Distribution by Scientific Domains

Kinds of Comp

  • j. comp

  • Terms modified by Comp

  • comp neurol

  • Selected Abstracts

    Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans,,

    HUMAN MUTATION, Issue 3 2007
    Joan C. Marini
    Abstract Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the pro,1(I) and pro,2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype,phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in ,1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691,823 and 910,964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril,matrix interactions. Recurrences at the same site in ,2(I) are generally concordant for outcome, unlike ,1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In ,2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype,phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events. Hum Mutat 28(3), 209,221, 2007. Published 2006 Wiley-Liss, Inc. [source]

    An immunohistochemical study of the triangular fibrocartilage complex of the wrist: regional variations in cartilage phenotype

    JOURNAL OF ANATOMY, Issue 1 2007
    S. Milz
    Abstract The triangular fibrocartilage complex (TFCC) transmits load from the wrist to the ulna and stabilizes the distal radioulnar joint. Damage to it is a major cause of wrist pain. Although its basic structure is well established, little is known of its molecular composition. We have analysed the immunohistochemical labelling pattern of the extracellular matrix of the articular disc and the meniscal homologue of the TFCC in nine elderly individuals (age range 69,96 years), using a panel of monoclonal antibodies directed against collagens, glycosaminoglycans, proteoglycans and cartilage oligomeric matrix protein (COMP). Although many of the molecules (types I, III and VI collagen, chondroitin 4 sulphate, dermatan sulphate and keratan sulphate, the oversulphated epitope of chondroitin 6 sulphate, versican and COMP) were found in all parts of the TFCC, aggrecan, link protein and type II collagen were restricted to the articular disc and to entheses. They were thus not a feature of the meniscal homologue. The shift in tissue phenotype within the TFCC, from a fibrocartilaginous articular disc to a more fibrous meniscal homologue, correlates with biomechanical data suggesting that the radial region is stiff and subject to considerable stress concentration. The presence of aggrecan, link protein and type II collagen in the articular disc could explain why the TFCC is destroyed in rheumatoid arthritis, given that it has been suggested that autoimmunity to these antigens results in the destruction of articular cartilage. The differential distribution of aggrecan within the TFCC is likely to be reflected by regional differences in water content and mobility on the radial and ulnar side. This needs to be taken into account in the design of improved MRI protocols for visualizing this ulnocarpal complex of the wrist. [source]

    Expression of extracellular matrix molecules typical of articular cartilage in the human scapholunate interosseous ligament

    JOURNAL OF ANATOMY, Issue 6 2006
    S. Milz
    Abstract The scapholunate interosseous ligament (SLIL) connects the scaphoid and lunate bones and plays a crucial role in carpal kinematics. Its rupture leads to carpal instability and impairment of radiocarpal joint function. As the ligament is one of the first structures affected in rheumatoid arthritis, we conducted an immunohistochemical study of cadaveric tissue to determine whether it contains known autoantigens for rheumatoid arthritis. We immunolabelled the ligament from one hand in 12 cadavers with monoclonal antibodies directed against a wide range of extracellular matrix (ECM) molecules associated with both fibrous and cartilaginous tissues. The labelling profile has also enabled us to comment on how the molecular composition of the ligament relates to its mechanical function. All regions of the ligament labelled for types I, III and VI collagens, chondroitin 4 and 6 sulphates, keratan sulphate, dermatan sulphate, versican, tenascin and cartilage oligomeric matrix protein (COMP). However, both entheses labelled strongly for type II collagen, aggrecan and link protein and were distinctly fibrocartilaginous. In some regions, the ligament attached to bone via a region of hyaline cartilage that was continuous with articular cartilage. Labelling for cartilage molecules in the midsubstance was most evident dorsally. We conclude that the SLIL has an ECM which is typical of other highly fibrocartilaginous ligaments that experience both tensile load and shear. The presence of aggrecan, link protein, COMP and type II collagen could explain why the ligament may be a target for autoantigenic destruction in some forms of rheumatoid arthritis. [source]

    Change in serum COMP concentration due to ambulatory load is not related to knee OA Status

    Annegret Mündermann
    Abstract The aim of this study was to test the hypothesis that a change in serum cartilage oligomeric matrix protein (COMP) concentration is related to joint load during a 30-min walking exercise in patients with medial compartment knee osteoarthritis (OA) and in age-matched control subjects. Blood samples were drawn from 42 patients with medial compartment knee OA and from 41 healthy age-matched control subjects immediately before, immediately after, and 0.5, 1.5, 3.5, and 5.5 h after a 30-min walking exercise on a level outdoor walking track at self-selected normal speed. Serum COMP concentrations were determined using a commercial ELISA. Basic time,distance gait variables were recorded using an activity monitor. Joint loads were measured using gait analysis. Serum COMP concentrations increased immediately after the walking exercise (+6.3% and +5.6%; p,<,0.001) and decreased over 5.5 h after the exercise (,11.1% and ,14.6%; p,<,0.040 and p,=,0.001) in patients and control subjects, respectively. The magnitude of increase in COMP concentration did not differ between groups (p,=,0.902) and did not correlate with any variables describing ambulatory loads at the joints of the lower extremity. These results, taken together with a previous study of a younger healthy population, suggest the possibility that the influence of ambulatory loads on cartilage turnover is dependent on age. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1408,1413, 2009 [source]

