, but even well differentiated, low-grade lesions can metastasize. This unpredictable behavior greatly complicates the clinical treatment of cartilage tumors, making better prognostic indicators desirable. To address this issue we used immunohistochemistry to compare telomerase reverse transcriptase expression in a collection of 61 tumors consisting of malignant chondrosarcomas of varying grade and benign enchondromas. Associated case histories were reviewed to test the hypothesis that telomerase reverse transcriptase expression levels correlated with subsequent tumor recurrence. We found that the relative abundance of telomerase reverse transcriptase-expressing cells correlated significantly with grade and recurrence. These findings indicate that telomerase reverse transcriptase immunostaining may be a useful adjunct to the conventional three-level grading system.

Biomarkers, Tumor↗
PubMed2004

Chondrocyte senescence, joint loading and osteoarthritis.

cellular level is not completely understood, but both aging and loading-induced stresses have been shown to undermine cell functions related to the maintenance and restoration of the cartilage matrix. Based on precedents set by studies of other age-related degenerative diseases, we have focused our laboratory work on senescence as the cause of age-dependent decline in chondrocytes and on the impact of excessive mechanical stresses in promoting senescence. We hypothesized that senescent chondrocytes accumulate with age in articular cartilage and we propose that excessive mechanical stress plays a role in this process by promoting oxidative damage in chondrocytes that ultimately causes them to senesce. To test this hypothesis, we measured cell senescence markers (beta-galactosidase expression, mitotic activity, and telomere length) in human articular cartilage chondrocytes, and determined the effects of chronic exposure to oxidative stress on chondrocyte growth and senescence. In addition, we measured the effects of abnormally high levels of mechanical shear stress on the release of oxidants in cartilage explants. We found that senescent chondrocytes accumulated with age in articular cartilage. In vitro studies showed that chronic oxidative stress caused by repeated exposure to peroxide, or by growth under superphysiologic oxygen tension caused chondrocyte populations to senesce prematurely, before extensive telomere erosion occurred. Mechanical shear stress applied to cartilage explants considerably increased the production of oxidants. These observations support the hypothesis that senescence accounts for age-related decline in chondrocyte function and indicate that mechanically induced oxidative damage plays a role in this process. This suggests that new efforts to prevent the development and progression of osteoarthritis should include strategies that slow the progression of chondrocyte senescence or replace senescent cells.

Adolescent↗
PubMed2004

Sports and osteoarthritis.

PURPOSE OF REVIEW: Participation in sports improves general health but increases the risk of osteoarthritis. This review analyzes the relationships among increased joint use, joint injuries, and injury-induced joint degeneration that causes posttraumatic osteoarthritis. The purpose is to help people who participate in sports minimize their risk of joint degeneration. RECENT FINDINGS: Participation in sports that cause minimal joint impact and torsional loading by people with normal joints and neuromuscular function may cause osteophyte formation, but it has minimal, if any, effect on the risk of osteoarthritis. In contrast, participation in sports that subject joints to high levels of impact and torsional loading increases the risk of injury-induced joint degeneration. People with abnormal joint anatomy or alignment, previous joint injury or surgery, osteoarthritis, joint instability, articular surface incongruity or dysplasia, disturbances of joint or muscle innervation, or inadequate muscle strength have increased risk of joint damage during participation in athletics. SUMMARY: Gaining the benefits of participation in athletics while minimizing the risk of osteoarthritis requires understanding of the relationships between sports participation and joint injury and the relationships between joint injury and joint degeneration. People who wish to participate in sports should have an evaluation of their joint structure and function, muscle strength, and neuromuscular function, and people with a history of joint injury or mild osteoarthritis should select sports that have limited risk of accelerating joint degeneration.

Animals↗
PubMed2004

Oxygen effects on senescence in chondrocytes and mesenchymal stem cells: consequences for tissue engineering.

Primary isolates of chondrocytes and mesenchymal stem cells are often insufficient for cell-based autologous grafting procedures, necessitating in vitro expansion of cell populations. However, the potential for expansion is limited by cellular senescence, a form of irreversible cell cycle arrest regulated by intrinsic and extrinsic factors. Intrinsic mechanisms common to most somatic cells enforce senescence at the so-called "Hayflick limit" of 60 population doublings. Termed "replicative senescence", this mechanism prevents cellular immortalization and suppresses oncogenesis. Although it is possible to overcome the Hayflick limit by genetically modifying cells, such manipulations are regarded as prohibitively dangerous in the context of tissue engineering. On the other hand, senescence associated with extrinsic factors, often called "stress-induced" senescence, can be avoided simply by modifying culture conditions. Because stress-induced senescence is "premature" in the sense that it can halt growth well before the Hayflick limit is reached, growth potential can be significantly enhanced by minimizing culture related stress. Standard culture techniques were originally developed to optimize the growth of fibroblasts but these conditions are inherently stressful to many other cell types. In particular, the 21% oxygen levels used in standard incubators, though well tolerated by fibroblasts, appear to induce oxidative stress in other cells. We reasoned that chondrocytes and MSCs, which are adapted to relatively low oxygen levels in vivo, might be sensitive to this form of stress. To test this hypothesis we compared the growth of MSC and chondrocyte strains in 21% and 5% oxygen. We found that incubation in 21% oxygen significantly attenuated growth and was associated with increased oxidant production. These findings indicated that sub-optimal standard culture conditions sharply limited the expansion of MSC and chondrocyte populations and suggest that cultures for grafting purposes should be maintained in a low-oxygen environment.

