PubMed Health⌕ Search

Biomedical subjects

Mark Genovese

Publications and source records attributed to Mark Genovese.

12 recordsLinked to original sources

Pharmacologic modulation of periprosthetic osteolysis.

Wear and periprosthetic osteolysis of total joint replacements continue to be the most important problems in arthroplasty surgery. Despite the introduction of improved technologies including alternative bearing surfaces for TJRs, wear is inevitable because of relative movement at different interfaces and processes such as electrolysis and material degradation. Worn, clinically failing implants need to be followed closely and revised when appropriate. However, early wear and minor osteolysis do not result necessarily in progressive failure of the prosthesis. Indeed such cases may be followed up clinically and radiographically to establish the functional and biologic sequelae of wear and the timeline of these events. This scenario provides an opportunity to modulate the adverse biologic reaction associated with wear particles that includes chronic inflammation, the foreign body response, and periprosthetic bone destruction. Currently, immunological events associated with wear particles are becoming understood more clearly. Strategies to mitigate adverse processes associated with wear debris include local or systemic administration of immune modulators, signaling molecules, anti-inflammatory agents and growth factors, and altering osteoclast function. Ultimately, prevention of accelerated wear and periprosthetic osteolysis will be achieved with improved bearing surfaces and prosthetic designs.

Anti-Inflammatory Agents↗

Magnetic resonance imaging of articular cartilage of the knee: comparison between fat-suppressed three-dimensional SPGR imaging, fat-suppressed FSE imaging, and fat-suppressed three-dimensional DEFT imaging, and correlation with arthroscopy.

PURPOSE: To compare signal-to-noise ratios (S/N) and contrast-to-noise ratios (C/N) in various MR sequences, including fat-suppressed three-dimensional spoiled gradient-echo (SPGR) imaging, fat-suppressed fast spin echo (FSE) imaging, and fat-suppressed three-dimensional driven equilibrium Fourier transform (DEFT) imaging, and to determine the diagnostic accuracy of these imaging sequences for detecting cartilage lesions in osteoarthritic knees, as compared with arthroscopy. MATERIALS AND METHODS: Two sagittal fat-suppressed FSE images (repetition time [TR] / echo time [TE], 4000/13 [FSE short TE] and 4000/39 [FSE long TE]), sagittal fat-suppressed three-dimensional SPGR images (60/5, 40 degrees flip angle), and sagittal fat-suppressed echo-planar three-dimensional DEFT images (400/21.2) were acquired in 35 knees from 28 patients with osteoarthritis of the knee. The S/N efficiencies (S/Neffs) of cartilage, synovial fluid, muscle, meniscus, bone marrow, and fat tissue, and the C/N efficiencies (C/Neffs) of these structures were calculated. Kappa values, exact agreement, sensitivity, specificity, positive predictive value, and negative predictive value were determined by comparison of MR grading with arthroscopic results. RESULTS: The synovial fluid S/Neff on fat-suppressed FSE short TE images, fat-suppressed FSE long TE images, and fat-suppressed three-dimensional DEFT images showed similar values. Fat-suppressed three-dimensional DEFT images showed the highest fluid-cartilage C/Neff of all sequences. All images showed fair to good agreement with arthroscopy (kappa, 0.615 in FSE short TE, 0.601 in FSE long TE, 0.583 in three-dimensional SPGR, and 0.561 in three-dimensional DEFT). Although the sensitivity of all sequences was high (100% in FSE short TE, FSE long TE, and DEFT; 96.7% in SPGR), specificity was relatively low (67.6% in FSE short TE and FSE long TE; 85.3% in SPGR; 58.3% in DEFT). The peripheral area of bone marrow edema or whole area of bone marrow edema on fat-suppressed FSE images was demonstrated as low or iso-signal intensity on fat-suppressed three-dimensional DEFT images. CONCLUSION: Fat-suppressed three-dimensional SPGR imaging and fat-suppressed FSE imaging showed high sensitivity and high negative predictive values, but relatively low specificity. The Kappa value and exact agreement was the highest on fat-suppressed FSE short TE images. Fat-suppressed three-dimensional DEFT images showed results similar to the conventional sequences.

Adult↗

Articular cartilage of knee: normal patterns at MR imaging that mimic disease in healthy subjects and patients with osteoarthritis.