    Expression of cartilage-related genes in bovine synovial tissue

    Nahoko Shintani
    Abstract The synovium contains mesenchymal stem cells with chondrogenic potential. Although synovial and articular cartilage tissue develop from a common pool of mesenchymal cells, little is known about their genetic commonalities. In the present study, the mRNA levels for several cartilage-related proteins, namely, cartilage oligomeric matrix protein (COMP), Sox9, aggrecan, and collagen types I, II, IX, X, and XI, were measured using the real-time polymerase chain reaction. Our data reveal the synovium of calf metacarpal joints to physiologically express not only type I collagen but also COMP, Sox9, aggrecan, and collagen types X and XI. The mRNA levels for the latter five proteins lie between 2% and 15% of those in articular cartilage. We speculate that these genes are being expressed by chondroprogenitor cells, whose presence in the synovium reflects a common ontogenetic phase in the fetal development of this tissue and of articular cartilage. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25: 813,819, 2007 [source]

    Expression of mutant cartilage oligomeric matrix protein in human chondrocytes induces the pseudoachondroplasia phenotype

    Thomas M. Merritt
    Abstract Over 70 mutations in the cartilage oligomeric matrix protein (COMP), a large extracellular pentameric glycoprotein synthesized by chondrocytes, have been identified as causing two skeletal dysplasias: multiple epiphyseal dysplasia (MED/EDM1), and a dwarfing condition, pseudoachondroplasia (PSACH). These mutations induce misfolding of intracellular COMP, resulting in retention of the protein in the rough endoplasmic reticulum (rER) of chondrocytes. This accumulation of COMP in the rER creates the phenotypic enlarged rER cisternae in the cells, which is believed to compromise chondrocyte function and eventually cause cell death. To study the molecular mechanisms involved with the disease, we sought to develop an in vitro model that recapitulates the PSACH phenotype. Normal human chondrocytes were transfected with wildtype (wt-) COMP or with mutant COMP (D469del; mt-) recombinant adenoviruses and grown in a nonattachment redifferentiating culture system that provides an environment allowing formation of a differentiated chondrocyte nodule. Visualization of normal cells expressing COMP suggested the hallmarks of the PSACH phenotype. Mutant COMP expressed in normal cells was retained in enlarged rER cisternae, which also retained IX collagen (COL9) and matrilin-3 (MATN3). Although these proteins were secreted normally into the ECM of the wt-COMP nodules, reduced secretion of these proteins was observed in nodules composed of cells transfected with mt-COMP. The findings complement those found in chondrocytes from PSACH patient growth plates. This new model system allows for production of PSACH chondrocyte pathology in normal costochondral chondrocytes and can be used for future mechanistic and potential gene therapy studies. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source]

    Synovial fluid biomarker levels predict articular cartilage damage following complete medial meniscectomy in the canine knee

    Cathy S. Carlson
    The purposes of this study were to document the histological changes present in the tibial plateaus 12 weeks after complete medial meniscectomy in dogs and to determine if synovial lavage fluid biomarker levels are predictive of the severity of joint damage. Twelve adult dogs underwent complete unilateral medial meniscectomy and synovial lavage fluid biomarker levels, including cartilage oligomeric matrix protein (COMP), keratan sulfate (5D4), 3B3(,), and 3B3(+), were measured serially at 4-week intervals. The dogs were euthanized 12 weeks after surgery and each medial and lateral tibial plateau from the meniscectomized and contralateral knees was graded histologically. Histological data were analyzed using principal components analysis, which resulted in 4 factors that explained 70% of the variation in the data. Factor 2 (weighted most heavily by subchondral bone thickness) and Factor 3 (representative of articular cartilage damage) were significantly affected by compartmental site (P < 0.01 for both). Both of these factors were highest in the medial tibial plateau of the meniscectomized knee, and Factor 3 was significantly higher in this site than in the medial tibial plateau of the contralateral knee (P < 0.01). Peak levels of all 4 synovial lavage fluid biomarkers occurred at 4 weeks post-meniscectomy and 4-week minus baseline levels of all biomarkers were significantly correlated with the Factor 3 scores. This study demonstrates that significant articular cartilage damage occurs relatively quickly following complete medial meniscectomy in dogs and establishes the content and criterion validity for these synovial fluid lavage biomarkers in canine meniscectomy as surrogate measures of articular cartilage damage. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source]

    PerioGlas® Regulates Osteoblast RNA Interfering

    Annalisa Palmieri PhD
    Abstract Purpose: PerioGlas® (PG) is an alloplastic material that has been used for grafting periodontal osseous defects since the 1990s. In animal models, it has been proven that PG achieves histologically good repairs of surgically created defects. In clinical trials, PG is effective as an adjunct to conventional surgery in the treatment of intrabony defects; however, how PG alters osteoblast activity to promote bone formation is poorly understood. We therefore attempted to address this question by using microRNA (miRNA) microarray techniques to investigate the translation process in osteoblasts exposed to PG. Materials and Methods: By using miRNA microarrays containing 329 probes designed from human miRNA sequences, we identified several miRNA whose expression was significantly modified in osteoblast-like cell lines (MG-63) cultured with PG. Results: There were ten up-regulated miRNA (mir-337, mir-377, mir-9, mir-516, mir-515-3p, mir-496, mir-200b, mir-489, mir-25, mir-423) and two down-regulated miRNA (mir-26a, mir-30d). Conclusion: PG acts on miRNAs, which in turn regulate several messengers. Among them there are mRNAs related to bone formation and skeletal and cartilage development. The vast majority of detected genes are down-regulated, and some are homeobox genes like NOG, EN1, and CHRD. Other down-regulated genes are receptors (like GHRHR) and extracellular matrix proteins (like COMP). Although the exact mechanism of PG action on osteoblasts is still incompletely understood, these data demonstrate that PG has not only an osteoconductive effect, but also regulates bone formation. [source]