Cartilage, Articular↗
PubMed2004

Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence.

Joint injuries frequently lead to progressive joint degeneration that causes the clinical syndrome of post-traumatic osteoarthritis. The pathogenesis of osteoarthritis remains poorly understood, but patient age is a significant risk factor for progressive joint degeneration. We have found that articular cartilage chondrocytes show strong evidence of senescence with increasing age, including synthesis of smaller more irregular aggrecans; increased expression of lysosomal beta-galactosidase and telomere erosion; and decreased proteoglycan synthesis, response to the anabolic cytokine IGF-I, proliferative capacity, and mitochondrial function. These observations help explain the strong association between age and joint degeneration, but they do not explain how joint injury increases the risk of joint degeneration in younger individuals. We hypothesized that excessive loading of articular surfaces due to acute joint trauma or post-traumatic joint instability, incongruity or mal-alignment increases release of reactive oxygen species, and that the increased oxidative stress on chondrocytes accelerates chondrocyte senescence thereby decreasing the ability of the cells to maintain or restore the tissue. To test this hypothesis, we exposed human articular cartilage chondrocytes from young adults to mechanical and oxidative stress. We found that shear stress applied to cartilage explants in a triaxial pressure vessel increased release of reactive oxygen species and oxidative stress induced chondrocyte senescence (as measured by expression of lysosomal beta-galactosidase, nuclear and mitochondrial DNA damage and decreased mitochondrial function). These observations support the hypothesis that joint injury accelerates chondrocyte senescence and that this acceleration plays a role in the joint degeneration responsible for post-traumatic osteoarthritis.

Cartilage, Articular↗
PubMed2003

The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair.

BACKGROUND: With increasing age, the prevalence of osteoarthritis increases and the efficacy of articular cartilage repair decreases. As chondrocytes age, they synthesize smaller, less uniform aggrecan molecules and less functional link proteins, their mitotic and synthetic activity decline, and their responsiveness to anabolic mechanical stimuli and growth factors decreases. These observations led us to hypothesize that progressive cell senescence decreases the ability of chondrocytes to maintain and to restore articular cartilage. METHODS: To test this hypothesis, we measured cell senescence markers (beta-galactosidase expression, mitotic activity, and telomere length) in human articular cartilage chondrocytes from twenty-seven donors ranging in age from one to eighty-seven years. We also assessed mitochondrial DNA, membrane potential, and numerical density. To determine if chondrocyte age changes are reversible, we transfected human articular cartilage chondrocytes with the human telomerase gene (hTERT) and human papilloma virus oncogenes (E6 and E7). RESULTS: Beta-galactosidase expression increased with age (r = 0.84, p = 0.0001), while mitotic activity and telomere length declined (r = -0.77, p = 0.001 and r = -0.71, p = 0.0004, respectively). Decreasing telomere length was closely correlated with increasing expression of beta-galactosidase and decreasing mitotic activity. As the number of population doublings increased, mitochondrial DNA was degraded, mitochondrial membrane potential was lost, and the number of mitochondria per cell declined. Transfection of human articular cartilage chondrocytes from a forty-seven-year-old donor with hTERT and human papilloma virus proto-oncogenes E6 and E7 created a cell line that has completed more than 300 population doublings as compared with an upper limit of twenty-five population doublings for normal cells. Telomere length increased in cells transduced with hTERT. CONCLUSIONS: These findings help to explain the previously reported age-related declines in chondrocyte synthetic activity, mitotic activity, and responsiveness to anabolic cytokines and mechanical stimuli. They also suggest that in vivo chondrocyte senescence contributes to the age-related increase in the prevalence of osteoarthritis and decrease in the efficacy of cartilage repair. The creation of immortal cells with increased telomere length suggests that the progression of human chondrocytes toward senescence is not inevitable.

Adolescent↗
PubMed2003

Effect of an individualized treatment protocol on restoration of competency in pretrial forensic inpatients.

