ORCID Profile
0000-0001-6027-2727
Current Organisations
Trinity College Dublin
,
Royal College of Surgeons in Ireland
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Publisher: Wiley
Date: 27-03-2008
DOI: 10.1002/ART.23388
Abstract: To evaluate histologic, immunohistochemical, and molecular changes in tendon induced by altered strain in a large-animal model. A full-thickness partial-width laceration of the infraspinatus tendon was created in 5 sheep, while 5 sham-operated sheep were used as controls. Sheep were killed after 4 weeks, and 4 differentially stressed tendon regions (tensile or near bone attachment from overstressed or stress-deprived halves) were evaluated for histopathology, proteoglycan (PG) accumulation, and characterization of glycosaminoglycans and aggrecan catabolites. Gene expression of matrix components, enzymes, and inhibitors was analyzed by reverse transcriptase-polymerase chain reaction. Histopathologic changes were detected in both overstressed and stress-deprived tensile tendon, but only in stress-deprived tendon near bone. In overstressed and stress-deprived tensile tendon, levels of keratan sulfate, chondroitin 4-sulfate, and chondroitin 6-sulfate were increased. In overstressed tensile tendon, levels of ADAMTS-generated aggrecan catabolites were increased. There was increased matrix metalloproteinase 13 (MMP-13) and decreased fibromodulin and decorin expression in all regions. Increased MMP-1, MMP-9, MMP-14, and ADAMTS-1 expression, and decreased type II collagen expression were restricted to stress-deprived tendon. In stress-deprived bone-attachment regions, messenger RNA (mRNA) for aggrecan was decreased, and ADAMTS was increased. In overstressed tensile tendon, aggrecan mRNA was increased, and ADAMTS was decreased. The distinct molecular changes in adjacent tissue implicate altered strain rather than humoral factors in controlling abnormal tenocyte metabolism, and highlight the importance of regional s ling. Tendon abnormalities induced by increased strain are accompanied by increased aggrecan, decreased ADAMTS, and low PG expression, which may negatively impact the structural integrity of the tissue and predispose to rupture.
Publisher: F1000 Research Ltd
Date: 28-01-2021
DOI: 10.12688/HRBOPENRES.13203.1
Abstract: Background: The relationship between procedural volume and outcomes for percutaneous coronary interventions (PCI) is contentious, with previous reviews suggesting an inverse volume-outcome relationship. The aim of this study was to systematically review contemporary evidence to re-examine this relationship. Methods: A systematic review and meta-analysis was undertaken to examine the relationship between PCI procedural volume (both at hospital- and operator-levels) and outcomes in adults. The primary outcome was mortality. The secondary outcomes were complications, healthcare utilisation and process outcomes. Searches were conducted from 1 January 2008 to 28 May 2019. Certainty of the evidence was assessed using ‘Grading of Recommendations, Assessment, Development and Evaluations’ (GRADE). Screening, data extraction, quality appraisal and GRADE assessments were conducted independently by two reviewers. Results: Of 1,154 unique records retrieved, 22 observational studies with 6,432,265 patients were included. No significant association was found between total PCI hospital volume and mortality (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.69-1.03, I 2 = 86%). A temporal trend from significant to non-significant pooled effect estimates was observed. The pooled effect estimate for mortality was found to be significantly in favour of high-volume operators for total PCI procedures (OR: 0.77, 95% CI: 0.63-0.94, I 2 = 93%), and for high-volume hospitals for primary PCI procedures (OR: 0.77, 95% CI: 0.62-0.94, I 2 = 78%). Overall, GRADE certainty of evidence was ‘very low’. There were mixed findings for secondary outcomes. Conclusions: A volume-outcome relationship may exist in certain situations, although this relationship appears to be attenuating with time, and there is ‘very low’ certainty of evidence. While volume might be important, it should not be the only standard used to define an acceptable PCI service and a broader evaluation of quality metrics should be considered that encompass patient experience and clinical outcomes. Systematic review registration: PROSPERO, CRD42019125288
Publisher: Springer Science and Business Media LLC
Date: 28-08-2011
DOI: 10.1007/S00418-011-0854-7