    The height of increasing trees

    N. Broutin
    Abstract We extend results about heights of random trees (Devroye, JACM 33 (1986) 489,498, SIAM J COMP 28 (1998) 409,432). In this paper, a general split tree model is considered in which the normalized subtree sizes of nodes converge in distribution. The height of these trees is shown to be in probability asymptotic to clog n for some constant c. We apply our results to obtain a law of large numbers for the height of all polynomial varieties of increasing trees (Bergeron et al. Lect Notes Comput Sci (1992) 24,48).© 2008 Wiley Periodicals, Inc. Random Struct. Alg., 2008 [source]

    Granulin-epithelin precursor binds directly to ADAMTS-7 and ADAMTS-12 and inhibits their degradation of cartilage oligomeric matrix protein

    ARTHRITIS & RHEUMATISM, Issue 7 2010
    Fengjin Guo
    Objective To determine 1) whether a protein interaction network exists between granulin-epithelin precursor (GEP), ADAMTS-7/ADAMTS-12, and cartilage oligomeric matrix protein (COMP); 2) whether GEP interferes with the interactions between ADAMTS-7/ADAMTS-12 metalloproteinases and COMP substrate, including the cleavage of COMP; 3) whether GEP affects tumor necrosis factor , (TNF,),mediated induction of ADAMTS-7/ADAMTS-12 expression and COMP degradation; and 4) whether GEP levels are altered during the progression of arthritis. Methods Yeast two-hybrid, in vitro glutathione S-transferase pull-down, and coimmunoprecipitation assays were used to 1) examine the interactions between GEP, ADAMTS-7/ADAMTS-12, and COMP, and 2) map the binding sites required for the interactions between GEP and ADAMTS-7/ADAMTS-12. Immunofluorescence cell staining was performed to visualize the subcellular localization of GEP and ADAMTS-7/ADAMTS-12. An in vitro digestion assay was employed to determine whether GEP inhibits ADAMTS-7/ADAMTS-12,mediated digestion of COMP. The role of GEP in inhibiting TNF,-induced ADAMTS-7/ADAMTS-12 expression and COMP degradation in cartilage explants was also analyzed. Results GEP bound directly to ADAMTS-7 and ADAMTS-12 in vitro and in chondrocytes, and the 4 C-terminal thrombospondin motifs of ADAMTS-7/ADAMTS-12 and each granulin unit of GEP mediated their interactions. Additionally, GEP colocalized with ADAMTS-7 and ADAMTS-12 on the cell surface of chondrocytes. More importantly, GEP inhibited COMP degradation by ADAMTS-7/ADAMTS-12 in a dose-dependent manner through 1) competitive inhibition through direct protein,protein interactions with ADAMTS-7/ADAMTS-12 and COMP, and 2) inhibition of TNF,-induced ADAMTS-7/ADAMTS-12 expression. Furthermore, GEP levels were significantly elevated in patients with either osteoarthritis or rheumatoid arthritis. Conclusion Our observations demonstrate a novel protein,protein interaction network between GEP, ADAMTS-7/ADAMTS-12, and COMP. Furthermore, GEP is a novel specific inhibitor of ADAMTS-7/ADAMTS-12,mediated COMP degradation and may play a significant role in preventing the destruction of joint cartilage in arthritis. [source]

    Genome-wide linkage analysis of quantitative biomarker traits of osteoarthritis in a large, multigenerational extended family

    ARTHRITIS & RHEUMATISM, Issue 3 2010
    Hsiang-Cheng Chen
    Objective The genetic contributions to the multifactorial disorder osteoarthritis (OA) have been increasingly recognized. The goal of the current study was to use OA-related biomarkers of severity and disease burden as quantitative traits to identify genetic susceptibility loci for OA. Methods In a large multigenerational extended family (n = 350), we measured 5 OA-related biomarkers: hyaluronan (HA), cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA collagen (PIIANP), C-propeptide of type II procollagen (CPII), and type II collagen neoepitope (C2C). Single-nucleotide polymorphism markers (n = 6,090) covering the whole genome were genotyped using the Illumina HumanLinkage-12 BeadChip. Variance components analysis, as implemented in the Sequential Oligogenic Linkage Analysis Routines, was used to estimate heritabilities of the quantitative traits and to calculate 2-point and multipoint logarithm of odds (LOD) scores using a polygenic model. Results After adjusting for age and sex, we found that 4 of the 5 biomarkers exhibited significant heritability (PIIANP 0.57, HA 0.49, COMP 0.43, C2C 0.30; P , 0.01 for all). Fourteen of the 19 loci that had multipoint LOD scores of >1.5 were near to or overlapped with previously reported OA susceptibility loci. Four of these loci were identified by more than 1 biomarker. The maximum multipoint LOD scores for the heritable quantitative biomarker traits were 4.3 for PIIANP (chromosome 8p23.2), 3.2 for COMP (chromosome 8q11.1), 2.0 for HA (chromosome 6q16.3), and 2.0 for C2C (chromosome 5q31.2). Conclusion Herein, we report the first evidence of genetic susceptibility loci identified by OA-related biomarkers in an extended family. Our results demonstrate that serum concentrations of PIIANP, HA, COMP, and C2C have substantial heritable components, and using these biomarkers, several genetic loci potentially contributing to the genetic diversity of OA were identified. [source]