In this study, we evaluated the effectiveness of individualized treatment on restoration of competency in patients adjudicated incompetent to stand trial. Treatment groups included deficit-focused remediation (six individual sessions and four group sessions; n = 8), legal rights education (control group; six individual sessions and four group sessions; n = 10), and standard hospital treatment (control group; four group sessions; n = 8). There were no significant baseline differences among groups. All groups differed significantly on competency measures obtained before and after testing. The deficit-focused remediation and the legal rights education groups both demonstrated significantly higher post-treatment scores on competency measures than the standard hospital treatment group. Both groups demonstrated approximately 50 percent more improvement on the competency measures than the standard hospital treatment group. There were no significant differences between the deficit-focused remediation and legal rights education groups on post-test competency scores, suggesting that focus on individual deficits may not be a useful treatment strategy. Results demonstrate, however, that more frequent legal rights education is a worthwhile endeavor in treatment of incompetency.

Adolescent↗
PubMed2002

Phacovitrectomy with internal limiting membrane peeling for idiopathic macular hole.

BACKGROUND: Progressive nuclear sclerosis is a known complication of macular hole surgery that hinders patients' recovery to their best visual acuity postoperatively. We report the visual outcome, complications and efficacy of combined phacoemulsification, intraocular lens (IOL) insertion and vitrectomy with internal limiting membrane (ILM) peeling for patients with cataract undergoing macular hole surgery. METHODS: We reviewed the records of 32 consecutive patients (36 eyes) who underwent phacoemulsification with insertion of a polymethylmethacrylate lens into the capsular bag and pars plana vitrectomy with ILM peeling in one session for repair of idiopathic macular hole. Patients were assessed between February 1998 and August 2001. RESULTS: The mean age of the patients was 70 (range 52 to 83) years, and 25 (78%) were women. The median duration of the holes before surgery was 8.3 months; in 19 eyes (53%) the duration was 6 months or less. Twenty eyes (56%) had stage 3 holes. The preoperative vision was 20/200 or worse in 29 eyes (80%). The mean grade of nuclear sclerosis was 2.4. The average length of follow-up after surgery was 11 (range 1.5 to 37) months. Primary hole closure was achieved in 28 eyes (78%). In five of the remaining eight cases the patient consented to a second procedure, which was successful in four cases, for a final closure rate of 89%. Postoperatively, the visual acuity improved by 2 lines or more in 22 eyes (61%). Of the 32 eyes with final closure, 11 (34%) attained a visual acuity of 20/40 or better, and 25 (78%) had an acuity of 20/100 or better. The most common complication was posterior capsular opacification (27 eyes [75%]), an expected complication when perfluoropropane or other gases are used for tamponade. INTERPRETATION: The results are comparable to those with standard macular hole surgery. Combined surgery is reliable and safe; the benefits support its use as a routine procedure for patients with cataract undergoing macular hole repair.

Aged↗
PubMed2002

Aging, articular cartilage chondrocyte senescence and osteoarthritis.

The incidence of osteoarthritis (OA), the disease characterized by joint pain and loss of joint form and function due to articular cartilage degeneration, is directly correlated with age. The strong association between age and increasing incidence of osteoarthritis (OA) marks OA as an age related disease. Yet, like many other age related diseases, OA is not an inevitable consequence of aging; instead, aging increases the risk of OA. Articular cartilage aging changes that may lead to articular cartilage degeneration include fraying and softening of the articular surface, decreased size and aggregation of proteoglycan aggrecans and loss of matrix tensile strength and stiffness. These changes most likely are the result of an age related decrease in the ability of chondrocytes to maintain and repair the tissue manifested by decreased mitotic and synthetic activity, decreased responsiveness to anabolic growth factors and synthesis of smaller less uniform aggrecans and less functional link proteins. Our recent work suggests that progressive chondrocyte senescence marked by expression of the senescence associated enzyme beta-galactosidase, erosion of chondrocyte telomere length and mitochondrial degeneration due to oxidative damage causes the age related loss of chondrocyte function. New efforts to prevent the development and progression of OA might include strategies that slow the progression of chondrocyte senescence or replace senescent cells.

Aging↗
PubMed2002

Cartilage extracellular matrix metabolism differs in serum and synovial fluid.

Most cartilage explant culture studies assume conventional serum-supplemented growth media are biologically equivalent to the natural synovial fluid which baths cartilage in vivo. Few studies have systematically compared the effects of serum versus synovial fluid in culture. To address this assumption we conducted a series of studies to determine if cartilage matrix synthesis is significantly different in serum-based versus synovial fluid-based media. Normal bovine cartilage explants were cultured in DMEM either alone or supplemented with bovine serum or bovine synovial fluid. Matrix synthesis was measured with radiolabeling techniques. We then compared responses to insulin-like growth factor I (IGF-I, a stimulator of matrix synthesis), and interleukin-1beta (IL-1beta, an inhibitor of matrix synthesis). We observed significantly lower matrix synthesis activity in synovial fluid versus serum. Caution shoud be used in extrapolating studies of cartilage grown in media supplemented with serum rather than synovial fluid.

Animals↗