Mapping tibiofemoral gonarthrosis: an MRI analysis of non-traumatic knee cartilage defects

OBJECTIVE Arthroscopy is "the gold standard" for the diagnosis of knee cartilage lesions. However, it is invasive and expensive, and displays all the potential complications of an open surgical procedure. Ultra-high-field MRI now offers good opportunities for the indirect assessment of the integrity and structural changes of joint cartilage of the knee. The goal of the present study is to determine the site of early cartilaginous lesions in adults with non-traumatic knee pain. METHODS 3-T MRI examinations of 200 asymptomatic knees with standard and three-dimensional double-echo steady-state (3D-DESS) cartilage-specific sequences were prospectively studied for early degenerative lesions of the tibiofemoral joint. Lesions were classified and mapped using the modified Outerbridge and modified International Cartilage Repair Society classifications. RESULTS A total of 1437 lesions were detected: 56.1% grade I, 33.5% grade II, 7.2% grade III and 3.3% grade IV. Cartographically, grade I lesions were most common in the anteromedial tibial areas; grade II lesions in the anteromedial L5 femoral areas; and grade III in the centromedial M2 femoral areas. CONCLUSION 3-T MRI with standard and 3D-DESS cartilage-specific sequences demonstrated that areas predisposed to early osteoarthritis are the central, lateral and ventromedial tibial plateau, as well as the central and medial femoral condyle. ADVANCES IN KNOWLEDGE In contrast with previous studies reporting early cartilaginous lesions in the medial tibial compartment and/or in the medial femoral condyle, this study demonstrates that, regardless of grade, lesions preferentially occur at the L5 and M4 tibial and L5 and L2 femoral areas of the knee joint.

Accuracy of cartilage-specific 3-Tesla 3D-DESS magnetic resonance imaging in the diagnosis of chondral lesions: comparison with knee arthroscopy

BACKGROUND Arthroscopy is considered as "the gold standard" for the diagnosis of traumatic intraarticular knee lesions. However, recent developments in magnetic resonance imaging (MRI) now offer good opportunities for the indirect assessment of the integrity and structural changes of the knee articular cartilage. The study was to investigate whether cartilage-specific sequences on a 3-Tesla MRI provide accurate assessment for the detection of cartilage defects. METHODS A 3-Tesla (3-T) MRI combined with three-dimensional double-echo steady-state (3D-DESS) cartilage specific sequences was performed on 210 patients with knee pain prior to knee arthroscopy. Sensitivity, specificity, and positive and negative predictive values of magnetic resonance imaging were calculated and correlated to the arthroscopic findings of cartilaginous lesions. Lesions were classified using the modified Outerbridge classification. RESULTS For the 210 patients (1260 cartilage surfaces: patella, trochlea, medial femoral condyle, medial tibia, lateral femoral condyle, lateral tibia) evaluated, the sensitivities, specificities, positive predictive values, and negative predictive values of 3-T MRI were 83.3, 99.8, 84.4, and 99.8 %, respectively, for the detection of grade IV lesions; 74.1, 99.6, 85.2, and 99.3 %, respectively, for grade III lesions; 67.9, 99.2, 76.6, and 98.2 %, respectively, for grade II lesions; and 8.8, 99.5, 80, and 92 %, respectively, for grade I lesions. CONCLUSIONS For grade III and IV lesions, 3-T MRI combined with 3D-DESS cartilage-specific sequences represents an accurate diagnostic tool. For grade II lesions, the technique demonstrates moderate sensitivity, while for grade I lesions, the sensitivity is limited to provide reliable diagnosis compared to knee arthroscopy.

T1ρ MRI detects cartilage damage in asymptomatic individuals with a cam deformity

Hips with a cam deformity are at risk for early cartilage degeneration, mainly in the anterolateral region of the joint. T1ρ MRI is a described technique for assessment of proteoglycan content in hyaline cartilage and subsequently early cartilage damage. In this study, 1.5 Tesla T1ρ MRI was performed on 20 asymptomatic hips with a cam deformity and compared to 16 healthy control hips. Cam deformity was defined as an alpha angle at 1:30 o'clock position over 60° and/or at 3:00 o'clock position over 50.5°. Hip cartilage was segmented and divided into four regions of interest (ROIs): anterolateral, anteromedial, posterolateral and posteromedial quadrants. Mean T1ρ value of the entire weight bearing cartilage in hips with a cam deformity (34.0 ± 4.6 ms) was significantly higher compared to control hips (31.3 ± 3.2 ms, p = 0.050). This difference reached significance in the anterolateral (p = 0.042) and posteromedial quadrants (p = 0.041). No significant correlation between the alpha angle and T1ρ values was detected. The results indicate cartilage damage occurs in hips with a cam deformity before symptoms occur. A significant difference in T1ρ values was found in the anterolateral quadrant, the area of direct engagement of the deformity, and in the posteromedial quadrant. To conclude, T1ρ MRI can detect early chondral damage in asymptomatic hips with a cam deformity. This article is protected by copyright. All rights reserved.