    A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis

    ARTHRITIS & RHEUMATISM, Issue 2 2010
    G. Farina
    Objective Improved outcome measures in systemic sclerosis (SSc) are critical to finding active therapeutics for this disease. The modified Rodnan skin thickness score (MRSS) is the current standard for evaluating skin disease in SSc, but it is not commonly used in the clinical setting, in part because it requires specialized training to perform accurately and consistently. The purpose of this study was to investigate whether skin gene expression might serve as a more objective surrogate outcome measure to supplement skin score evaluations. Methods Skin RNAs from a group of patients with diffuse cutaneous SSc were studied for expression levels of genes known to be regulated by transforming growth factor , (TGF,) and interferon (IFN). These levels were correlated with the MRSS, using multiple regression analyses to obtain best-fit models. Results Skin expression of the TGF,-regulated genes cartilage oligomeric matrix protein (COMP) and thrombospondin 1 (TSP-1) correlated moderately well with the MRSS, but the addition of other TGF,-regulated genes failed to significantly improve best-fit models. IFN-regulated genes were also found to correlate with the MRSS, and the addition of interferon-inducible 44 (IFI44) and sialoadhesin (Siglec-1) to COMP and TSP-1 in multiple regression analyses significantly improved best-fit models, achieving an R2 value of 0.89. These results were validated using an independent group of skin biopsy samples. Longitudinal scores using this 4-gene biomarker indicated that it detects change over time that corresponds to changes in the MRSS. Conclusion We describe a 4-gene predictor of the MRSS and validate its performance. This objective measure of skin disease could provide a strong surrogate outcome measure for patient care and for clinical trials. [source]

    Combined role of type IX collagen and cartilage oligomeric matrix protein in cartilage matrix assembly: Cartilage oligomeric matrix protein counteracts type IX collagen,induced limitation of cartilage collagen fibril growth in mouse chondrocyte cultures

    ARTHRITIS & RHEUMATISM, Issue 12 2009
    K. Blumbach
    Objective Defects in the assembly and composition of cartilage extracellular matrix are likely to result in impaired matrix integrity and increased susceptibility to cartilage degeneration. The aim of this study was to determine the functional interaction of the collagen fibril,associated proteins type IX collagen and cartilage oligomeric matrix protein (COMP) during cartilage matrix formation. Methods Primary chondrocytes from mice deficient in type IX collagen and COMP (double-deficient) were cultured in monolayer or alginate beads. Anchorage of matrix proteins, proteoglycan and collagen content, collagen crosslinks, matrix metalloproteinase activity, and mechanical properties of the matrix were measured. Electron microscopy was used to study the formation of fibrillar structures. Results In cartilage lacking both type IX collagen and COMP, matrilin 3 showed decreased matrix anchorage. Less matrilin 3 was deposited in the matrix of double-deficient chondrocytes, while larger amounts were secreted into the medium. Proteoglycans were less well retained in the matrix formed in alginate cultures, while collagen deposition was not significantly affected. Electron microscopy revealed similar cartilage collagen fibril diameters in the cultures of double-deficient and wild-type chondrocytes. In contrast, a larger fibril diameter was observed in the matrix of chondrocytes deficient in only type IX collagen. Conclusion Our results show that type IX collagen and COMP are involved in matrix assembly by mediating the anchorage and regulating the distribution of other matrix macromolecules such as proteoglycans and matrilins and have counteracting effects on collagen fibril growth. Loss of type IX collagen and COMP leads to matrix aberrations that may make cartilage more susceptible to degeneration. [source]

    Whole-body bone scintigraphy provides a measure of the total-body burden of osteoarthritis for the purpose of systemic biomarker validation

    ARTHRITIS & RHEUMATISM, Issue 11 2009
    Shelby Addison
    Objective To evaluate the association of serum and synovial fluid cartilage oligomeric matrix protein (COMP) with systemic and local measures of osteoarthritis (OA) activity by bone scintigraphy. Methods Samples of serum and knee joint synovial fluid (275 knees) were obtained from 159 patients with symptomatic OA of at least 1 knee. Bone scintigraphy using 99mTc-labeled methylene diphosphonate was performed, and early-phase knee scans and late-phase whole-body bone scans of 15 additional joint sites were scored semiquantitatively. To control for within-subject correlations of knee data, generalized linear modeling was used in the correlation of the bone scan scores with the COMP levels. Principal components analysis was used to explore the contribution of each joint site to the variance in serum COMP levels. Results The correlation between synovial fluid and serum COMP levels was significant (r = 0.206, P = 0.006). Synovial fluid COMP levels correlated most strongly with the early-phase knee bone scan scores (P = 0.0003), even after adjustment for OA severity according to the late-phase bone scan scores (P = 0.015), as well as synovial fluid volumes (P < 0.0001). Serum COMP levels correlated with the total-body bone scan scores (r = 0.188, P = 0.018) and with a factor composed of the bone scan scores in the shoulders, spine, lateral knees, and sacroiliac joints (P = 0.0004). Conclusion Synovial fluid COMP levels correlated strongly with 2 indicators of knee joint inflammation: early-phase bone scintigraphic findings and synovial fluid volume. Serum COMP levels correlated with total-body joint disease severity as determined by late-phase bone scintigraphy, supporting the hypothesis that whole-body bone scintigraphy is a means of quantifying the total-body burden of OA for systemic biomarker validation. [source]

    The combination of the biomarkers urinary C-terminal telopeptide of type II collagen, serum cartilage oligomeric matrix protein, and serum chondroitin sulfate 846 reflects cartilage damage in hemophilic arthropathy