Abstract: We have colocalized elastin and fibrillin-1 with perlecan in extracellular matrix of tensional and weight-bearing connective tissues. Elastin and fibrillin-1 were identified as prominent components of paraspinal blood vessels, and posterior longitudinal ligament in the human fetal spine and outer annulus fibrosus of the fetal intervertebral disc. We also colocalized perlecan with a synovial elastic basal lamina, where the attached synovial cells were observed to produce perlecan. Elastin, fibrillin-1 and perlecan were co-localized in the intima and media of small blood vessels in the synovium and in human fetal paraspinal blood vessels. Elastic fibers were observed at the insertion point of the anterior cruciate ligament to bone in the ovine stifle joint where they colocalized with perlecan. Elastin has not previously been reported to be spatially associated with perlecan in these tissues. Interactions between the tropoelastin and perlecan heparan sulfate chains were demonstrated using quartz crystal microbalance with dissipation solid phase binding studies. Electrostatic interactions through the heparan sulfate chains of perlecan and core protein mediated the interactions with tropoelastin, and were both important in the coacervation of tropoelastin and deposition of elastin onto perlecan immobilized on the chip surface. This may help us to understand the interactions which are expected to occur in vivo between the tropoelastin and perlecan to facilitate the deposition of elastin and formation of elastic microfibrils in situ and would be consistent with the observed distributions of these components in a number of connective tissues.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2022
Publisher: Springer Science and Business Media LLC
Date: 13-06-2013
DOI: 10.1007/S10719-013-9475-9
Abstract: Composite agarose (1.2 %) polyacrylamide (0.6 %) gel electrophoresis was used to separate discrete populations of native aggrecan and perlecan in newborn to 10 year old ovine intervertebral discs (IVDs). Semi-dry immunoblotting using core-protein and glycosaminoglycan (GAG) side chain specific monoclonal antibodies in combination with chondroitin ABC lyase demonstrated intra-chain native 7-D-4 chondroitin sulphate (CS) sulphation motifs and variable proportions of non-reducing terminal Δ4,5-unsaturated uronate-N-acetylgalactosamine-4-sulphate [2B6(+)] and Δ4,5-unsaturated glucuronate-N-acetylgalactosamine-6-sulphate [3B3(+)] disaccharides. The relative abundance of 2-B-6(+) aggrecan increased with advancing age of the IVD s les while the converse was true for the 3-B-3(+) aggrecan population. Relative 7D4 levels in aggrecan and perlecan were highest in the newborn IVD and significantly lower in the older IVD and other cartilage s les. Quantitation of 7D4 proteoglycan by enzyme linked immunosorbent inhibition assay confirmed the newborn ovine nucleus pulposus (NP) and inner annulus fibrosus (AF) contained higher levels (1.2-1.32 μg 7-D-4-proteoglycan/mg tissue wet weight) than the 2 (0.35-0.42 μg/mg wet weight tissue) and 10 year old IVD s les (0.16-0.22 μg/mg tissue wet weight) with the outer AF zones consistently containing lower levels of 7-D-4 epitope in all cases (P < 0.001). Cell populations on the margins of the AF and cartilaginous vertebral rudiments in newborn ovine and human foetal IVD strongly expressed 7-D-4 CS epitope and perlecan, This was co-distributed with Notch-1 expression in human foetal IVDs consistent with the 7-D-4 CS sulphation motif representing a marker of tissue development expressed by disc progenitor cell populations.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Informa UK Limited
Date: 2008
DOI: 10.1080/10520290801990414
Abstract: Histochoice is a proprietary nontoxic, non-cross-linking fixative designed by the manufacturer to replace formaldehyde based fixation protocols. We compared Histochoice and formalin fixation for several cartilaginous tissues including, articular and growth plate cartilage, meniscus and intervertebral disc. The tissues were stained with general histology stains including toluidine blue for tissue proteoglycans, picrosirius red to evaluate collagenous organization, and hematoxylin and eosin to assess cell morphology. The chondroitin sulfate and heparin sulfate substituted proteoglycans aggrecan and perlecan were also immunolocalized in some of the tissues to provide a comparison. Histochoice did not fix deep into the tissue blocks resulting in focal loss of aggrecan and other matrix components from the more central regions of the blocks. This was evident in toluidine blue stained sections of immature tibial articular cartilage where loss of glycosaminoglycan was significant in Histochoice fixed tissues. Histochoice fixation worked well, however, in the aggrecan and perlecan immunohistology applications where its non-cross-linking traits were conducive to epitope retrieval and identification by primary antibodies to extracellular matrix components.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2007