Transforming growth factor beta signaling is essential for the autonomous formation of cartilage-like tissue by expanded chondrocytes.

Cartilage is a tissue with limited self-healing potential. Hence, cartilage defects require surgical attention to prevent or postpone the development of osteoarthritis. For cell-based cartilage repair strategies, in particular autologous chondrocyte implantation, articular chondrocytes are isolated from cartilage and expanded in vitro to increase the number of cells required for therapy. During expansion, the cells lose the competence to autonomously form a cartilage-like tissue, that is in the absence of exogenously added chondrogenic growth factors, such as TGF-βs. We hypothesized that signaling elicited by autocrine and/or paracrine TGF-β is essential for the formation of cartilage-like tissue and that alterations within the TGF-β signaling pathway during expansion interfere with this process. Primary bovine articular chondrocytes were harvested and expanded in monolayer culture up to passage six and the formation of cartilage tissue was investigated in high density pellet cultures grown for three weeks. Chondrocytes expanded for up to three passages maintained the potential for autonomous cartilage-like tissue formation. After three passages, however, exogenous TGF-β1 was required to induce the formation of cartilage-like tissue. When TGF-β signaling was blocked by inhibiting the TGF-β receptor 1 kinase, the autonomous formation of cartilage-like tissue was abrogated. At the initiation of pellet culture, chondrocytes from passage three and later showed levels of transcripts coding for TGF-β receptors 1 and 2 and TGF-β2 to be three-, five- and five-fold decreased, respectively, as compared to primary chondrocytes. In conclusion, the autonomous formation of cartilage-like tissue by expanded chondrocytes is dependent on signaling induced by autocrine and/or paracrine TGF-β. We propose that a decrease in the expression of the chondrogenic growth factor TGF-β2 and of the TGF-β receptors in expanded chondrocytes accounts for a decrease in the activity of the TGF-β signaling pathway and hence for the loss of the potential for autonomous cartilage-like tissue formation.

Cell mixing induced by myc is required for competitive tissue invasion and destruction

Cell-cell intercalation is used in several developmental processes to shape the normal body plan. There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition. Cell competition is a conserved mechanism driving the elimination of slow-proliferating cells (so-called 'losers') by faster-proliferating neighbours (so-called 'winners') through apoptosis and is important in preventing developmental malformations and maintain tissue fitness. Here we show, using long-term live imaging of myc-driven competition in the Drosophila pupal notum and in the wing imaginal disc, that the probability of elimination of loser cells correlates with the surface of contact shared with winners. As such, modifying loser-winner interface morphology can modulate the strength of competition. We further show that elimination of loser clones requires winner-loser cell mixing through cell-cell intercalation. Cell mixing is driven by differential growth and the high tension at winner-winner interfaces relative to winner-loser and loser-loser interfaces, which leads to a preferential stabilization of winner-loser contacts and reduction of clone compactness over time. Differences in tension are generated by a relative difference in F-actin levels between loser and winner junctions, induced by differential levels of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate. Our results establish the first link between cell-cell intercalation induced by a proto-oncogene and how it promotes invasiveness and destruction of healthy tissues.

Destruction, Alteration, Simples and World-Stuff

When a tree is chopped to bits, or a sweater unraveled, its matter still exists. Since antiquity, it has sometimes been inferred that nothing really has been destroyed: what has happened is just that this matter has assumed new form. Contemporary versions hold that apparent destruction of a familiar object is just rearrangement of microparticles or of 'physical simples' or 'world stuff'. But if destruction of a familiar object is genuinely to be reduced to mere alteration of something else, we must identify an alternation proper to the career, the course of existence, of this something else; relatedly, the alteration must be characterizable without asserting the existence of the familiar object. All contemporary views fail one of these requirements.

The history of the Jews : from the destruction of Jerusalem to the present time

by Hannah Adams

Post-biblical history of the Jews : from the close of the Old Testament, about the year 420 B.C.E. till the destruction of the second temple, in the year 70 C.E. ; in two volumes

by Morris J. Raphall

Osterix inhibits bone destruction in osteosarcoma through transcriptional repression of Interleukin-1alpha expression