    ARTHRITIS & RHEUMATISM, Issue 1 2009
    Nathalie W. D. Jansen
    Objective Hemophilic arthropathy, with characteristics of inflammatory (rheumatoid arthritis) and degenerative (osteoarthritis) joint damage, occurs at an early age, is associated with minor comorbidity, and is restricted to 3 pairs of large joints. The aim of this study was to determine whether commonly used serum and/or urinary biomarkers of cartilage and bone turnover for which assay kits are commercially available are associated with the severity of joint damage in patients with various degrees of hemophilic arthropathy and, thus, whether this disease could be useful in the identification and evaluation of such biomarkers. Methods Blood and urine samples were collected from 36 patients with various degrees of hemophilic arthropathy. Commercially available assays for the most frequently investigated serum and urine biomarkers were performed: urinary C-terminal telopeptide of type I collagen (CTX-I), urinary CTX-II, serum CTX-I, serum CTX-II, serum cartilage oligomeric matrix protein (COMP), serum cartilage cleavage products C1,2C and C2C, and serum chondroitin sulfate 846 (CS-846). Radiographs of the ankles, knees, and elbows in all patients were evaluated for the degree of joint damage according to the Pettersson score, which is based on cartilage and periarticular bone changes and is specific for hemophilic arthropathy. Results Urinary CTX-II, serum C1,2C, and serum CS-846 levels correlated with the overall Pettersson score and with the joint space narrowing component. Regression analysis showed that combined indexes of different markers increased the degree of correlation for the combination of urinary CTX-II, serum COMP, and serum CS-846. Bone-specific markers (urinary/serum CTX-I and serum C1,2C) did not correlate with specific bone-related items of the Pettersson score (osteoporosis and erosions). Conclusion These results support the idea that a combination of biomarkers relates significantly better to the severity of joint damage than do individual biomarkers. The combination of urinary CTX-II, serum COMP, and serum CS-846 correlated best with the degree of arthropathy. Because of its specific characteristics and restricted involvement, hemophilic arthropathy may prove useful in the screening of newly developed biomarkers of joint damage. [source]

    Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis

    ARTHRITIS & RHEUMATISM, Issue 8 2006
    S. Y. Kong
    Objective To evaluate diurnal variation of biomarkers in subjects with osteoarthritis (OA) of the knee. Methods Twenty subjects with radiographic knee OA were admitted to the General Clinical Research Center of Duke University for an overnight stay to undergo serial blood and urine sampling. Biomarkers measured included serum hyaluronan (HA), cartilage oligomeric matrix protein (COMP), keratan sulfate (KS-5D4), aggrecan neoepitope (CS846), high-sensitivity C-reactive protein (hsCRP), osteocalcin, transforming growth factor ,1 (TGF,1), and type II collagen (CII),related epitopes (neoepitope from cleavage of CII [C2C], carboxy-terminus of three-quarter peptide from cleavage of CI and CII [C1,2C], and type II procollagen carboxy-propeptide [CPII] in serum, and C-terminal telopeptides of CII [CTX-II] and C2C in urine). Results Levels of serum HA, COMP, KS-5D4, and TGF,1 increased significantly from T0 (before arising from bed) to T1 (1 hour after arising). More diurnal variation in HA was observed in patients with higher daily mean HA concentrations. CPII increased significantly from T0 to T2 (4 hours after arising). Urinary concentrations of CTX-II were also found to vary with morning activity, decreasing significantly from T0 to T2. Urinary C2C concentrations increased significantly from T0 until T3 (early evening). No diurnal variations in CS846, hsCRP, osteocalcin, serum C2C, or C1,2C were observed. Six biomarkers (serum C2C, C1,2C, COMP, KS-5D4, TGF,1, and urinary CTX-II) were associated with radiographic knee OA (expressed as the sum of Kellgren/Lawrence radiographic severity grades), with the strongest correlations observed with measurements obtained at later time points (either T2 or T3). Conclusion Our study results suggest that serum and urine sampling for HA, COMP, KS-5D4, TGF,1, CPII, urinary CTX-II, and urinary C2C should be standardized in future OA clinical trials. Serum and urine sampling at late midday time points may be the optimal approach for OA studies, although this result should be validated in a larger cohort. [source]

    Synaptic contacts between an identified type of ON cone bipolar cell and ganglion cells in the mouse retina

    Bin Lin
    Abstract We surveyed the potential contacts between an identified type of bipolar cell and retinal ganglion cells in the mouse. By crossing two existing mouse strains (line 357 and line GFP-M), we created a double transgenic strain in which GFP is expressed by all members of a single type of ON cone bipolar cell and a sparse, mixed population of retinal ganglion cells. The GFP-expressing bipolar cells appear to be those termed CB4a of Pignatelli & Strettoi [(2004) J. Comp. Neurol., 476, 254,266] and type 7 of Ghosh et al. [(2004) J. Comp. Neurol., 469, 70,82 and J. Comp. Neurol., 476, 202,203]. The labelled ganglion cells include examples of most or all types of ganglion cells present in the mouse. By studying the juxtaposition of their processes in three dimensions, we could learn which ganglion cell types are potential synaptic targets of the line 357 bipolar cell. Of 12 ganglion cell types observed, 10 types could be definitively ruled out as major synaptic targets of the line 357 bipolar cells. One type of monostratified ganglion cell and one bistratified cell tightly cofasciculate with axon terminals of the line 357 bipolar cells. Double labelling for kinesin II demonstrates colocalization of bipolar cell ribbons at the sites of contact between these two types of ganglion cell and the line 357 bipolar cells. [source]

    A combination of implicit and adaptative upwind tools for the numerical solution of incompressible free surface flows

    V. G. Ferreira
    Abstract This paper is concerned with the numerical solutions of time dependent two-dimensional incompressible flows. By using the primitive variables of velocity and pressure, the Navier,Stokes and mass conservation equations are solved by a semi-implicit finite difference projection method. A new bounded higher order upwind convection scheme is employed to deal with the non-linear (advective) terms. The procedure is an adaptation of the GENSMAC (J. Comput. Phys. 1994; 110:171,186) methodology for calculating confined and free surface fluid flows at both low and high Reynolds numbers. The calculations were performed by using the 2D version of the Freeflow simulation system (J. Comp. Visual. Science 2000; 2:199,210). In order to demonstrate the capabilities of the numerical method, various test cases are presented. These are the fully developed flow in a channel, the flow over a backward facing step, the die-swell problem, the broken dam flow, and an impinging jet onto a flat plate. The numerical results compare favourably with the experimental data and the analytical solutions. Copyright © 2006 John Wiley & Sons, Ltd. [source]