PURPOSE: To evaluate normal magnetic resonance (MR) imaging findings that may mimic articular cartilage diseases in healthy subjects and patients with osteoarthritis of the knee. MATERIALS AND METHODS: Sagittal fat-suppressed intermediate-weighted fast spin-echo (FSE) (repetition time msec/echo time [TE] msec, 4,000/13), sagittal T2-weighted FSE (4,000/39), and sagittal fat-suppressed three-dimensional (3D) spoiled gradient-echo (SPGR) (60/5, 40 degrees flip angle) MR images were acquired in 28 patients and four volunteers. FSE images with a TE of 13 msec were considered "short-TE images"; those with a TE of 39 msec were considered "long-TE images." Presence of normal MR imaging appearance of articular cartilage was determined by one author. Contrast between cartilage and adjacent structures (meniscus, joint capsule, synovial fluid, muscle) was calculated in posterior regions of the femoral condyle on images obtained with each sequence; Wilcoxon signed rank testing was performed. RESULTS: The following appearances were observed in patients with knee osteoarthritis (on short-TE FSE, long-TE FSE, and SPGR MR images, respectively): (a) ambiguity of surface contour in posterior region of the femoral condylar cartilage (in zero, zero, and 20 patients), (b) linear area of high signal intensity in deep zone adjacent to subchondral bone of femoral condyle (in zero, zero, and 26 patients), (c) pseudolaminar appearance in posterior region of femoral condylar cartilage (in seven, nine, and 24 patients), (d) truncation artifact in patellofemoral compartment (in seven, six, and 27 patients), (e) susceptibility artifact on cartilage surface caused by air or metal (in three, three, and 11 patients), (f) decreased signal intensity in distal part of trochlear cartilage (in 28, 28, and 28 patients), (g) cartilage thinning adjacent to the anterior horn of the lateral meniscus (in 19, 19, and 21 patients), and (h) focal cartilage flattening in posterior region of femoral condyle (in 16, 16, and nine patients). Cartilage-meniscus and cartilage-synovial fluid contrast was significantly higher on fat-suppressed FSE than on fat-suppressed 3D SPGR MR images (P <.001). CONCLUSION: Fat-suppressed FSE and 3D SPGR MR images showed nonuniform signal intensity arising from articular cartilage and cartilage thinning, both of which could mimic disease.

Adult↗

Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial.

OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Antirheumatic Agents↗

Modulation of bone ingrowth and tissue differentiation by local infusion of interleukin-10 in the presence of ultra-high molecular weight polyethylene (UHMWPE) wear particles.

Interleukin-10 (IL-10) is a cytokine that plays a major role in suppressing the inflammatory response, particularly cell-mediated immunity that is characteristic of the TH1 response. The purpose of this study was to determine whether local infusion of IL-10 could mitigate the suppression of bone ingrowth associated with polyethylene wear particles. Drug test chambers were implanted in the proximal tibia of 20 mature New Zealand White rabbits. The DTC provided a continuous 1 x 1 x 5-mm canal for tissue ingrowth. After a 6-week period for osseointegration, the DTC was then connected to an osmotic diffusion pump. IL-10 at doses of 0.1-100 ng/mL (0.25 microL/h) was infused with or without ultra-high molecular weight polyethylene particles (0.5 +/- 0.2 microm diameter, 10(12) particles/mL) present in the chamber for a 3- or 6-week period. The tissue in the chamber was harvested after each treatment; sections were stained with hematoxylin and eosin for morphometric analysis. Osteoclast-like cells were identified by immunohistochemical staining using a monoclonal antibody directed against the alpha chain of the vitronectin receptor, CD51. Osteoblasts were identified using alkaline phosphatase staining. In dose-response studies, infusion of 1 ng/mL IL-10 yielded the greatest bone ingrowth in the presence of particles. The addition of polyethylene particles evoked a marked foreign body reaction and fibrosis; bone ingrowth was significantly suppressed (p = 0.0003). Bone ingrowth was increased by over 48% with infusion of IL-10 for the final 3 weeks of a 6-week ultra-high molecular weight polyethylene particle exposure compared with particles alone (p = 0.027). IL-10 is a cytokine that plays a major role in suppressing the inflammatory response, especially cell-mediated immunity that is characteristic of the TH1 response. Local infusion of immune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis.