Publisher: Oxford University Press (OUP)
Date: 31-07-2018
DOI: 10.1002/STEM.2860
Abstract: This study reviewed the occurrence of chondroitin sulfate (CS) motifs 4-C-3, 7-D-4, and 3-B-3(-), which are expressed by progenitor cells in tissues undergoing morphogenesis. These motifs have a transient early expression pattern during tissue development and also appear in mature tissues during pathological remodeling and attempted repair processes by activated adult stem cells. The CS motifs are information and recognition modules, which may regulate cellular behavior and delineate stem cell niches in developmental tissues. One of the difficulties in determining the precise role of stem cells in tissue development and repair processes is their short engraftment period and the lack of specific markers, which differentiate the activated stem cell lineages from the resident cells. The CS sulfation motifs 7-D-4, 4-C-3, and 3-B-3 (-) decorate cell surface proteoglycans on activated stem rogenitor cells and appear to identify these cells in transitional areas of tissue development and in tissue repair and may be applicable to determining a more precise role for stem cells in tissue morphogenesis.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.TICE.2012.10.001
Abstract: Perlecan is a widely distributed, heparan sulphate proteoglycan with roles in the sequestration of FGFs, PDGF, VEGF through which it promotes cell proliferation and matrix production. Perlecan also stabilises extracellular matrices through interaction with a erse range of matrix components. This study examined the distribution of perlecan in an ovine partial transection tendinopathy model. In normal tendon, perlecan was immunolocalised to small blood vessels in intrafascicular regions in the tendon-bone and muscle-tendon attachments and to linear arrays of oval shaped tenocytes in the tendon mid-region. Partial transection in the mid-tendon region significantly increased perlecan accumulation within the fascicles, in granulation tissue filling the transection site and in the tendon-bone and tendon-muscle attachments. The accumulation of perlecan in the transected tendon and its known roles in matrix stabilisation and cell proliferation indicate possible roles in tendon remodelling and repair. Perlecan domain-1 has been used as a growth factor delivery vehicle for FGF-2, BMP-2 and BMP-7 in regenerative medicine but has yet to be evaluated in infraspinatus tendon repair. A better understanding of perlecan's contributions to pathobiological processes in remodelling tendon may be useful in such regenerative strategies in the future.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2007
Publisher: Springer Science and Business Media LLC
Date: 06-08-2010
DOI: 10.1007/S00418-010-0730-X
Abstract: We undertook a comparative immunolocalisation study on type II collagen, aggrecan and perlecan in a number of 12- to 14-week-old human foetal and postnatal (7-19 months) ovine joints including finger, toe, knee, elbow, hip and shoulder. This demonstrated that perlecan followed a virtually identical immunolocalisation pattern to that of type II collagen in the foetal tissues, but a slightly ergent localisation pattern in adult tissues. Aggrecan was also localised in the cartilaginous joint tissues, which were clearly delineated by toluidine blue staining and the type II collagen immunolocalisations. It was also present in the capsular joint tissues and in ligaments and tendons in the joint, which stained poorly or not at all with toluidine blue. In higher power microscopic views, antibodies to perlecan also stained small blood vessels in the synovial lining tissues of the joint capsule however, this was not discernable in low power macroscopic views where the immunolocalisation of perlecan to pericellular regions of cells within the cartilaginous rudiments was a predominant feature. Perlecan was also evident in small blood vessels in stromal connective tissues associated with the cartilage rudiments and with occasional nerves in the vicinity of the joint tissues. Perlecan was expressed by rounded cells in the enthesis attachment points of tendons to bone and in rounded cells in the inner third of the meniscus, which stained prominently with type II collagen and aggrecan identifying the chondrogenic background of these cells and local compressive loads. Flattened cells within the tendon and in the surface laminas of articular cartilages and the meniscus did not express perlecan. Collected evidence presented herein, therefore, indicates that besides being a basement membrane component, perlecan is also a marker of chondrogenic cells in prenatal cartilages. In postnatal cartilages, perlecan displayed a pericellular localisation pattern rather than the territorial or interterritorial localisation it displayed in foetal cartilages. This may reflect processing of extracellular perlecan presumably as a consequence of intrinsic biomechanical loading on these tissues or to ergent functions for perlecan and type II collagen in adult compared to prenatal tissues.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2009