    Performance of very-high-order upwind schemes for DNS of compressible wall-turbulence

    G. A. Gerolymos
    Abstract The purpose of the present paper is to evaluate very-high-order upwind schemes for the direct numerical simulation (DNS) of compressible wall-turbulence. We study upwind-biased (UW) and weighted essentially nonoscillatory (WENO) schemes of increasingly higher order-of-accuracy (J. Comp. Phys. 2000; 160:405,452), extended up to WENO17 (AIAA Paper 2009-1612, 2009). Analysis of the advection,diffusion equation, both as ,x,0 (consistency), and for fixed finite cell-Reynolds-number Re,x (grid-resolution), indicates that the very-high-order upwind schemes have satisfactory resolution in terms of points-per-wavelength (PPW). Computational results for compressible channel flow (Re,[180, 230]; M,CL,[0.35, 1.5]) are examined to assess the influence of the spatial order of accuracy and the computational grid-resolution on predicted turbulence statistics, by comparison with existing compressible and incompressible DNS databases. Despite the use of baseline O(,t2) time-integration and O(,x2) discretization of the viscous terms, comparative studies of various orders-of-accuracy for the convective terms demonstrate that very-high-order upwind schemes can reproduce all the DNS details obtained by pseudospectral schemes, on computational grids of only slightly higher density. Copyright © 2009 John Wiley & Sons, Ltd. [source]

    Adaptive approach for nonlinear sensitivity analysis of reaction kinetics

    Illia Horenko
    Abstract We present a unified approach for linear and nonlinear sensitivity analysis for models of reaction kinetics that are stated in terms of systems of ordinary differential equations (ODEs). The approach is based on the reformulation of the ODE problem as a density transport problem described by a Fokker,Planck equation. The resulting multidimensional partial differential equation is herein solved by extending the TRAIL algorithm originally introduced by Horenko and Weiser in the context of molecular dynamics (J. Comp. Chem. 2003, 24, 1921) and discussed it in comparison with Monte Carlo techniques. The extended TRAIL approach is fully adaptive and easily allows to study the influence of nonlinear dynamical effects. We illustrate the scheme in application to an enzyme-substrate model problem for sensitivity analysis w.r.t. to initial concentrations and parameter values. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 941,948, 2005 [source]

    On the solutions of the linear integral equations of Volterra type

    smet Özdemir
    Abstract Some boundaries about the solution of the linear Volterra integral equations of the form f(t)=1,K*f were obtained as |f(t)|,1, |f(t)|,2 and |f(t)|,4 in (J. Math. Anal. Appl. 1978; 64:381,397; Int. J. Math. Math. Sci. 1982; 5(1):123,131). The boundary of the solution function of an equation in this type was found as |f(t)|,2n in (Integr. Equ. Oper. Theory 2002; 43:466,479), where t,[0, ,) and n is a natural number such that n,2. In (Math. Comp. 2006; 75:1175,1199), it is shown that the boundary of the solution function of an equation in the same form can also be derived as that of (Integr. Equ. Oper. Theory 2002; 43:466,479) under different conditions than those of (Integr. Equ. Oper. Theory 2002; 43:466,479). In the present paper, the sufficient conditions for the boundedness of functions f, f,, f,,, ,, f(n+3), (n,,) defined on the infinite interval [0, ,) are given by our method, where f is the solution of the equation f(t)=1,K*f. Copyright © 2007 John Wiley & Sons, Ltd. [source]

    Lp error estimates and superconvergence for covolume or finite volume element methods

    So-Hsiang Chou
    Abstract We consider convergence of the covolume or finite volume element solution to linear elliptic and parabolic problems. Error estimates and superconvergence results in the Lp norm, 2 , p , ,, are derived. We also show second-order convergence in the Lp norm between the covolume and the corresponding finite element solutions and between their gradients. The main tools used in this article are an extension of the "supercloseness" results in Chou and Li [Math Comp 69(229) (2000), 103,120] to the Lp based spaces, duality arguments, and the discrete Green's function method. © 2003 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 19: 463,486, 2003 [source]

    Parameter and state estimation in nonlinear stochastic continuous-time dynamic models with unknown disturbance intensity

    M. S. Varziri
    Abstract Approximate Maximum Likelihood Estimation (AMLE) is an algorithm for estimating the states and parameters of models described by stochastic differential equations (SDEs). In previous work (Varziri et al., Ind. Eng. Chem. Res., 47(2), 380-393, (2008); Varziri et al., Comp. Chem. Eng., in press), AMLE was developed for SDE systems in which process-disturbance intensities and measurement-noise variances were assumed to be known. In the current article, a new formulation of the AMLE objective function is proposed for the case in which measurement-noise variance is available but the process-disturbance intensity is not known a priori. The revised formulation provides estimates of the model parameters and disturbance intensities, as demonstrated using a nonlinear CSTR simulation study. Parameter confidence intervals are computed using theoretical linearization-based expressions. The proposed method compares favourably with a Kalman-filter-based maximum likelihood method. The resulting parameter estimates and information about model mismatch will be useful to chemical engineers who use fundamental models for process monitoring and control. L'estimation des vraisemblances maximums approximatives (AMLE) est un algorithme destiné à l'estimation des états et des paramètres de modèles décrits par les équations différentielles stochastiques (SDE). Dans un précédent travail (Varziri et al., 2008a, 2008b), l'AMLE a été mis au point pour des systèmes SDE dans lesquels les intensités de perturbations et les variances de bruits de mesure sont supposées connues. On propose dans cet article une nouvelle formulation de la fonction objectif de l'AMLE pour le cas où la variance de bruit de mesure est disponible mais où l'intensité des perturbations de procédé n'est pas connue a priori. La formulation révisée fournit des estimations des paramètres de modèle et des intensités de perturbations, comme le démontre une étude de simulation en CSTR non linéaire. Les intervalles de confiance des paramètres sont calculés par ordinateur au moyen d'expressions basées sur la linéarisation théorique. La méthode proposée se compare favorablement à une méthode de vraisemblance maximun reposant sur le filtre de Kalman. Les estimations de paramètres qui en résultent et l'information sur la discordance de modèle seront utiles aux ingénieurs en génie chimique qui utilisent des modèles fondamentaux pour la surveillance et le contrôle des procédés. [source]