Osteosarcoma, a malignant bone tumor, rapidly destroys the cortical bone. We demonstrated that mouse K7M2 osteosarcoma cells were deficient in osterix (osx), a zinc finger-containing transcription factor required for osteoblasts differentiation and bone formation. These cells formed lytic tumors when injected into the tibia. The destruction of bone is mediated by osteoclasts in osteosarcoma. The less expression of osterix with osteolytic phenotype was also observed in more tumor cell lines. Replacement of osterix in K7M2 cells suppressed lytic bone destruction, inhibited tumor growth in vitro and in vivo, and suppressed lung metastasis in vivo and the migration of K7M2 to lung conditioned medium in vitro. By contrast, inhibiting osterix by vector-based small interfering RNA (siRNA) in two cell lines (Dunn and DLM8) that expressed high levels of osterix converted osteoblastic phenotype to lytic. Recognizing and binding of Receptor Activator of NF-κB (RANK) on osteoclast precursors by its ligand RANKL is the key osteoclastogenic event. Increased RANKL results in more osteoclast activity. We investigated whether K7M2-mediated bone destruction was secondary to an effect on RANKL. The conditioned medium from K7M2 could upregulate RANKL in normal osteoblast MC3T3, which might lead to more osteoclast formation. By contrast, the conditioned medium from K7M2 cells transfected with osx-expressing plasmid did not upregulate RANKL. Furthermore, Interleukin-1alpha (IL-1α) was significantly suppressed following osx transfection. IL-1α increased RANKL expression in MC3T3 cells, suggesting that osx may control RANKL via a mechanism involving IL-1α. Using a luciferase reporter assay, we demonstrated that osx downregulated IL-1α through a transcription-mediated mechanism. Following suppression of osterix in Dunn and DLM8 cells led to enhanced IL-1α promoter activity and protein production. Site-directed mutagenesis and Chromatin immunoprecipitation (ChIP) indicated that osterix downregulated IL-1α through a Sp1-binding site on the IL-1α promoter. These data suggest that osterix is involved in the lytic phenotype of osteosarcoma and that this is mediated via transcriptional repression of IL-1α. ^

Studies of pseudoachondroplasia chondrocytes and knockdown of the cartilage oligomeric matrix protein

Cartilage oligomeric matrix protein (COMP) is a large, homopentameric, extracellular matrix glycoprotein. Mutations in COMP cause two skeletal dysplasias: pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EMD1). These dwarfing conditions are caused by retention of misfolded mutant COMP with type IX collagen and matrilin-3 (MATN3) in the rough endoplasmic reticulum (rER) of the chondrocyte. These proteins form a matrix in the rER that continues to expand until it fills the entire cell, eventually causing cell death. Interestingly, loss of COMP in COMP null mice does not affect normal bone development or growth, suggesting that elimination of COMP (wildtype and mutant) expression may prevent PSACH. The hypothesis of these studies was that a hammerhead ribozyme could eliminate or knockdown COMP mRNA expression in PSACH chondrocytes . To test this hypothesis, a human chondrocyte model system that recapitulates the PSACH chondrocyte phenotype was developed by over-expressing mutant (mt-) COMP in normal chondrocytes using a recombinant adenovirus. Chondrocytes over-expressing mt-COMP developed giant rER cisternae containing COMP, type IX collagen and MATN3. Deconvolution microscopy and computer modeling showed that these proteins formed an ordered matrix surrounding a type II pro-collagen core. Additionally, the results show that a hammerhead ribozyme, ribozyme 56 (Ribo56) reduced over-expressed mt-COMP in COS cells and endogenous COMP in normal chondrocytes and mt-COMP in three PSACH chondrocytes cell line (with different mutations) by 40-70%. Altogether, these studies show that the PSACH cellular phenotype can be created in vitro and that the mt-COMP protein burden can be reduced by the presence of a COMP-specific ribozyme. Future studies will focus on designing ribozymes or short interfering RNA (siRNA) technologies that will result in better knockdown of COMP expression as well as the temporal constraints imposed by the PSACH phenotype. ^

Concentration and production of bacteria and bacterial destruction in the photic layer of the Sodruzhestvo Sea area, Southern Ocean

Bacterioplankton in the photic layer of the Sodruzhestvo Sea area and adjoining waters consists in summer primarily of cocci, with fractions smaller than 2 ?m predominating. The average abundance and biomass of microorganisms are 427 thousand cells/ml and 438 mg C/m**2, with ranges of 150-1770 thousand cells/ml and 221-1146 mg C/m**2. The average daily production and bacterial destruction increase from 49 and 104 mg C/m**2 at the beginning of the growth period to 85 and 180 mg C/m**2 in the middle of the period and remain at this level till the end. Despite low rate of increase (daily P/B coefficient averages 0.12), because of its high abundance bacterioplankton in Antarctic waters plays a major role in destruction of organic matter, accounting for 60-85% of energy consumed by heterotrophs.

Approximate Analytical Model for the Squeeze-Film Lubrication of the Human Ankle Joint with Synovial Fluid Filtrated by Articular Cartilage

The aim of this article is to propose an analytical approximate squeeze-film lubrication model of the human ankle joint for a quick assessment of the synovial pressure field and the load carrying due to the squeeze motion. The model starts from the theory of boosted lubrication for the human articular joints lubrication (Walker et al., Rheum Dis 27:512–520, 1968; Maroudas, Lubrication and wear in joints. Sector, London, 1969) and takes into account the fluid transport across the articular cartilage using Darcy’s equation to depict the synovial fluid motion through a porous cartilage matrix. The human ankle joint is assumed to be cylindrical enabling motion in the sagittal plane only. The proposed model is based on a modified Reynolds equation; its integration allows to obtain a quick assessment on the synovial pressure field showing a good agreement with those obtained numerically (Hlavacek, J Biomech 33:1415–1422, 2000). The analytical integration allows the closed form description of the synovial fluid film force and the calculation of the unsteady gap thickness.