DOI: 10.1007/S00418-009-0623-Z
Abstract: We evaluated the immunohistochemical distribution of three major proteoglycans of cartilage, i.e., aggrecan, versican and perlecan vis-a-vis collagens I and II in the developing human spine of first-trimester foetuses. Aggrecan and perlecan were prominently immunolocalised in the cartilaginous vertebral body rudiments and to a lesser extent within the foetal intervertebral disc. In contrast, versican was only expressed in the developing intervertebral disc interspace. Using domain-specific monoclonal antibodies against the various modules of versican, we discovered the V0 isoform as the predominant form present. Versican immunolocalisations conducted with antibodies directed to epitopes in its N and C termini and GAG-alpha and GAG-beta core protein domains provided evidence that versican in the nucleus pulposus was either synthesised devoid of a G3 domain or this domain was proteolytically removed in situ. The V0 versican isoform was localised with prominent fibrillar components in the annular lamellae of the outer annulus fibrosus. Perlecan was a notable pericellular proteoglycan in the annulus fibrosus and nucleus pulposus but poorly immunolocalised in the marginal tissues of the developing intervertebral disc, apparently delineating the intervertebral disc-vertebral body interface region destined to become the cartilaginous endplate in the mature intervertebral disc. The distribution of collagens I and II in the foetal spine was mutually exclusive with type I present in the outer annulus fibrosus, marginal tissues around the vertebral body rudiment and throughout the developing intervertebral disc, and type II prominent in the vertebral rudiment, absent in the outer annulus fibrosus and diffusely distributed in the inner annulus fibrosus and nucleus pulposus. Collectively, our findings suggest the existence of an intricate and finely balanced interplay between various proteoglycans and collagens and the spinal cell populations which synthesise and assemble these components during spinal development.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2012
DOI: 10.1007/S00418-012-0968-6
Abstract: Novel sulphation motifs within the glycosaminoglycan chain structure of chondroitin sulphate (CS) containing proteoglycans (PGs) are associated with sites of growth, differentiation and repair in many biological systems and there is compelling evidence that they function as molecular recognition sites that are involved in the binding, sequestration or presentation of soluble signalling molecules (e.g. morphogens, growth factors and cytokines). Here, using monoclonal antibodies 3B3(-), 4C3 and 7D4, we examine the distribution of native CS sulphation motifs within the developing connective tissues of the human foetal knee joint, both during and after joint cavitation. We show that the CS motifs have broad, overlapping distributions within the differentiating connective tissues before the joint has fully cavitated however, after cavitation, they all localise very specifically to the presumptive articular cartilage tissue. Comparisons with the labelling patterns of heparan sulphate (HS), HS-PGs (perlecan, syndecan-4 and glypican-6) and FGF-2, molecules with known signalling roles in development, indicate that these also become localised to the future articular cartilage tissue after joint cavitation. Furthermore, they display interesting, overlapping distributions with the CS motifs, reflective of early tissue zonation. The overlapping expression patterns of these molecules at this site suggests they are involved, or co-participate, in early morphogenetic events underlying articular cartilage formation thus having potential clinical relevance to mechanisms involved in its repair/regeneration. We propose that these CS sulphation motifs are involved in modulating the signalling gradients responsible for the cellular behaviours (proliferation, differentiation, matrix turnover) that shape the zonal tissue architecture present in mature articular cartilage.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2008
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1186/AR1898
No related grants have been discovered for Susan Smith.