    A Distinctive layering pattern of mouse dentate granule cells is generated by developmental and adult neurogenesis

    Emily A. Mathews
    Abstract New neurons are continuously added throughout life to the dentate gyrus of the mammalian hippocampus. During embryonic and early postnatal development, the dentate gyrus is formed in an outside-in layering pattern that may extend through adulthood. In this work, we sought to quantify systematically the relative position of dentate granule cells generated at different ages. We used 5,-bromo-2,-deoxyuridine (BrdU) and retroviral methodologies to birth date cells born in the embryonic, early postnatal, and adult hippocampus and assessed their final position in the adult mouse granule cell layer. We also quantified both developmental and adult-born cohorts of neural progenitor cells that contribute to the pool of adult progenitor cells. Our data confirm that the outside-in layering of the dentate gyrus continues through adulthood and that early-born cells constitute most of the adult dentate gyrus. We also found that substantial numbers of the dividing cells in the adult dentate gyrus were derived from early-dividing cells and retained BrdU, suggesting that a subpopulation of hippocampal progenitors divides infrequently from early development onward. J. Comp. Neurol. 518:4479,4490, 2010. © 2010 Wiley-Liss, Inc. [source]

    Axonal branching patterns of nucleus accumbens neurons in the rat

    Anushree Tripathi
    Abstract The patterns of axonal collateralization of nucleus accumbens (Acb) projection neurons were investigated in the rat by means of single-axon tracing techniques using the anterograde tracer biotinylated dextran amine. Seventy-three axons were fully traced, originating from either the core (AcbC) or shell (AcbSh) compartment, as assessed by differential calbindin D28k-immunoreactivity. Axons from AcbC and AcbSh showed a substantial segregation in their targets; target areas were either exclusively or preferentially innervated from AcbC or AcbSh. Axon collaterals in the subthalamic nucleus were found at higher than expected frequencies; moreover, these originated exclusively in the dorsal AcbC. Intercompartmental collaterals were observed from ventral AcbC axons into AcbSh, and likewise, interconnections at pallidal and mesencephalic levels were also observed, although mostly from AcbC axons toward AcbSh targets, possibly supporting crosstalk between the two subcircuits at several levels. Cell somata giving rise to short-range accumbal axons, projecting to the ventral pallidum (VP), were spatially intermingled with others, giving rise to long-range axons that innervated VP and more caudal targets. This anatomical organization parallels that of the dorsal striatum and provides the basis for possible dual direct and indirect actions from a single axon on either individual or small sets of neurons. J. Comp. Neurol. 518:4649,4673, 2010. © 2010 Wiley-Liss, Inc. [source]

    Astroglial structures in the zebrafish brain,

    Larissa Grupp
    Abstract To understand components shaping the neuronal environment we studied the astroglial cells in the zebrafish brain using immunocytochemistry for structural and junctional markers, electron microscopy including freeze fracturing, and probed for the water channel protein aquaporin-4. Glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) showed largely overlapping immunoreactivity: GFAP in the main glial processes and GS in main processes and smaller branches. Claudin-3 immunoreactivity was spread in astroglial cells along their major processes. The ventricular lining was immunoreactive for the tight-junction associated protein ZO-1, in the telencephalon located on the dorsal, lateral, and medial surface due to the everting morphogenesis. In the tectum, subpial glial endfeet were also positive for ZO-1. Correspondingly, electron microscopy revealed junctional complexes between subpial glial endfeet. However, in freeze-fracture analysis tight junctional strands were not found between astroglial membranes, either in the optic tectum or in the telencephalon. Occurrence of aquaporin-4, the major astrocytic water channel in mammals, was demonstrated by polymerase chain reaction (PCR) analysis and immunocytochemistry in tectum and telencephalon. Localization of aquaporin-4 was not polarized but distributed along the entire radial extent of the cell. Interestingly, their membranes were devoid of the orthogonal arrays of particles formed by aquaporin-4 in mammals. Finally, we investigated astroglial cells in proliferative areas. Brain lipid basic protein, a marker of early glial differentiation but not GS, were present in some proliferation zones, whereas cells lining the ventricle were positive for both markers. Thus, astroglial cells in the zebrafish differ in many aspects from mammalian astrocytes. J. Comp. Neurol. 518:4277,4287, 2010. © 2010 Wiley-Liss, Inc. [source]

    Immunohistochemical parcellation of the ferret (Mustela putorius) visual cortex reveals substantial homology with the cat (Felis catus)