Alkaline Phosphatase↗

Imaging of the articular cartilage in osteoarthritis of the knee joint: 3D spatial-spectral spoiled gradient-echo vs. fat-suppressed 3D spoiled gradient-echo MR imaging.

PURPOSE: To compare three-dimensional (3D) spatial-spectral (SS) spoiled gradient-recalled acquisition in the steady state (SPGR) imaging with fat-suppressed 3D SPGR sequences in MR imaging of articular cartilage of the knee joint in patients with osteoarthritis. MATERIALS AND METHODS: MR images of six patients with osteoarthritis of the knee were prospectively examined with a 1.5T MR scanner. For quantitative analyses, the signal-to-noise ratios, contrast-to-noise ratios, and contrast of cartilage and adjacent structures including meniscus, synovial fluid, muscle, fat tissue, and bone marrow were measured. RESULTS: In patients with osteoarthritis, 3DSS-SPGR images demonstrated higher spatial resolution and higher mean signal-to-noise (S/N) ratios (cartilage, 24.9; synovial fluid, 12.3; muscle, 20.7; meniscus, 21.6), with shorter acquisition times (7 minutes 20 seconds), when compared to fat-suppressed 3D SPGR images (cartilage, 22.3; synovial fluid, 10.8; muscle, 16.7; meniscus, 13.4). CONCLUSION: 3DSS-SPGR imaging is a promising method for evaluating cartilage pathology in patients with osteoarthritis of the knee and has the potential to replace fat-suppressed 3D SPGR imaging.

Cartilage, Articular↗

Allele and antigen-specific treatment of rheumatoid arthritis: a double blind, placebo controlled phase 1 trial.

OBJECTIVE: Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263). METHODS: Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria. RESULTS: Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263. CONCLUSION: AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.

Aged↗

Interleukin 1 receptor antagonist inhibits localized bone formation in vivo.

OBJECTIVE: To test the in vivo effects of interleukin 1 receptor antagonist (IL-1ra) on bone formation and tissue ingrowth using an implantable bone ingrowth chamber that can be infused with test solutions. METHODS: The bone ingrowth chamber was implanted in the proximal tibia of 10 mature NZW rabbits unilaterally. After an initial osseointegration period, the chambers were emptied of tissue and infused with either 0.05% bovine serum albumin (BSA) in phosphate buffered saline (PBS) or an IL-1ra solution for 4-week periods, which were separated by 4-week periods of no infusion. Tissue samples harvested from each chamber were snap-frozen and examined by histology and immunohistochemistry. RESULTS: The chambers were filled with longitudinally-oriented woven bone in a fibrovascular stroma during periods of infusion of 0.05% BSA in PBS or during periods without infusion. In contrast, infusion of IL-1ra for 4 weeks prevented tissue ingrowth in 4 of 6 chambers, and in 2 chambers exhibiting tissue ingrowth, bone formation was decreased. Bone formation remained at a lower level during the subsequent two 4-week periods without infusion after IL-1ra was discontinued, compared to samples prior to the IL-1ra treatment. CONCLUSION: The results showed that tissue ingrowth and bone formation were suppressed in an in vivo model by continuous infusion of IL-1ra at an early phase of tissue regeneration and differentiation.

Acid Phosphatase↗

COX-2 selective NSAID decreases bone ingrowth in vivo.

Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the tibiae of eight mature, New Zealand white rabbits. After a 6-week period for osseointegration of the chamber, the following oral treatments were given for 4 weeks each, followed by a harvest in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1 and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested specimens were snap frozen, cut into serial 6 microm sections and stained with hematoxylin and eosin for general morphological characterization, and alkaline phosphatase (osteoblast marker). Sections were also processed for immunoperoxidase staining using monoclonal antibodies to identify cells expressing the vitronectin receptor (osteoclast-like cells). With drinking water alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5% respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p = 0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026) and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like cells per section compared with drinking water alone. Rofecoxib decreased the area of osteoblasts per section area (p = 0.014) compared to controls, although the value for Naproxen sodium did not reach statistical significance. The results of the present study suggest that bone formation is suppressed by oral administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors currently taken for arthritis and other conditions may potentially delay fracture healing and bone ingrowth.

Animals↗