    Jihane Homman-Ludiye
    Abstract Electrophysiological mapping of the adult ferret visual cortex has until now determined the existence of 12 retinotopically distinct areas; however, in the cat, another member of the Carnivora, 20 distinct visual areas have been identified by using retinotopic mapping and immunolabeling. In the present study, the immunohistochemical approach to demarcate the areal boundaries of the adult ferret visual cortex was applied in order to overcome the difficulties in accessing the sulcal surfaces of a small, gyrencephalic brain. Nonphosphorylated neurofilament (NNF) expression profiles were compared with another classical immunostain of cortical nuclei, Cat-301 chondroitin sulfate proteoglycan (CSPG). Together, these two markers reliably demarcated the borders of the 12 previously defined areas and revealed further arealization beyond those borders to a total of 19 areas: 21a and 21b; the anterolateral, posterolateral, dorsal, and ventral lateral suprasylvian areas (ALLS, PLLS, DLS, and VLS, respectively); and the splenial and cingulate visual areas (SVA and CVA). NNF expression profile and location of the newly defined areas correlate with previously defined areas in the cat. Moreover, NNF and Cat-301 together revealed discrete expression domains in the posteroparietal (PP) cortex, demarcating four subdivisions in the caudal lateral and medial domains (PPcL and PPcM) and rostral lateral and medial domains (PPrL and PPrM), where only two retinotopic maps have been previously identified (PPc and PPr). Taken together, these studies suggest that NNF and Cat-301 can illustrate the homology between cortical areas in different species and draw out the principles that have driven evolution of the visual cortex. J. Comp. Neurol. 518:4439,4462, 2010. © 2010 Wiley-Liss, Inc. [source]

    Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling,deficient mouse forebrain

    Matthew C. Judson
    Abstract Human genetic findings and murine neuroanatomical expression mapping have intersected to implicate Met receptor tyrosine kinase signaling in the development of forebrain circuits controlling social and emotional behaviors that are atypical in autism-spectrum disorders (ASD). To clarify roles for Met signaling during forebrain circuit development in vivo, we generated mutant mice (Emx1Cre/Metfx/fx) with an Emx1-Cre-driven deletion of signaling-competent Met in dorsal pallially derived forebrain neurons. Morphometric analyses of Lucifer yellow-injected pyramidal neurons in postnatal day 40 anterior cingulate cortex (ACC) revealed no statistically significant changes in total dendritic length but a selective reduction in apical arbor length distal to the soma in Emx1Cre/Metfx/fx neurons relative to wild type, consistent with a decrease in the total tissue volume sampled by individual arbors in the cortex. The effects on dendritic structure appear to be circuit-selective, insofar as basal arbor length was increased in Emx1Cre/Metfx/fx layer 2/3 neurons. Spine number was not altered on the Emx1Cre/Metfx/fx pyramidal cell populations studied, but spine head volume was significantly increased (,20%). Cell-nonautonomous, circuit-level influences of Met signaling on dendritic development were confirmed by studies of medium spiny neurons (MSN), which do not express Met but receive Met-expressing corticostriatal afferents during development. Emx1Cre/Metfx/fx MSN exhibited robust increases in total arbor length (,20%). As in the neocortex, average spine head volume was also increased (,12%). These data demonstrate that a developmental loss of presynaptic Met receptor signaling can affect postsynaptic morphogenesis and suggest a mechanism whereby attenuated Met signaling could disrupt both local and long-range connectivity within circuits relevant to ASD. J. Comp. Neurol. 518:4463,4478, 2010. © 2010 Wiley-Liss, Inc. [source]

    Implementation of pigment-dispersing factor-immunoreactive neurons in a standardized atlas of the brain of the cockroach Leucophaea maderae

    Hongying Wei
    Abstract The cockroach Leucophaea maderae is an established model in circadian rhythm research. Its circadian clock is located in the accessory medulla of the brain. Pigment-dispersing factor-immunoreactive (PDF-ir) neurons of the accessory medulla act as circadian pacemakers controlling locomotor activity rhythms. To characterize the neuronal network of the circadian system in L. maderae, the PDF-ir neurons were implemented into a standardized three-dimensional atlas of the cockroach brain. Serial confocal images from 20 wholemount brains were used for the construction of the atlas comprising 21 neuropils. Two different standardization protocols were employed: the iterative shape averaging (ISA) procedure using an affine transformation followed by iterative non-rigid registrations, and the virtual insect brain (VIB) protocol employing local non-rigid transformations after global and local rigid transformations. Quantitative analysis of the 20 brains revealed that volumes of the accessory medulla are directly correlated with the volumes of the medulla, the protocerebral bridge, and the upper division of the central body, suggesting functional connections among these neuropils. For a standardized reconstruction of the circadian pacemaker network, the ISA protocol was used to register PDF-ir neurons in the standard cockroach brain. The registration revealed that two PDF-ir arborization areas in the brain are highly interconnected with other PDF-ir projection sites and appear to be contacted both by fibers in the posterior and the anterior optic commissures. The distances between PDF-ir branching areas show specific numerical relationships that might be physiologically relevant for temporal encoding. J. Comp. Neurol. 518:4113,4133, 2010. © 2010 Wiley-Liss, Inc. [source]

    Structure and composition of the postsynaptic density during development

    Matthew T. Swulius
    Abstract In this study, we used electron tomography as well as immunogold labeling to analyze the morphology and distribution of proteins within postsynaptic densities (PSDs) isolated from rats before birth (embryonic day 19) and at postnatal days 2, 21, and 60. Our data provide direct evidence of distinct morphological and compositional differences in PSDs throughout development. Not all PSD components are present at the early stages of development, with a near lack of the scaffolding molecule PSD-95 at E19 and P2. The presence of NR1 and NR2b suggests that PSD-95 is not directly required for clustering of N-methyl-D-aspartic acid (NMDA) receptors in PSDs early in development. ,-Actinin is abundant by E19, suggesting that it is a core structural component of the PSD. Both , and , isoforms of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are present early on but then rise in labeling density by approximately fourfold by P21. Among all the molecules studied, only calmodulin (CaM) was found in higher abundance early in PSD development and then fell in amount over time. Spatial analysis of the immunogold label shows a nonrandom distribution for all the proteins studied, lending support to the idea that the PSD is systematically assembled in an organized fashion. Morphological data from electron tomography shows that the PSD undergoes major structural changes throughout development. J. Comp. Neurol. 518:4243,4260, 2010. © 2010 Wiley-Liss, Inc. [source]